Hyunseok Kang

All Publications

• A Patient With Prior Skin Cancers and New Diagnosis of Bell Palsy. JAMA oncology Rahmani, R., Kang, H., Chan, J. W. 2025

  View details for DOI 10.1001/jamaoncol.2025.2577

  View details for PubMedID 40773185

• Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement. The lancet. Diabetes & endocrinology Leboulleux, S., Boucai, L., Busaidy, N., Durante, C., Fagin, J. A., Fazeli, S., Gianoukakis, A. G., Haugen, B. R., Kang, H., Konda, B., Laetsch, T. W., Locati, L., Ryder, M., Spitzweg, C., Worden, F. P., Wirth, L., Ho, A. 2025; 13 (6): 516-527

  Abstract

  In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation-ie, the restoration of tumoural 131I uptake with systemic therapy-is now possible. The use of mitogen-activated protein kinase (MAPK) inhibitors for a short period of time before the administration of high activity 131I shows promising results with iodine uptake restoration and tumour response. Redifferentiation has been used in patients with BRAF-mutated and RAS-mutated tumours in prospective trials and in the case of patients with RET or NTRK fusions. The iodine uptake restoration ranges from 33% to 95%, and tumour response rates from 11% to 80%. There is substantial variability between trials with regards to inclusion criteria, duration of redifferentiation drug therapy, activity of radioactive iodine, and use of dosimetry. Randomised studies are missing to clearly establish the effectiveness and applicability of redifferentiation. Thus, long-term studies are needed to establish the most effective redifferentiation protocols. The objectives of this Review are to: (1) provide a comprehensive review of the available results from prospective trials and case reports, including results regarding the restoration of radioiodine uptake and treatment efficacy (morphological and biological); (2) describe the differences in redifferentiation trial design between studies and discuss their potential impact on treatment efficacy; (3) describe the implications and limitations of dosimetry; and (4) outline the key questions to be addressed in future redifferentiation trials.

  View details for DOI 10.1016/S2213-8587(25)00064-6

  View details for PubMedID 40318680

• A pilot study of PSMA-targeted F-18-DCFPyL PET imaging of patients with adenoid cystic carcinoma. Scientific reports Voter, A. F., Amindarolzarbi, A., Shen, C. J., Wang, J., Kang, H., Sharma, R., Solnes, L. B., Pomper, M. G., Bishop, J. A., Rowe, S. P., Kiess, A. P. 2025; 15 (1): 17104

  Abstract

  Adenoid cystic carcinoma (ACC) is a rare malignancy of the salivary glands with poor long-term outcomes and with a need for improved imaging and therapeutic options. Prostate-specific membrane antigen (PSMA) expression has been observed in ACC and preliminary studies have demonstrated PET imaging using 68Ga-functionalized PSMA agents for positron emission tomography (PET). We aimed to assess the extent of PSMA expression in a collection of archival ACC samples and demonstrate the feasibility of using 18F-DCFPyL for PSMA PET imaging of ACC. PSMA expression levels were assessed in 77 ACC and 11 unaffected parotid gland control samples by immunohistochemistry and quantified by mean H-score. Three patients with metastatic ACC, who had previously undergone local resection, were imaged with18F-DCFPyL PSMA PET in a prospective, pilot trial setting. Demographic, oncologic, and treatment history from the PET patient cohort were acquired at the time of imaging. Maximum standardized uptake values (SUVmax) were obtained from representative presumptive metastatic lesions on the 18F-DCFPyL scans by manual placement of regions-of-interest. PSMA expression was detected in 52% of archival ACC samples, compared to 18% in the unaffected salivary glands. Moderate or high levels of PSMA expression (H-score > 5) were seen in 37% of samples. Radiotracer avid disease was identified on PET imaging of all three patients with tumor SUVmax values of 4.1, 4.0, and 2.0, corresponding to tumor-to-liver ratios of 0.7, 1.0, and 0.4 respectively. We find that PSMA is expressed in a majority of histologic samples from patients with ACC. We also demonstrated the feasibility of 18F-DCFPyL PSMA-targeted PET imaging in the assessment of ACC. Overall, the tumor uptake on 18F-DCFPyL PET was modest compared to lesional uptake seen in prostate cancer. Given the potential role of PSMA-targeted agents in the management of ACC, broadening access to PSMA PET through F-18-labeled PSMA PET agents is important. Clinical trials investigating the use of PSMA-targeted radioligand therapies for ACC are underway.

  View details for DOI 10.1038/s41598-025-01515-z

  View details for PubMedID 40379702

  View details for PubMedCentralID PMC12084296

• Neutrophil-to-Lymphocyte Ratio and Pembrolizumab Outcomes in Oral Cavity Squamous Cell Carcinoma. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Truong, A. A., Lee, R. H., Wu, X., Algazi, A. P., Kang, H., El-Sayed, I. H., George, J. R., Heaton, C. M., Ryan, W. R., Jeon, Y., Kim, M. O., Ha, P. K., Wai, K. C. 2025; 172 (2): 548-555

  Abstract

  To determine the relationship between pretreatment neutrophil-to-lymphocyte ratio (NLR) and 6-month progression-free survival (PFS)/2-year overall survival (OS) among patients with recurrent or metastatic (R/M) oral cavity cancer on pembrolizumab.This study was a retrospective, observational study performed at a tertiary care academic center.Participants included patients with oral cavity squamous cell carcinoma (OCSCC) who began pembrolizumab treatment at the University of California, San Francisco between May 2016 and May 2022.The primary outcome was a 6-month PFS. The secondary outcome was a 2-year OS. NLR was treated as a continuous variable. Disease progression was determined using radiographic criteria, adopted from the Response Evaluation Criteria in Solid Tumors.Fifty-two patients with OCSCC were included. Immune checkpoint inhibitor (ICI) indication was recurrence/metastasis for all patients. The median pretreatment NLR was 5.7 (interquartile range: 3.6-7.6). Twenty-seven (55%) patients received pembrolizumab alone. Of those receiving treatment for R/M prior to ICI, 9 (18%) received salvage surgery and adjuvant therapy, 2 (4%) received chemotherapy alone, 1 (2%) received chemoradiation, and 10 (20%) received salvage surgery. Nineteen (36.5%) patients had distant metastases at the start of ICI. Six-month PFS was 46%. Two-year OS was 44%. NLR was independently associated with 6-month PFS [hazard ratio, HR: 1.05 (95% confidence interval, CI: 1.01-1.11), P = .028] and 2-year OS [HR: 1.12 (95% CI: 1.05-1.20), P < .001].Higher pretreatment NLR was associated with poorer 6-month PFS and 2-year OS in OCSCC patients treated with pembrolizumab.

  View details for DOI 10.1002/ohn.1088

  View details for PubMedID 39675043

• CYLD Alterations Are Associated With Metastasis and Poor Prognosis in Human Papilloma Virus-Positive Head and Neck Cancer. Head & neck Cui, Z., Kang, H., Li, H., Lee, E. D., Lee, Y. S., Peterson, C. N., Long, S. R., Grandis, J. R., Johnson, D. E. 2025; 47 (2): 606-614

  Abstract

  Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an emerging epidemic and a subset of HPV-positive patients experience aggressive disease with metastases. The CYLD gene is frequently altered in HPV-positive HNSCC, but the role of these alterations in disease progression is poorly understood.We identified 11 HPV-positive HNSCC patients with CYLD alterations and assessed their clinical course. We also characterized a unique, HPV-positive, metastatic, HNSCC patient-derived xenograft (PDX).All 11 patients developed metastasis with reduced overall survival when compared with metastatic HPV-positive patients with wild-type CYLD. The metastatic PDX harbored a CYLD mutation (S371*) and exhibited reduced expression of connexin 43, a potentially antimetastatic protein. We also investigated the functional impact of the S371* mutation, as well as 2 CYLD mutations from our 11-patient cohort.Our findings indicate that alterations in CYLD in HPV-positive HNSCC are associated with metastasis and poor prognosis.

  View details for DOI 10.1002/hed.27944

  View details for PubMedID 39347568

  View details for PubMedCentralID PMC11845079

• Immune-related encephalitis after immune checkpoint inhibitor therapy. The oncologist Buckley, M. W., Balaji Warner, A., Brahmer, J., Cappelli, L. C., Sharfman, W. H., Fuchs, E., Kang, H., Forde, P. M., Gladstone, D. E., Ambinder, R., Kelly, R. J., Lipson, E. J., Gojo, I., Lee, E. J., Johnson, T. P., Saidha, S., Llinas, R., Ostrow, L. W., Naidoo, J., Probasco, J. C. 2025; 30 (1)

  Abstract

  Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature.Retrospective series of patients with immune-related encephalitis and literature review.Fourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3.Immune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

  View details for DOI 10.1093/oncolo/oyae186

  View details for PubMedID 39066587

  View details for PubMedCentralID PMC11783331

• Withdrawal pain following patients discontinuing Trk inhibitors. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners Chin, A., Lindsay, S., Bergsland, E. K., Kang, H. 2025; 31 (1): 147-150

  Abstract

  This article aims to expand on the existing literature regarding the incidence of withdrawal pain following discontinuation of Trk inhibitors and to explore strategies that mitigate this withdrawal pain.A retrospective observational study was conducted among patients who were at least 18 years-old or older and had documentation of starting larotrectinib or entrectinib at University of California, San Francisco (UCSF) between November 2018 and November 2022. Data were collected from electronic records and pharmacy databases and a total of 21 patients were identified in this study.Of the 21 patients included in this study, five patients (24%) experienced pain during temporary or permanent discontinuation of Trk inhibitor with the onset of withdrawal pain ranging from a few hours to three days following discontinuation. Various strategies were implemented to manage this pain including restarting of Trk inhibitor, tapering of Trk inhibitor on discontinuation, minimizing dose interruptions and use of prescription pain medications.This article illustrates the presence of withdrawal pain syndrome in patients stopping a Trk inhibitor treatment and highlight the need for patient education to avoid missing any doses and for development of a guideline for Trk inhibitor discontinuation.

  View details for DOI 10.1177/10781552241279196

  View details for PubMedID 39191376

  View details for PubMedCentralID PMC11771077

• Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers. Journal of clinical medicine Diwanji, D., Carrodeguas, E., Seo, Y., Kang, H., Soe, M. H., Chiang, J. M., Zhang, L., Liu, C., Behr, S. C., Flavell, R. R. 2024; 13 (13)

  Abstract

  Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

  View details for DOI 10.3390/jcm13133963

  View details for PubMedID 38999527

  View details for PubMedCentralID PMC11242608

• Patient-reported outcomes with selpercatinib treatment in patients with RET-driven cancers in the phase I/II LIBRETTO-001 trial. ESMO open Raez, L. E., Kang, H., Ohe, Y., Khanal, M., Han, Y., Szymczak, S., Barker, S. S., Gilligan, A. M. 2024; 9 (5): 103444

  Abstract

  This post-hoc retrospective study describes long-term patient-reported outcomes (PROs) for REarranged during Transfection (RET)-altered non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC), and tumor agnostic (TA) patients (Data cut-off: January 2023) from the LIBRETTO-001 trial.Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Patients with MTC also completed a modified version of the Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The proportion of patients with improved, stable, or worsened status after baseline was reported. PROs were summarized at 3 years (cycle 37) post-baseline for the NSCLC and MTC cohorts, and at 2 years (cycle 25) post-baseline for the TC and TA cohorts. Time-to-event outcomes (time to first improvement or worsening and duration of improvement) were reported.The baseline assessment was completed by 200 (63.3%), 209 (70.8%), 50 (76.9%), and 38 (73.1%) patients in the NSCLC, MTC, TC, and TA cohorts, respectively. The total compliance rate was 80%, 82%, 70%, and 85%, respectively. Approximately 75% (NSCLC), 81% (MTC), 75% (TC), and 40% (TA) of patients across all cohorts reported improved or stable QLQ-C30 scores at year 3 (NSCLC and MTC) or year 2 (TC and TA) with continuous selpercatinib use. Across cohorts, the median time to first improvement ranged from 2.0 to 19.4 months, the median duration of improvement ranged from 1.9 to 28.2 months, and the median time to first worsening ranged from 5.6 to 44.2 months. The total compliance rate for the mSTIDAT was 83.7% and the proportion of patients with MTC who reported diarrhea on the mSTIDAT was reduced from 80.8% at baseline to 35.6% at year 3.A majority of patients with RET-driven cancers improved or remained stable on most QLQ-C30 domains, demonstrating favorable health-related quality of life as measured by the QLQ-C30 during long-term treatment with selpercatinib.

  View details for DOI 10.1016/j.esmoop.2024.103444

  View details for PubMedID 38749381

  View details for PubMedCentralID PMC11108846

• Treatment Modality Impact on Patient-Reported Quality of Life in Human Papilloma Virus-Associated Oropharyngeal Carcinoma. The Laryngoscope Plonowska-Hirschfeld, K. A., Gulati, A., Stephens, E. M., Ochoa, E., Xu, M. J., Ha, P. K., Heaton, C. M., Yom, S. S., Chan, J. W., Algazi, A., Kang, H., Ryan, W. R. 2024; 134 (4): 1687-1695

  Abstract

  To prospectively compare the impact of treatment modality on patient-reported quality of life (QOL) in human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC).Prospective cohort study.Academic medical center.One hundred one patients with American Joint Committee on Cancer (AJCC) 8th edition T1-3 N0-2 HPV + OPSCC completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire and Head and Neck Module pretreatment and 3-month and 1-year posttreatment. Mean score changes were compared to published minimal clinically important differences.Patients underwent surgery alone (SA: N = 42, 42%), surgery with adjuvant radiation (S-RT: N = 10, 10%), surgery with adjuvant chemoradiation (S-CRT: N = 8, 8%), definitive radiation (RT: N = 11, 11%), or definitive chemoradiation (CRT: N = 30, 30%). SA, S-[C]RT, and [C]RT patients all reported clinically significant difficulty with sense of taste/smell persisting at 1 year. S-[C]RT and [C]RT patients reported statistically and clinically significant worse salivary dysfunction and problems with social eating at 1 year than SA. S-[C]RT patients reported statistically and clinically significant worse fatigue and head and neck pain compared to [C]RT and SA patients at 3 months, but normalized at 1 year. S-CRT compared to S-RT had statistically and clinically worse physical and role functioning and swallowing difficulties at 3 months but this difference was resolved by 1-year posttreatment.HPV + OPSCC patients after SA report the lowest posttreatment QOL impact, whereas after S-CRT report the highest symptom burden. Careful selection for definitive surgery is important given the possibility of adjuvant CRT. Patients can experience persistent sense taste and smell difficulties at 1 year with all treatment modalities.3 Laryngoscope, 134:1687-1695, 2024.

  View details for DOI 10.1002/lary.31065

  View details for PubMedID 37767815

• PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study. Oral oncology Ferrarotto, R., Swiecicki, P. L., Zandberg, D. P., Baiocchi, R. A., Wesolowski, R., Rodriguez, C. P., McKean, M., Kang, H., Monga, V., Nath, R., Palmisiano, N., Babbar, N., Sun, W., Hanna, G. J. 2024; 149: 106634

  Abstract

  Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC.This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy.Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease.In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

  View details for DOI 10.1016/j.oraloncology.2023.106634

  View details for PubMedID 38118249

• Carboplatin and paclitaxel after anti-PD-1 or anti-PD-L1 antibody therapy in recurrent and/or metastatic squamous cell carcinoma of head and neck HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Humphries, A., Zhou, C. J., Welsh, M., Lem, M., Kang, H., Algazi, A. P. 2024; 46 (2): 321-327

  Abstract

  The impact of concurrent chemotherapy and immunotherapy has been well characterized in patients with recurrent and metastatic head and neck squamous cell carcinoma (RM-SCCHN). Here, we report outcomes in patients treated sequentially with immune checkpoint inhibition (ICI) followed by carboplatin and paclitaxel.Patients with RM-SCCHN treated with ICI followed by carboplatin/paclitaxel at a single institution were identified retrospectively. ICI therapy history, p16, and PD-L1 status were collected. The best overall response was assessed by RECIST v1.1.Twelve patients met inclusion criteria. Eight patients received pembrolizumab, three durvalumab, and one nivolumab. The median duration of ICI was 3.44 months, median PFS was 5.8 months, and median OS was 15.2 months. 66.7% of patients had an objective response on carboplatin/paclitaxel.Carboplatin/paclitaxel can induce objective responses in patients with prior treatment with ICI and clinical outcomes in this small series compare favorably to those seen in ICI naïve patients.

  View details for DOI 10.1002/hed.27580

  View details for Web of Science ID 001109098400001

  View details for PubMedID 37997549

• A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Hanna, G. J., Ahn, M. J., Muzaffar, J., Keam, B., Bowles, D. W., Wong, D. J., Ho, A. L., Kim, S. B., Worden, F., Yun, T., Meng, X., Van Tornout, J. M., Conlan, M. G., Kang, H. 2023; 29 (22): 4555-4563

  Abstract

  This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC).Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC).Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity.In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs.

  View details for DOI 10.1158/1078-0432.CCR-23-1030

  View details for PubMedID 37643133

  View details for PubMedCentralID PMC10643996

• The neutrophil-to-lymphocyte ratio in salivary gland cancers treated with pembrolizumab HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Lee, R. H., Truong, A., Wu, X., Kang, H., Algazi, A. P., El-Sayed, I. H., George, J. R., Heaton, C. M., Ryan, W. R., Ha, P. K., Wai, K. C. 2024; 46 (1): 129-137

  Abstract

  A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response prediction.Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6-month progression-free survival (PFS) and secondary outcome of 2-year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed.Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6-month PFS (HR 1.30, 95% CI 1.10-1.54, p = 0.002) and 2-year OS (HR 1.33, 95% CI 1.07-1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17-76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67-75.77, p = 0.013).Higher pretreatment NLR was independently associated with inferior 6-month PFS and 2-year OS in pembrolizumab-treated R/M SGC patients.

  View details for DOI 10.1002/hed.27565

  View details for Web of Science ID 001092083100001

  View details for PubMedID 37897202

• A prospective evaluation of neck and shoulder function following treatments of early-stage human papillomavirus-associated oropharynx cancer. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery Gulati, A., Plonowska-Hirschfeld, K., Stephens, E. M., Kansara, S., Zebolsky, A. L., Ochoa, E., Xu, M. J., Ha, P. K., Heaton, C. M., Yom, S. S., Chan, J. W., Algazi, A. P., Kang, H., Ryan, W. R. 2023; 48 (5): 756-765

  Abstract

  To compare post-treatment neck and shoulder function between human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC) treatments.Prospective, repeated-measures study.Tertiary care center.Treatment-naïve patients with American Joint Committee on Cancer eighth edition stage T0-3/N0-2 HPV+OPSCC.Patients completed the Neck Dissection Impairment Index (NDII) pre-treatment and 3-months and 1-year post-treatment. The NDII assesses 10 neck and shoulder functions scored 0-5 (total score 0-100), with higher scores suggesting better function.A total of 106 patients underwent: surgery alone (SA, n = 46, 43%), surgery with adjuvant radiation ± chemotherapy (S + a[C]XRT, n = 18, 17%), or definitive radiation ± chemotherapy (d[C]XRT, n = 42, 40%). cTN classification and pre-treatment NDII scores did not differ between groups. SA patients reported worsened 3-month post-treatment versus pre-treatment self-care (4.6 vs. 5.0), lifting light (4.6 vs. 5.0) and heavy (4.2 vs. 4.8) objects, overhead reach (4.5 vs. 4.9), activity (4.5 vs. 4.9), socialization (4.7 vs. 4.9), recreation (4.6 vs. 4.9), and overall score (86.8 vs. 95.3) (all p < 0.05). One-year post-treatment scores (n = 34) were no different than pre-treatment in all domains. S + a[C]XRT patients reported worsened 3-month versus pre-treatment stiffness (4.0 vs. 4.8), lifting heavy objects (3.8 vs. 4.9), overhead reach (4.2 vs. 4.9), socialization (4.6 vs. 5.0), recreation (4.4 vs. 4.9) and overall score (82.4 vs. 96.0) (all p < 0.05). One-year post-treatment scores (n = 13) were no different than pre-treatment in all domains. d[C]XRT patients reported worsened 3-month versus pre-treatment difficulty lifting heavy objects (4.3 vs. 4.7) and recreation (4.3 vs. 4.7). One-year posttreatment scores (n = 21) were no different than pre-treatment in all domains.HPV + OPSCC patients may experience mild shoulder/neck dysfunction 3 months after treatment that usually resolves by 1 year, independent of treatment modality.

  View details for DOI 10.1111/coa.14076

  View details for PubMedID 37212448

• Biomarkers predictive of response to pembrolizumab in head and neck cancer. Cancer medicine Pfister, D. G., Haddad, R. I., Worden, F. P., Weiss, J., Mehra, R., Chow, L. Q., Liu, S. V., Kang, H., Saba, N. F., Wirth, L. J., Sukari, A., Massarelli, E., Ayers, M., Albright, A., Webber, A. L., Mogg, R., Lunceford, J., Huang, L., Cristescu, R., Cheng, J., Seiwert, T. Y., Bauml, J. M. 2023; 12 (6): 6603-6614

  Abstract

  We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored.We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS).Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method.TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.

  View details for DOI 10.1002/cam4.5434

  View details for PubMedID 36479637

  View details for PubMedCentralID PMC10067081

• Phase II Study of Enzalutamide for Patients With Androgen Receptor-Positive Salivary Gland Cancers (Alliance A091404). Journal of clinical oncology : official journal of the American Society of Clinical Oncology Ho, A. L., Foster, N. R., Zoroufy, A. J., Campbell, J. D., Worden, F., Price, K., Adkins, D., Bowles, D. W., Kang, H., Burtness, B., Sherman, E., Morton, R., Morris, L. G., Nadeem, Z., Katabi, N., Munster, P., Schwartz, G. K. 2022; 40 (36): 4240-4249

  Abstract

  The androgen receptor (AR) is expressed (+) in a subset of salivary gland cancers (SGCs). This phase II trial evaluated the efficacy of the antiandrogen enzalutamide in AR+ SGC.Patients with locally advanced/unresectable or metastatic AR+ SGCs were enrolled. Enzalutamide (160 mg) was given orally once daily. The primary end point was the best overall response rate per RECIST v1.1 within eight cycles. Confirmed responses in ≥ 5 of 41 patients would be considered promising. Secondary end points were progression-free survival, overall survival, and safety.Forty-six patients were enrolled; 30 (65.2%) received prior systemic therapy, including 13 (28.3%) with AR-targeted drugs. Of seven (15.2%) partial responses (PRs), only two (4.3%) were confirmed per protocol and counted toward the primary end point. Twenty-four patients (52.2%) had stable disease; 15 (32.6%) had progression of disease as best response. Twenty-six patients (56.5%) experienced tumor regression in target lesions; 18 (39.1%) had partial response/stable disease ≥ 6 months. Tumor regressions were observed in female patients (5 of 6 [83.3%]) and those who received prior AR- (6 of 13 [46.2%]) or human epidermal growth factor receptor 2-targeted therapies (5 of 8 [62.5%]). Three patients remained on treatment at data cutoff (duration, 32.2-49.8 months). The median progression-free survival was 5.6 months (95% CI, 3.7 to 7.5); the median overall survival was 17.0 months (95% CI, 11.8 to 30.0). The most common adverse events were fatigue, hypertension, hot flashes, and weight loss. Total and free testosterone levels increased by a mean of 61.2% and 48.8%, respectively, after enzalutamide.Enzalutamide demonstrated limited activity in AR+ SGC, failing to meet protocol-defined success in part because of a lack of response durability. Strategies to enhance the efficacy of antiandrogen therapy are needed.

  View details for DOI 10.1200/JCO.22.00229

  View details for PubMedID 35867947

  View details for PubMedCentralID PMC9916043

• Approaches to the Management of Metastatic Adenoid Cystic Carcinoma. Cancers Lee, R. H., Wai, K. C., Chan, J. W., Ha, P. K., Kang, H. 2022; 14 (22)

  Abstract

  High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

  View details for DOI 10.3390/cancers14225698

  View details for PubMedID 36428790

• Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. The Lancet. Oncology Subbiah, V., Wolf, J., Konda, B., Kang, H., Spira, A., Weiss, J., Takeda, M., Ohe, Y., Khan, S., Ohashi, K., Soldatenkova, V., Szymczak, S., Sullivan, L., Wright, J., Drilon, A. 2022; 23 (10): 1261-1273

  Abstract

  Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population).LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants.Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred.Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib.Loxo Oncology.

  View details for DOI 10.1016/S1470-2045(22)00541-1

  View details for PubMedID 36108661

  View details for PubMedCentralID PMC11702314

• Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. Journal of the National Cancer Institute Rodriguez, C. P., Kang, H., Geiger, J. L., Burtness, B., Chung, C. H., Pickering, C. R., Fakhry, C., Le, Q. T., Yom, S. S., Galloway, T. J., Golemis, E., Li, A., Shoop, J., Wong, S., Mehra, R., Skinner, H., Saba, N. F., Flores, E. R., Myers, J. N., Ford, J. M., Karchin, R., Ferris, R. L., Kunos, C., Lynn, J. M., Malik, S. 2022

  Abstract

  TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in over 80% of patients with HPV-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53 mutated tumors. The National Cancer Institute (NCI) sponsored a Clinical Trials Planning Meeting (CTPM) to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or Breakout Groups, were tasked with developing clinical studies in both the locally advanced and recurrent/metastatic disease settings as well consider signal seeking trial designs. A fourth Breakout Group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other Breakout Groups prior to the meeting to aid in study development. A total of four concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the CTPM with the goal of developing clinical trials for patients with TP53 mutant HNSCC that can be conducted within the National Clinical Trials Network.

  View details for DOI 10.1093/jnci/djac163

  View details for PubMedID 36053203

• Non-Iodine-Avid Disease Is Highly Prevalent in Distant Metastatic Differentiated Thyroid Cancer With Papillary Histology. The Journal of clinical endocrinology and metabolism Soe, M. H., Chiang, J. M., Flavell, R. R., Khanafshar, E., Mendoza, L., Kang, H., Liu, C. 2022; 107 (8): e3206-e3216

  Abstract

  Patients with radioactive iodine (RAI) refractory metastatic differentiated thyroid cancer (DTC) have poor prognosis. Early identification of RAI refractoriness may improve care.This work aimed to characterize DTC patients with distant metastases (DM) at diagnosis who presented with non-iodine-avid disease.Retrospective analyses of DTC patients with DM at diagnosis who presented between 2012 and 2020 were performed. Iodine uptake in DM was correlated with tumor histology and mutational profile. The difference in uptake between BRAFV600E-like (BVL) and RAS-like (RL) cancers based on insights from The Cancer Genome Atlas was evaluated.Among 78 patients, 48.7% had negative uptake in DM on the first posttherapy scan. Negative scans were highly prevalent in papillary thyroid carcinoma (PTC) with papillary architecture, PTC with BRAFV600E mutation, and PTC with both BRAFV600E and TERT promoter mutations (71.1%, 80.9%, and 100%, respectively). BVL and RL tumors exhibited distinct uptake patterns with negative scan prevalence of 76.9% and 14.3% (P = .005). Multivariate logistical regression confirmed high odds of negative uptake in BVL tumors with either BVL mutations or papillary architecture, 19.8 (95% CI, 2.72-144), and low odds of negative uptake in RL tumors with either RL mutations or follicular architecture, 0.048 (95% CI, 0.006-0.344), after adjusting for age, sex, race, RAI preparation method, bone metastases, and RAI dose. Patients with negative scans were significantly older (62.4 vs 47.0 years, P = .03).Among DTC patients with DM at diagnosis, non-iodine-avid disease is highly prevalent in patients with BVL cancers, particularly with BRAFV600E and TERT promoter mutations, and is associated with an older age. Better strategies are needed to improve RAI treatment response for these patients.

  View details for DOI 10.1210/clinem/dgac305

  View details for PubMedID 35556126

  View details for PubMedCentralID PMC9282362

• Real-World Experience of NTRK Fusion-Positive Thyroid Cancer. JCO precision oncology Park, J. C., Ashok, A., Liu, C., Kang, H. 2022; 6: e2100442

  View details for DOI 10.1200/PO.21.00442

  View details for PubMedID 35171659

  View details for PubMedCentralID PMC8865519

• Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma. Journal for immunotherapy of cancer Haddad, R. I., Seiwert, T. Y., Chow, L. Q., Gupta, S., Weiss, J., Gluck, I., Eder, J. P., Burtness, B., Tahara, M., Keam, B., Kang, H., Muro, K., Albright, A., Mogg, R., Ayers, M., Huang, L., Lunceford, J., Cristescu, R., Cheng, J., Mehra, R. 2022; 10 (2)

  Abstract

  To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study.Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106).TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=-0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods.TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed.NCT01848834.

  View details for DOI 10.1136/jitc-2021-003026

  View details for PubMedID 35217573

  View details for PubMedCentralID PMC8883256

• Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma. The Journal of clinical investigation Jin, N., Keam, B., Cho, J., Lee, M. J., Kim, H. R., Torosyan, H., Jura, N., Ng, P. K., Mills, G. B., Li, H., Zeng, Y., Barbash, Z., Tarcic, G., Kang, H., Bauman, J. E., Kim, M. O., VanLandingham, N. K., Swaney, D. L., Krogan, N. J., Johnson, D. E., Grandis, J. R. 2021; 131 (22)

  Abstract

  Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

  View details for DOI 10.1172/JCI150335

  View details for PubMedID 34779417

  View details for PubMedCentralID PMC8592538

• Effect of chemotherapy and radiotherapy on cognitive impairment in colorectal cancer: evidence from Korean National Health Insurance Database Cohort. Epidemiology and health Kim, K., Kim, C. W., Shin, A., Kang, H., Jung, S. J. 2021; 43: e2021093

  Abstract

  We investigated the risk of chemotherapy-related and radiotherapy-related cognitive impairment in colorectal cancer patients.Medical use data of colorectal cancer patients were obtained from the Korean National Health Insurance Database from 2004 to 2018. We randomly selected 40% of all colorectal cancer patients (n=148,848). Cognitive impairment was defined as having 1 or more International Classification of Diseases, 10th revision diagnostic codes for dementia or mild cognitive impairment. Patients aged 18 years or younger, patients diagnosed with cognitive impairment before colorectal cancer diagnosis (n=8,225), and patients who did not receive primary resection (n=45,320) were excluded. The effects of individual chemotherapy regimens on cognitive impairment were estimated. We additionally estimated the effect of radiotherapy in rectal cancer patients. Time-dependent competing risk Cox regression was conducted to estimate the overall and age-specific hazard ratios (HR) separately for colon and rectal cancer. Landmark analyses with different lag times were conducted as sensitivity analyses.Chemotherapy did not increase the risk of cognitive impairment in colorectal cancer patients (colon cancer: HR, 0.92; 95% confidence interval [CI], 0.83 to 1.03; rectal cancer: HR, 0.88; 95% CI, 0.75 to 1.04), while radiotherapy was negatively associated with cognitive impairment in rectal cancer patients (HR, 0.01; 95% CI, 0.84 to 0.99). Varying directions of the associations between regimens and cognitive impairment were detected. The adverse effect of certain chemotherapy regimens on cognition was more prominent in older adults.Chemotherapy and radiotherapy did not increase the risk of cognitive impairment. Older patients with low cognitive reserve could be affected by the adverse cognitive effects of chemotherapy.

  View details for DOI 10.4178/epih.e2021093

  View details for PubMedID 34735757

  View details for PubMedCentralID PMC8920736

• Treatment of Fanconi Anemia-Associated Head and Neck Cancer: Opportunities to Improve Outcomes. Clinical cancer research : an official journal of the American Association for Cancer Research Lee, R. H., Kang, H., Yom, S. S., Smogorzewska, A., Johnson, D. E., Grandis, J. R. 2021; 27 (19): 5168-5187

  Abstract

  Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection toward multiple malignancies, including a greater than 500-fold incidence of head and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiotherapy to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 patients with FA-HNSCC including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, radiotherapy, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation. Although there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.

  View details for DOI 10.1158/1078-0432.CCR-21-1259

  View details for PubMedID 34045293

  View details for PubMedCentralID PMC8626541

• Ovarian Failure Preceding Head and Neck Squamous Cell Carcinoma Identifies an Adult-Onset Cancer-Prone Syndrome Caused by FANCM Mutations. JCO precision oncology Vellanki, P. J., DeBoy, E. A., Bawadkji, M. M., Schuchter, L., Rooper, L., Mehra, R., Kang, H., Armanios, M. 2021; 5

  View details for DOI 10.1200/PO.21.00110

  View details for PubMedID 34568721

  View details for PubMedCentralID PMC8457871

• Molecular Markers that Matter in Salivary Malignancy. Otolaryngologic clinics of North America Wai, K. C., Kang, H., Ha, P. K. 2021; 54 (3): 613-627

  Abstract

  Despite aggressive initial interventions, recurrent/metastatic salivary gland cancer is not uncommon. Standard chemotherapy has not been shown to have durable clinical benefits. Several potential molecular markers have been identified in different histologic subtypes of salivary cancers. The objective of this review is to highlight the molecular markers that have been targeted in clinical trials for salivary gland cancers.

  View details for DOI 10.1016/j.otc.2021.01.007

  View details for PubMedID 34024488

• Newly Identified Members of FGFR1 Splice Variants Engage in Cross-talk with AXL/AKT Axis in Salivary Adenoid Cystic Carcinoma. Cancer research Humtsoe, J. O., Kim, H. S., Leonard, B., Ling, S., Keam, B., Marchionni, L., Afsari, B., Considine, M., Favorov, A. V., Fertig, E. J., Kang, H., Ha, P. K. 2021; 81 (4): 1001-1013

  Abstract

  Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis and outlier statistics on RNA sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC. In ACC cells and patient-derived xenografts, FGFR1 was a uniquely expressed ASE. Detailed PCR analysis identified three novel, truncated, intracellular domain-lacking FGFR1 variants (FGFR1v). Cloning and expression analysis suggest that the three FGFR1v are cell surface proteins, that expression of FGFR1v augmented pAKT activity, and that cells became more resistant to pharmacologic FGFR1 inhibitor. FGFR1v-induced AKT activation was associated with AXL function, and inhibition of AXL activity in FGFR1v knockdown cells led to enhanced cytotoxicity in ACC. Moreover, cell killing effect was increased by dual inhibition of AXL and FGFR1 in ACC cells. This study demonstrates that these previously undescribed FGFR1v cooperate with AXL and desensitize cells to FGFR1 inhibitor, which supports further investigation into combined FGFR1 and AXL inhibition as an effective ACC therapy.This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor suggestive of a potential resistance mechanism in ACC. SIGNIFICANCE: This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor, suggestive of a potential resistance mechanism in ACC.

  View details for DOI 10.1158/0008-5472.CAN-20-1780

  View details for PubMedID 33408119

• CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers. Molecular cancer research : MCR Cui, Z., Kang, H., Grandis, J. R., Johnson, D. E. 2021; 19 (1): 14-24

  Abstract

  Genetic alterations of CYLD lysine 63 deubiquitinase (CYLD), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic CYLD alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma), CYLD alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function CYLD alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of CYLD somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor CYLD alterations are also discussed. IMPLICATIONS: Alterations in CYLD gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.

  View details for DOI 10.1158/1541-7786.MCR-20-0565

  View details for PubMedID 32883697

  View details for PubMedCentralID PMC7840145

• The efficacy of anti-PD-1 immune checkpoint inhibitor in nasopharyngeal carcinoma. Oral oncology Park, J. C., Durbeck, J., Boudadi, K., Ho, W. J., Kang, H. 2020; 108: 104935

  View details for DOI 10.1016/j.oraloncology.2020.104935

  View details for PubMedID 32792211

• Squamous cell carcinoma of head and neck: what internists should know. The Korean journal of internal medicine Jung, K., Narwal, M., Min, S. Y., Keam, B., Kang, H. 2020; 35 (5): 1031-1044

  Abstract

  Squamous cell carcinoma of head and neck (SCCHN) is a group of cancer arising from mucosal surfaces of the head and neck. Optimal management of SCCHN requires a multidisciplinary team of surgical oncologists, radiation oncologists, medical oncologists, nutritionist, and speech-language pathologists, due to the complexity of anatomical structure and importance of functional outcome. Human papilloma virus (HPV)-related SCCHN represents a distinct subset from HPV negative SCCHN which is associated with carcinogen exposure such as cigarette smoking, betel nut use and alcohol. HPV related SCCHN responds better to concurrent chemoradiation and has better overall prognosis, compared to HPV negative SCCHN. Radiation therapy has been introduced to the treatment of SCCHN, administered concurrently with systemic chemotherapy for locoregional SCCHN, as well as a palliative measure for recurrent and/or metastatic (R/M) SCCHN. Recently, immune checkpoint inhibitors have been shown to improve overall survival in R/M-SCCHN and have been incorporated into the standard of care. Combination approaches with immune therapy and targeted therapy for biomarker enriched population based on genomics are being actively investigated and will shape the future of SCCHN treatment.

  View details for DOI 10.3904/kjim.2020.078

  View details for PubMedID 32663913

  View details for PubMedCentralID PMC7487309

• Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. The New England journal of medicine Wirth, L. J., Sherman, E., Robinson, B., Solomon, B., Kang, H., Lorch, J., Worden, F., Brose, M., Patel, J., Leboulleux, S., Godbert, Y., Barlesi, F., Morris, J. C., Owonikoko, T. K., Tan, D. S., Gautschi, O., Weiss, J., de la Fouchardière, C., Burkard, M. E., Laskin, J., Taylor, M. H., Kroiss, M., Medioni, J., Goldman, J. W., Bauer, T. M., Levy, B., Zhu, V. W., Lakhani, N., Moreno, V., Ebata, K., Nguyen, M., Heirich, D., Zhu, E. Y., Huang, X., Yang, L., Kherani, J., Rothenberg, S. M., Drilon, A., Subbiah, V., Shah, M. H., Cabanillas, M. E. 2020; 383 (9): 825-835

  Abstract

  RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

  View details for DOI 10.1056/NEJMoa2005651

  View details for PubMedID 32846061

  View details for PubMedCentralID PMC10777663

• Immune checkpoint inhibitor in nasopharyngeal carcinoma: Multi-institution experience. Park, J., Wirth, L. J., Clark, J. R., Durbeck, J., Ho, W., Boudadi, K., Kang, H. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368303042

• Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study. Annals of oncology : official journal of the European Society for Medical Oncology Kurzrock, R., Bowles, D. W., Kang, H., Meric-Bernstam, F., Hainsworth, J., Spigel, D. R., Bose, R., Burris, H., Sweeney, C. J., Beattie, M. S., Blotner, S., Schulze, K., Cuchelkar, V., Swanton, C. 2020; 31 (3): 412-421

  Abstract

  Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics.MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR).As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred.Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

  View details for DOI 10.1016/j.annonc.2019.11.018

  View details for PubMedID 32067683

  View details for PubMedCentralID PMC9743163

• Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial JAMA ONCOLOGY Burtness, B., Haddad, R., Dinis, J., Trigo, J., Yokota, T., Viana, L., Romanov, I., Vermorken, J., Bourhis, J., Tahara, M., Martins Segalla, J., Psyrri, A., Vasilevskaya, I., Nangia, C., Chaves-Conde, M., Kiyota, N., Homma, A., Holeckova, P., Del Campo, J., Asarawala, N., Nicolau, U., Rauch, D., Even, C., Wang, B., Gibson, N., Ehrnrooth, E., Harrington, K., Cohen, E. W., Eduardo Giglio, R., Raul Blajman, C., Mario Freue, J., Graciela Pilnik, N., Salvador Palazzo, F., McGrath, M., Fureder, T., Kornek, G., Pichler, A., Bauernhofer, T., Tinchon, C., Greil, R., Burian, M., Kienzer, H., Specenier, P., Sautois, B., Debruyne, P., Graas, M., Maes, A., Lonchay, C., Daisne, J., Fontaine, C., Castro Junior, G., de Oliveira, F., Pereira, R., Martins De Marchi, P., Viana, L., Martins Segalla, J., Nicolau, U., Lazaretti, N., Kulkarni, S., Alam, Y., Ho, C., Shenouda, G., Soulieres, D., Sultanem, K., Singh, S., Gonzalez Mella, P., Solis Campos, J., Holeckova, P., Prausova, J., Obermannova, R., Friborg, J., Specht, L., Elsaid, A., Minn, H., Martin, L., Rolland, F., Ceruse, P., Calais, G., Even, C., Guigay, J., Ferte, C., Peyrade, F., Duffaud, F., Champeaux-Orange, E., Coutte, A., Clatot, F., Fournel, P., Le Moal, L., Dietz, A., Gruenwald, V., Gauler, T., Guntinas-Lichius, O., Hildebrandt, G., Kuhnt, T., Schmidt, H., Henke, M., Rueckert, A., Brugger, W., Rotter, N., Mahlberg, R., Karavasilis, V., Fountzilas, G., Psyrri, D., Lang, I., Boer, A., Kocsis, J., Pajkos, G., Tamas, L., Anand, A. L., Sharma, A., Sharma, Voona, M., Pandy, A., Kumar, K., Nathan, R., Srinivasan, V., Zade, B., Jain, M., Srinivasa, B. J., Naik, R., Mohanty, B. K., Asarawala, N., Charas, T., Billan, S., Popovtzer, A., Licitra, L., Ferrari, D., Fao, P., Merlano, M., Rocca, M., Homma, A., Fujii, H., Tahara, M., Minami, S., Fujii, M., Yokota, T., Kadowaki, S., Muro, K., Kiyota, N., Okami, K., Yagi, T., Yoshino, K., Matsumoto, K., Takahashi, S., Matsuura, K., Alvarez Avitia, M., Gonzalez Riestra, H., van Meerten, E., Buter, J., Gelderblom, A. J., Kawecki, A., Golusinski, W., Dinis, J., Dinis, R., Ribeiro, L., Silva, R., Mansinho, H., Selezneva, I., Biakhov, M., Galiulin, R., Izmailov, A., Romanov, I., Vladimirov, V., Vinogradov, V., Mufazalov, F., Vasilevskaya, I., Baste, N., Ma del Campo, J., Mesia Nin, R., Lopez Pousa, A., Jose Grau de Castro, J., Reig, O., Vera, R., Trigo, J., Iglesias, L., Martinez Trufero, J., Vazquez, S., Rubio, B., Enrique Ales, J., Villar, E., Rubio, J., Escobar, Y., Soria, A., Chaves, M., Johansson, G., Friesland, S., Tell, R., Nyman, J., Rothschild, S., Zippelius, A., Rauch, D., Usluoglu, N., Gogunska, I., Zabolotniy, D., Vinnyk, Y., Burian, O., Harrington, K., Sykes, A., Peel, D., Lester, J., Robinson, M., Srinivasan, D., Fragkandrea-Nixon, I., Junor, E., Gollins, S., Evans, M., Newbold, K., Hwang, D., Schipani, S., Rizwanullah, M., Atiq, O., Arnaoutakis, K., Bauman, J., Burtness, B., Mehra, R., Kang, H., Chung, C., Davis, T., Haddad, R., Jimeno, A., Keresztes, R., Nangia, C., Ignatius, S., Su, Y., Overton, L., Garrison, M. A., Jeong, W., Wehbe, A., Argiris, A., Chiang, A., Morgensztern, D., Haigentz, M., Martincic, D., Porosnicu, M., LUX-HEAD & Neck 2 Investigators 2019; 5 (8): 1170-1180

  Abstract

  Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population.Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal.The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life.A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group).This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended.ClinicalTrials.gov identifier: NCT01345669.

  View details for DOI 10.1001/jamaoncol.2019.1146

  View details for Web of Science ID 000480303500014

  View details for PubMedID 31194247

  View details for PubMedCentralID PMC6567846

• PD-L1 expression and the tumor immune microenvironment in NUT carcinoma Rooper, L. M., London, N. R., Taube, J. M., Westra, W. H., Bishop, J. A., Kang, H. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-1191

  View details for Web of Science ID 000488129903279

• Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. The oncologist Kang, H., Pettinga, D., Schubert, A. D., Ladenson, P. W., Ball, D. W., Chung, J. H., Schrock, A. B., Madison, R., Frampton, G. M., Stephens, P. J., Ross, J. S., Miller, V. A., Ali, S. M. 2019; 24 (6): 791-797

  Abstract

  Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics.We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy.There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1-mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73-mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity.CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors.Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.

  View details for DOI 10.1634/theoncologist.2018-0334

  View details for PubMedID 30373905

  View details for PubMedCentralID PMC6656481

• Tumor-Associated Lymphoid Proliferation Creates an Immunomodulatory Environment that Facilitates Local Control in Acinic Cell Carcinoma Rooper, L., Allison, D., Hammon, R., Eisele, D., Kang, H. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102219

• Tumor-Associated Lymphoid Proliferation Creates an Immunomodulatory Environment that Facilitates Local Control in Acinic Cell Carcinoma Rooper, L., Allison, D., Hammon, R., Eisele, D., Kang, H. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915502465

• More on Mu-Opioid Receptor Antagonists in PD-1 Blockade-Induced Pruritus REPLY NEW ENGLAND JOURNAL OF MEDICINE Kwatra, S. G., Staender, S., Kang, H. 2019; 380 (6): 601-602

  View details for Web of Science ID 000457854200021

• More on Mu-Opioid Receptor Antagonists in PD-1 Blockade-Induced Pruritus. The New England journal of medicine Kwatra, S. G., Ständer, S., Kang, H. 2019; 380 (6): 602

  View details for DOI 10.1056/NEJMc1815143

  View details for PubMedID 30726685

• Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1-Deficient Carcinoma. The oncologist Karantanos, T., Rooper, L., Kang, Y., Lin, C. T., Wenga, P., Sagorsky, S., Lauring, J., Kang, H. 2019; 24 (2): 146-150

  Abstract

  Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next-generation-sequencing-based targeted cancer-related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single-patient expanded-use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI-1-deficient tumors, warranting further evaluation in clinical studies. KEY POINTS: Loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1), which encodes integrase interactor 1 (INI-1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity.INI-1-deficient carcinoma can be very aggressive, and there is no known treatment option available.There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI-1-deficient malignancies, including INI-1-deficient carcinomas.Loss of INI-1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer.Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options.

  View details for DOI 10.1634/theoncologist.2018-0279

  View details for PubMedID 30297384

  View details for PubMedCentralID PMC6369939

• Exceptional responses to pertuzumab, trastuzumab, and docetaxel in human epidermal growth factor receptor-2 high expressing salivary duct carcinomas. Head & neck Park, J. C., Ma, T. M., Rooper, L., Hembrough, T., Foss, R. D., Schmitt, N. C., Sawhney, R., Flanders, A., Kang, H. 2018; 40 (12): E100-E106

  Abstract

  Alterations in the human epidermal growth factor receptor-2 (HER2) pathway have been identified in a subset of salivary duct carcinomas. Dual HER2 inhibition with trastuzumab and pertuzumab has superior antitumor efficacy to trastuzumab monotherapy in HER2-positive breast cancer, yet its efficacy in HER2-positive salivary duct carcinoma is unknown.We report 2 cases of exceptional responses of HER2-positive salivary duct carcinomas to dual HER2 blockade and docetaxel combination and their molecular characteristics.A 54-year-old man with recurrent metastatic HER2 expressing salivary duct carcinoma of the parotid gland after definitive concurrent chemoradiation achieved a complete response (CR) after 6 cycles of trastuzumab, pertuzumab, and docetaxel (TPH). A 42-year-old woman with HER2-positive salivary duct carcinoma of the parotid gland with bone and liver metastases had CR with TPH and remains in remission on maintenance trastuzumab and pertuzumab.Dual HER2 blockage resulted in CR in patients with HER expressing salivary duct carcinoma and warrants further evaluation in this patient population.

  View details for DOI 10.1002/hed.25392

  View details for PubMedID 30478962

• Pattern of planned systemic therapy usage in newly diagnosed, nonmetastatic squamous cell carcinoma of the head and neck in a commercially insured population in the United States. Head & neck Park, J. C., Gourin, C. G., Kiess, A. P., Mehra, R., Forastiere, A. A., Kang, H. 2018; 40 (12): 2612-2620

  Abstract

  We analyzed systemic therapy plans submitted for commercially insured patients with untreated, newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) to investigate patterns of practice.Consecutive chemotherapy treatment plans were submitted using Eviti Connect (https://www.marylandphysicianscare.com/content/dam/centene/maryland/pdfs/evitiConnectFactSheet.pdf) portal for preauthorization between June 1, 2011, and June 30, 2015, were analyzed.A total of 387 treatment plans were submitted for 340 patients; 68 and 272 patients were from academic centers and community practices, respectively. Single agent cisplatin (57%), cetuximab (18%), and carboplatin (9%) were the most commonly proposed regimens concurrent with definitive radiotherapy (RT). The frequency of cetuximab use was not significantly different between academic centers and community practices. A clinical trial was proposed in only 15% of patients.Among commercially insured patients with newly diagnosed, nonmetastatic SCCHN, the choice of systemic therapy in initial treatment plans was not significantly different between academic centers and community practices. Clinical trials are underutilized and should be encouraged.

  View details for DOI 10.1002/hed.25333

  View details for PubMedID 30421818

• PD-1 Blockade-Induced Pruritus Treated with a Mu-Opioid Receptor Antagonist. The New England journal of medicine Kwatra, S. G., Ständer, S., Kang, H. 2018; 379 (16): 1578-1579

  View details for DOI 10.1056/NEJMc1805637

  View details for PubMedID 30332571

• Quality indicators of oropharyngeal cancer care in the elderly. The Laryngoscope Gourin, C. G., Herbert, R. J., Fakhry, C., Quon, H., Kang, H., Kiess, A. P., Koch, W. M., Eisele, D. W., Frick, K. D. 2018; 128 (10): 2312-2319

  Abstract

  To examine associations between quality of care, survival, and costs in elderly patients treated for oropharyngeal squamous cell cancer (OPSCC).Retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data.We evaluated 666 patients diagnosed with OPSCC from 2004 to 2007 using multivariate regression and survival analysis. Using quality indicators derived from guidelines for recommended care, summary measures of quality were calculated for diagnosis, initial treatment, surveillance, treatment for recurrence, end-of-life care, performance, and an overall summary measure of quality.Higher-quality care was associated with significant differences in survival for initial treatment (hazard ratio [HR] = 0.55 [0.41 to 0.73]), surveillance (HR = 0.32 [0.22 to 0.48]), treatment of recurrence (HR = 2.37 [1.56 to 3.60]), performance measures (HR = 0.50 [0.36 to 0.69]), and the overall summary measure of quality (HR = 0.53 [0.39 to 0.71]). Higher-quality salvage surgery was associated with improved survival (HR = 0.16 [0.04 to 0.54]), whereas higher-quality chemotherapy given for recurrence was associated with worse survival (HR = 5.70 [1.92 to 16.94]). Overall, higher-quality care was not associated with differences in costs. Higher-quality care was associated with significantly lower mean incremental costs for treatment of recurrence and end-of-life care, and higher costs for diagnosis and surveillance.Higher-quality OPSCC care in elderly patients was associated with improved survival; however, higher-quality care was not associated with reduced costs, and higher-quality care for treatment of recurrence was associated with poorer survival, primarily due to poorer survival in patients treated with palliative chemotherapy. These data demonstrate a complex relationship between quality and costs in elderly OPSCC patients, which can be used to frame discussions of value and guide disease-specific quality-measure development.2c. Laryngoscope, 128:2312-2319, 2018.

  View details for DOI 10.1002/lary.27050

  View details for PubMedID 29243261

• Detection of AR-V7 transcript with RNA in situ hybridization in human salivary duct cancer. Oral oncology Kang, H., Antonarakis, E. S., Luo, J., Zheng, Q., Rooper, L., De Marzo, A. M., Westra, W. H., Lotan, T. L. 2018; 84: 134-136

  View details for DOI 10.1016/j.oraloncology.2018.06.026

  View details for PubMedID 30122219

• Short- and long-term outcomes of oropharyngeal cancer care in the elderly. The Laryngoscope Motz, K., Herbert, R. J., Fakhry, C., Quon, H., Kang, H., Kiess, A. P., Eisele, D. W., Koch, W. M., Frick, K. D., Gourin, C. G. 2018; 128 (9): 2084-2093

  Abstract

  To examine associations between pretreatment variables, short-term and long-term swallowing and airway impairment, and survival in elderly patients (age > 65 years) treated for oropharyngeal squamous cell cancer (SCCA).Retrospective analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data.Longitudinal data from 666 patients diagnosed with oropharyngeal SCCA from 2004 to 2007 were evaluated using cross-tabulations, multivariate logistic regression, and survival analysis.Dysphagia (odds ratio [OR] = 1.3, 1.0-1.7), esophageal stricture (OR = 5.5, 2.6-11.9), and airway obstruction (OR = 1.6, 1.1-2.2) increased 1 year after treatment. The odds of airway obstruction, esophageal stricture, and pneumonia increased over subsequent years, with significantly increased risk at 5 years for airway obstruction (OR = 3.0, 1.4-6.4), pneumonia (OR = 4.5, 1.8-11.2), and stricture (OR = 5.5, 1.8-17.6). Pretreatment dysphagia was a significant predictor of long-term dysphagia, airway obstruction, and pneumonia. Chemoradiation, advanced stage disease, high-volume hospital care, male sex, and salvage surgery were significant predictors of long-term gastrostomy use. Long-term dysphagia, gastrostomy or tracheostomy dependence, weight loss, airway obstruction, and pneumonia were associated with poorer survival, with tracheostomy dependence (hazard ratio [HR] = 2.2, 1.7-2.9) and pneumonia (HR = 2.0, 1.7-2.4) associated with the greatest risk of late mortality.Airway and swallowing impairment is common after treatment of oropharyngeal SCCA in elderly patients, increases over time, and is associated with poorer survival. Patients with pretreatment dysphagia, advanced stage disease, initial treatment with chemoradiation, and salvage surgery represent a high-risk group with an increased risk of disability and death.2c. Laryngoscope, 128:2084-2093, 2018.

  View details for DOI 10.1002/lary.27153

  View details for PubMedID 29573418

• Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas. Journal for immunotherapy of cancer Ho, W. J., Yarchoan, M., Hopkins, A., Mehra, R., Grossman, S., Kang, H. 2018; 6 (1): 84

  Abstract

  Low absolute lymphocyte count (ALC) has previously been established as a marker of poor prognosis in multiple cancer types. There is growing evidence that ALC may also be associated with response to immunotherapy. This study explores whether response to PD1 inhibitors in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is associated with pretreatment ALC.Thirty-four R/M HNSCC patients who received either nivolumab or pembrolizumab between January 2014 and May 2018 at Johns Hopkins were identified retrospectively. Pretreatment blood counts in patients with and without clinical benefit from PD1 inhibitors were compared. Time-to-progression analyses were performed by dichotomizing the study cohort with the threshold of ALC 600 cells/μl, which is approximately 1.5 standard deviations away from treatment-naïve baseline mean.Patients with lower ALC appeared to have significantly less clinical benefit from anti-PD1 therapy. Those patients with pretreatment ALC < 600 cells/μl also had shorter PFS than patients with pretreatment ALC ≥ 600 cells/μl (median PFS 60 days vs. 141 days, p < 0.05). These results were consistent with multivariate proportional hazards analyses demonstrating significant association with progression. These observations were further supported by an expansion cohort analysis incorporating additional fourteen R/M HNSCC patients who received other checkpoint immunotherapy regimens at our institution.This study for the first time demonstrates that pretreatment ALC is significantly associated with response to PD1 inhibitors in R/M HNSCC patients.

  View details for DOI 10.1186/s40425-018-0395-x

  View details for PubMedID 30170629

  View details for PubMedCentralID PMC6117944

• Androgen deprivation therapy is associated with decreased second primary lung cancer risk in the United States veterans with prostate cancer. Epidemiology and health Jung, K., Park, J. C., Kang, H., Brandes, J. C. 2018; 40: e2018040

  Abstract

  We investigated whether androgen deprivation therapy (ADT) in prostate cancer patients was associated with a decreased risk for second primary lung cancer in US veterans.Prostate cancer diagnoses in the US Veterans Affairs Cancer Registry between 1999 and 2008 were identified. Use of hormonal therapy and diagnoses of second primary lung cancer were determined from the registry. Synchronous prostate and lung cancers, defined as 2 diagnoses made within 1 year, were excluded from the analysis. Cancer-free survival was estimated using the Kaplan-Meier method and hazard ratios were estimated using Cox proportional hazard models.Among the 63,141 identified patients with prostate cancer, 18,707 subjects were eligible for the study. Hormonal therapy was used in 38% of patients and the median follow-up period was 28 months. ADT use was associated with longer lung cancer-free survival in prostate cancer patients (log-rank p=0.01). After adjusting for age, race, smoking and prostate cancer stage, ADT use was associated with decreased lung cancer risk by 15, 21, and 24% after 1, 2, and 3 years, respectively.ADT in prostate cancer patients may be associated with decreased second primary lung cancer risk among US veterans.

  View details for DOI 10.4178/epih.e2018040

  View details for PubMedID 30121970

  View details for PubMedCentralID PMC6232654

• Salivary Secretory Carcinoma With a Novel ETV6-MET Fusion: Expanding the Molecular Spectrum of a Recently Described Entity. The American journal of surgical pathology Rooper, L. M., Karantanos, T., Ning, Y., Bishop, J. A., Gordon, S. W., Kang, H. 2018; 42 (8): 1121-1126

  Abstract

  Secretory carcinoma of the salivary glands, also known as mammary analogue secretory carcinoma, is a recently described tumor characterized by generally indolent clinical behavior and recurrent ETV6-NTRK3 fusions. However, a small subset of recent cases with high-grade histology, aggressive behavior, or alternate molecular findings are expanding the spectrum of this entity. In this case, a 59-year-old female presented with an infiltrative submandibular gland tumor that was originally classified as a high-grade acinic cell carcinoma, papillary-cystic variant. She developed persistent local disease and, 11 years after initial presentation, was found to have widespread metastases. Rereview of her primary tumor highlighted microcystic, papillary, and solid architecture, eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli, abundant mitotic figures, and necrosis. Immunostains showed the tumor cells to be positive for S100 and mammaglobin and negative for DOG-1, and fluorescence in situ hybridization highlighted an ETV6 rearrangement, supporting a diagnosis of high-grade secretory carcinoma. Finally, next-generation sequencing demonstrated a novel ETV6-MET fusion. To our knowledge, this is the first ETV6-MET fusion reported in secretory carcinoma. This finding further expands the definition of secretory carcinoma while carrying implications for selecting appropriate targeted therapy.

  View details for DOI 10.1097/PAS.0000000000001065

  View details for PubMedID 29683815

• Biomarkers predictive of response to pembrolizumab in head and neck cancer (HNSCC) Seiwert, T. Y., Haddad, R., Bauml, J., Weiss, J., Pfister, D. G., Gupta, S., Mehra, R., Gluck, I., Kang, H., Worden, F., Eder, J., Tahara, M., Burtness, B., Liu, S. V., Webber, A., Huang, L., Mogg, R., Cristescu, R., Cheng, J., Chow, L. Q. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-LB-339

  View details for Web of Science ID 000468818900477

• Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. British journal of cancer Mehra, R., Seiwert, T. Y., Gupta, S., Weiss, J., Gluck, I., Eder, J. P., Burtness, B., Tahara, M., Keam, B., Kang, H., Muro, K., Geva, R., Chung, H. C., Lin, C. C., Aurora-Garg, D., Ray, A., Pathiraja, K., Cheng, J., Chow, L. Q., Haddad, R. 2018; 119 (2): 153-159

  Abstract

  Second-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up.Multi-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review).Median follow-up was 9 months (range, 0.2-32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13-24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%.Some patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.

  View details for DOI 10.1038/s41416-018-0131-9

  View details for PubMedID 29955135

  View details for PubMedCentralID PMC6048158

• Potential drug targets for adenoid cystic carcinoma elucidated by proteogenomic analysis Thyparambil, S. P., Kim, Y., Chambers, A. G., Yan, D., Sellappan, S., Sedgewick, A. J., Newton, Y., Sanborn, J., Vaske, C. J., Benz, S. C., Cecchi, F., Kang, H., Hembrough, T. A. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-778

  View details for Web of Science ID 000468818902282

• Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC). Cancers of the head & neck Jung, K., Kang, H., Mehra, R. 2018; 3: 3

  Abstract

  The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute 'gain of function' mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested.

  View details for DOI 10.1186/s41199-018-0030-z

  View details for PubMedID 31093356

  View details for PubMedCentralID PMC6460806

• Response to R-CHOP in HPV-related squamous cell carcinoma of base of tongue: a case report. Cancers of the head & neck Ma, T. M., Kang, H., Rowe, S. P., Kiess, A. P. 2018; 3: 2

  Abstract

  Synchronous squamous cell carcinoma of the head and neck (HNSCC) and non-Hodgkin's lymphoma is a rare clinical scenario. It is unknown whether the R-CHOP chemotherapy for lymphoma would also be active against HNSCC. Herein, we present such a case and a review of the literature.A 64 year-old female presented with painless jaundice. CT demonstrated a retroperitoneal mass and pathology showed follicular lymphoma. A base-of-tongue HPV+ squamous cell carcinoma was found incidentally on staging CT. R-CHOP chemotherapy was initiated. After 3 cycles of R-CHOP the lymphoma had a complete metabolic response and, unexpectedly, the HNSCC also demonstrated excellent response. The patient received another 3 cycles followed by radiation to the HNSCC and to date is in remission for both cancers.This case highlights the exquisite sensitivity of HPV-related HNSCC, which should be taken into consideration in treatment prioritization of a concurrent diagnosis of a second cancer.

  View details for DOI 10.1186/s41199-018-0028-6

  View details for PubMedID 31093355

  View details for PubMedCentralID PMC6460839

• Comprehensive proteomic and genomic profiling to identify therapeutic targets in adenoid cystic carcinoma. Thyparambil, S. P., Kim, Y., Chambers, A., Yan, D., Sellappan, S., Gong, C., Sedgewick, A., Newton, Y., Sanborn, J., Vaske, C., Benz, S., Cecchi, F., Kang, H., Hembrough, T. A. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.6053

  View details for Web of Science ID 000442916002343

• A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report. Journal for immunotherapy of cancer Ho, W. J., Rooper, L., Sagorsky, S., Kang, H. 2018; 6 (1): 33

  Abstract

  Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms.This report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months.Combination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.

  View details for DOI 10.1186/s40425-018-0348-4

  View details for PubMedID 29743117

  View details for PubMedCentralID PMC5943998

• Treatment, survival, and costs of oropharyngeal cancer care in the elderly. The Laryngoscope Gourin, C. G., Fakhry, C., Quon, H., Kang, H., Kiess, A. P., Herbert, R. J., Eisele, D. W., Frick, K. D. 2018; 128 (5): 1103-1112

  Abstract

  To examine associations between treatment, survival, and costs in elderly patients with oropharyngeal squamous cell cancer (OPSCC).Retrospective cross-sectional analysis of Surveillance, Epidemiology, and End Results-Medicare data.We evaluated 666 patients diagnosed with OPSCC from 2004 to 2007 using cross-tabulations, multivariate logistic and generalized linear regression modeling, and survival analysis.The majority of patients were nonsmokers (79%), had advanced-stage disease (59%), and received chemoradiation (38%) or radiation (28%). Surgery with postoperative radiation (hazard ratio [HR]: 0.33 [95% CI: 0.20-0.53]) and chemoradiation (HR: 0.45 [95% CI: 0.29-0.71]) were associated with improved survival, whereas stage IV disease was associated with poorer survival (HR: 1.95 [95% CI: 1.13-3.38]). Additional cancer-directed treatment after primary treatment was more likely following chemoradiation (odds ratio [OR]: 3.44 [95% CI: 1.78-6.63]). Salvage surgery was performed in 25% of patients undergoing subsequent additional cancer-directed treatment, and was associated with high-volume hospitals (OR: 2.81 [95% CI: 1.07-7.74]). Additional radiation (HR: 0.47 [95% CI: 0.31-0.72]) and salvage surgery (HR: 0.61 [95% CI: 0.38-0.99]) were associated with improved overall survival when performed >6 months following initial treatment, whereas salvage neck dissection alone was not significantly associated with survival after controlling for time to salvage (HR: 0.38 [95% CI: 0.05-2.78]). Treatment and 5-year overall costs were highest for chemoradiation, surgery with postoperative radiation, and additional cancer-directed treatment.Multimodality treatment in elderly OPSCC patients was associated with improved survival and increased costs. Chemoradiation was associated with an increased likelihood of additional cancer-directed treatment. Salvage surgery was centralized at high-volume hospitals, and was associated with improved survival when performed >6 months after last initial treatment date, but was performed in <20% of patients undergoing additional treatment.2c. Laryngoscope, 128:1103-1112, 2018.

  View details for DOI 10.1002/lary.26887

  View details for PubMedID 28988469

• Treatment, short-term outcomes, and costs associated with larynx cancer care in commercially insured patients. The Laryngoscope Day, A. T., Chang, H. Y., Quon, H., Kang, H., Kiess, A. P., Eisele, D. W., Frick, K. D., Gourin, C. G. 2018; 128 (1): 91-101

  Abstract

  To examine associations between treatment, complications, and costs in patients with laryngeal cancer.Retrospective cross-sectional analysis of MarketScan Commercial Claim and Encounters data.We evaluated 10,969 patients diagnosed with laryngeal cancer from 2010 to 2012 using cross-tabulations and multivariate regression.Chemoradiation was significantly associated with supraglottic tumors (relative risk ratio [RRR] = 5.9 [4.4-7.8]), pretreatment gastrostomy (RRR = 4.0 [2.7-6.1]), and alcohol abuse (RRR = 0.5 [0.3-0.9]). Treatment-related complications occurred in 23% of patients, with medical complications in 22% and surgical complications in 7%. Chemoradiation (odds ratio [OR] = 3.7 [2.6-5.2]), major surgical procedures (OR = 4.9 [3.5-6.8]), reconstruction (OR = 7.7 (4.1-14.7)], and advanced comorbidity (OR = 9.7 [5.7-16.5] were associated with acute complications. Recurrent/persistent disease occurred in 23% of patients and was associated with high-volume care (OR = 1.4 [1.1-1.8]). Salvage surgery was performed in 46% of patients with recurrent/persistent disease and was less likely for supraglottic disease (OR = 0.5 [0.4-0.8]) and after chemoradiation (OR = 0.4 [0.2-0.6]). Initial treatment and 1-year overall costs for chemoradiation were higher than all other treatment categories, after controlling for all other variables including complications and salvage. High-volume care was associated with significantly lower costs of care for surgical patients but was not associated with differences in costs of care for nonoperative treatment.In commercially insured patients <65 years old with laryngeal cancer, chemoradiation was associated with increased costs, an increased likelihood of treatment-related medical complications, and a reduced likelihood of surgical salvage. Higher-volume surgical care was associated with lower initial treatment and 1-year costs of care. These data have implications for discussions of value and quality in an era of healthcare reform.2c. Laryngoscope, 128:91-101, 2018.

  View details for DOI 10.1002/lary.26717

  View details for PubMedID 28685830

• High-resolution microbiome profiling uncovers Fusobacterium nucleatum, Lactobacillus gasseri/johnsonii, and Lactobacillus vaginalis associated to oral and oropharyngeal cancer in saliva from HPV positive and HPV negative patients treated with surgery and chemo-radiation. Oncotarget Guerrero-Preston, R., White, J. R., Godoy-Vitorino, F., Rodríguez-Hilario, A., Navarro, K., González, H., Michailidi, C., Jedlicka, A., Canapp, S., Bondy, J., Dziedzic, A., Mora-Lagos, B., Rivera-Alvarez, G., Ili-Gangas, C., Brebi-Mieville, P., Westra, W., Koch, W., Kang, H., Marchionni, L., Kim, Y., Sidransky, D. 2017; 8 (67): 110931-110948

  Abstract

  Microbiome studies show altered microbiota in head and neck squamous cell carcinoma (HNSCC), both in terms of taxonomic composition and metabolic capacity. These studies utilized a traditional bioinformatics methodology, which allows for accurate taxonomic assignment down to the genus level, but cannot accurately resolve species level membership. We applied Resphera Insight, a high-resolution methodology for 16S rRNA taxonomic assignment that is able to provide species-level context in its assignments of 16S rRNA next generation sequencing (NGS) data. Resphera Insight applied to saliva samples from HNSCC patients and healthy controls led to the discovery that a subset of HNSCC saliva samples is significantly enriched with commensal species from the vaginal flora, including Lactobacillus gasseri/johnsonii (710x higher in saliva) and Lactobacillus vaginalis (52x higher in saliva). These species were not observed in normal saliva from Johns Hopkins patients, nor in 16S rRNA NGS saliva samples from the Human Microbiome Project (HMP). Interestingly, both species were only observed in saliva from Human Papilloma Virus (HPV) positive and HPV negative oropharyngeal cancer patients. We confirmed the representation of both species in HMP data obtained from mid-vagina (n=128) and vaginal introitus (n=121) samples. Resphera Insight also led to the discovery that Fusobacterium nucleatum, an oral cavity flora commensal bacterium linked to colon cancer, is enriched (600x higher) in saliva from a subset of HNSCC patients with advanced tumors stages. Together, these high-resolution analyses on 583 samples suggest a possible role for bacterial species in the therapeutic outcome of HPV positive and HPV negative HNSCC patients.

  View details for DOI 10.18632/oncotarget.20677

  View details for PubMedID 29340028

  View details for PubMedCentralID PMC5762296

• Quality indicators of laryngeal cancer care in commercially insured patients. The Laryngoscope Britt, C. J., Chang, H. Y., Quon, H., Kang, H., Kiess, A. P., Eisele, D. W., Frick, K. D., Gourin, C. G. 2017; 127 (12): 2805-2812

  Abstract

  To examine associations between quality, complications, and costs in commercially insured patients treated for laryngeal cancer.Retrospective cross-sectional analysis of MarketScan Commercial Claim and Encounters data (Truven Health Analytics, Ann Arbor, Michigan, U.S.A.).We evaluated 10,969 patients diagnosed with laryngeal cancer from 2010 to 2012 using cross-tabulations and multivariate regression. Using quality indicators derived from guidelines for recommended care, summary measures of quality were calculated for diagnosis, initial treatment, surveillance, treatment for recurrence, performance, and an overall summary measure of quality.Higher-quality care in the initial treatment period was associated with lower odds of 30-day mortality (odds ratio [OR] = 0.21, 95% confidence interval [CI] [0.04-0.98]), surgical complications (OR = 0.39 [0.17-0.88]), and medical complications (OR = 0.68 [0.49-0.96]). Mean incremental 1-year costs were higher for higher-quality diagnosis ($20,126 [$14,785-$25,466]), initial treatment ($17,918 [$10,481-$25,355]), and surveillance ($25,424 [$20,014-$30,834]) quality indicators, whereas costs were lower for higher-quality performance measures (-$45,723 [-$56,246--$35,199]) after controlling for all other variables. Higher-quality care was associated with significant differences in mean incremental costs for initial treatment in surgical patients ($-37,303 [-$68,832--$5,775]), and for the overall summary measure of quality in patients treated nonoperatively ($10,473 [$1,121-$19,825]). After controlling for the overall summary measure of quality, costs were significantly lower for patients receiving high-volume surgical care (mean -$18,953 [-$28,381--$9,426]).Higher-quality larynx cancer care in commercially insured patients was associated with lower 30-day mortality and morbidity. High-volume surgical care was associated with lower 1-year costs, even after controlling for quality. These data have implications for discussions of value and quality in an era of healthcare reform.2c. Laryngoscope, 127:2805-2812, 2017.

  View details for DOI 10.1002/lary.26728

  View details for PubMedID 28688188

• Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy. Oral oncology Schmitt, N. C., Kang, H., Sharma, A. 2017; 74: 40-48

  Abstract

  Salivary duct carcinoma (SDC) is a rare, aggressive salivary malignancy that is often diagnosed at an advanced stage. Previously, little was known about outcomes of this disease due to its rarity. In the past several years, much has been learned about salivary duct carcinoma after publication of outcomes from several large single-institution series and national database searches. Recent studies of genomic alterations have helped elucidate the biology and pathogenesis of this aggressive disease. Here we review outcomes of the disease, effects of treatment, prognostic factors, and genomic alterations in SDC. Studies of targeted therapy and promising future directions are also discussed.

  View details for DOI 10.1016/j.oraloncology.2017.09.008

  View details for PubMedID 29103750

  View details for PubMedCentralID PMC5685667

• SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells CLINICAL CANCER RESEARCH Ozawa, H., Ranaweera, R. S., Izumchenko, E., Makarev, E., Zhavoronkov, A., Fertig, E. J., Howard, J. D., Markovic, A., Bedi, A., Ravi, R., Perez, J., Quynh-Thu Le, Kong, C. S., Jordan, R. C., Wang, H., Kang, H., Quon, H., Sidransky, D., Chung, C. H. 2017; 23 (17): 5162–75

  Abstract

  Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC.Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivoResults: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss.Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162-75. ©2017 AACR.

  View details for PubMedID 28522603

• The role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma. Cancer metastasis reviews Fung, N., Faraji, F., Kang, H., Fakhry, C. 2017; 36 (3): 449-461

  Abstract

  Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management.

  View details for DOI 10.1007/s10555-017-9686-9

  View details for PubMedID 28812214

• Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board. JCO precision oncology Dalton, W. B., Forde, P. M., Kang, H., Connolly, R. M., Stearns, V., Gocke, C. D., Eshleman, J. R., Axilbund, J., Petry, D., Geoghegan, C., Wolff, A. C., Loeb, D. M., Pratilas, C. A., Meyer, C. F., Christenson, E. S., Slater, S. A., Ensminger, J., Parsons, H. A., Park, B. H., Lauring, J. 2017; 2017

  Abstract

  Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice.A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing.One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports.The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

  View details for DOI 10.1200/PO.16.00046

  View details for PubMedID 30003184

  View details for PubMedCentralID PMC6039131

• An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Delord, J., Hollebecque, A., De Boer, J. P., De Greve, J., Machiels, J. H., Leidner, R. S., Ferris, R. L., Rao, S., Soumaoro, I., Cao, Z., Kang, H., Topalian, S. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.6025

  View details for Web of Science ID 000411931705023

• Comprehensive genomic profiling of parathyroid carcinoma. Kang, H., Schubert, A., Ladenson, P., Ball, D., Chung, J., Schrock, A., Ross, J. S., Miller, V. A., Stephens, P. J., Ali, S. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.6088

  View details for Web of Science ID 000411931705084

• Evaluation of proposed staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma. Cancer Malm, I. J., Fan, C. J., Yin, L. X., Li, D. X., Koch, W. M., Gourin, C. G., Pitman, K. T., Richmon, J. D., Westra, W. H., Kang, H., Quon, H., Eisele, D. W., Fakhry, C. 2017; 123 (10): 1768-1777

  Abstract

  Patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC) have improved survival when compared with those with HPV-negative OPC. Unfortunately, the American Joint Committee on Cancer seventh edition (AJCC-7ed) staging system does not account for the prognostic advantage observed with HPV-positive OPC. The purpose of the current study was to validate and compare 2 recently proposed staging systems for HPV-positive OPC.Patients treated for HPV-positive OPC from 2005 to 2015 at Johns Hopkins Hospital (JHH) were included for analysis. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) and The University of Texas MD Anderson Cancer Center (MDACC) staging systems were applied and survival was calculated using Kaplan-Meier methods. Cox proportional hazard regression was used to determine the relationship between stage of disease and survival. Models were compared using the Akaike information criterion (AIC).A total of 435 patients were eligible for analysis. There was a dramatic shift in lymph node category and overall stage of disease when ICON-S and MDACC stage were applied to the JHH cohort. There was superior stratification of overall survival and progression-free survival by ICON-S stage. Both proposed models had an improved fit based on AIC scores (P<.001 for both) over the AJCC-7ed. The ICON-S staging system had the lowest AIC score, and thus a better fit within the JHH population.The current analysis provides external validation for both staging systems in an independent and heterogeneously treated patient population. Although the MDACC staging system is an improvement over the AJCC-7ed, the ICON-S stage provides superior stratification of overall and progression-free survival, thereby supporting its use as the updated AJCC staging system for OPC. Cancer 2017;123:1768-1777. © 2017 American Cancer Society.

  View details for DOI 10.1002/cncr.30512

  View details for PubMedID 28055120

• Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Bauml, J., Seiwert, T. Y., Pfister, D. G., Worden, F., Liu, S. V., Gilbert, J., Saba, N. F., Weiss, J., Wirth, L., Sukari, A., Kang, H., Gibson, M. K., Massarelli, E., Powell, S., Meister, A., Shu, X., Cheng, J. D., Haddad, R. 2017; 35 (14): 1542-1549

  Abstract

  Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

  View details for DOI 10.1200/JCO.2016.70.1524

  View details for PubMedID 28328302

  View details for PubMedCentralID PMC5946724

• Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer discovery Anagnostou, V., Smith, K. N., Forde, P. M., Niknafs, N., Bhattacharya, R., White, J., Zhang, T., Adleff, V., Phallen, J., Wali, N., Hruban, C., Guthrie, V. B., Rodgers, K., Naidoo, J., Kang, H., Sharfman, W., Georgiades, C., Verde, F., Illei, P., Li, Q. K., Gabrielson, E., Brock, M. V., Zahnow, C. A., Baylin, S. B., Scharpf, R. B., Brahmer, J. R., Karchin, R., Pardoll, D. M., Velculescu, V. E. 2017; 7 (3): 264-276

  Abstract

  Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235.

  View details for DOI 10.1158/2159-8290.CD-16-0828

  View details for PubMedID 28031159

  View details for PubMedCentralID PMC5733805

• Differences in the Prevalence of Human Papillomavirus (HPV) in Head and Neck Squamous Cell Cancers by Sex, Race, Anatomic Tumor Site, and HPV Detection Method. JAMA oncology D'Souza, G., Westra, W. H., Wang, S. J., van Zante, A., Wentz, A., Kluz, N., Rettig, E., Ryan, W. R., Ha, P. K., Kang, H., Bishop, J., Quon, H., Kiess, A. P., Richmon, J. D., Eisele, D. W., Fakhry, C. 2017; 3 (2): 169-177

  Abstract

  Human papillomavirus (HPV) causes an increasing proportion of oropharyngeal squamous cell carcinomas (OPSCCs), particularly in white men. The prevalence of HPV among other demographic groups and other anatomic sites of HNSCC is unclear.To explore the role of HPV tumor status among women and nonwhites with OPSCC and patients with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC).Retrospective cohort study at 2 tertiary academic centers including cases diagnosed 1995 through 2012, oversampled for minorities and females. A stratified random sample of 863 patients with newly diagnosed SCC of the oral cavity, oropharynx, larynx, or nasopharynx was used.Outcomes were HPV status as measured by p16 immunohistochemical analysis, HPV16 DNA in situ hybridization (ISH), and high-risk HPV E6/E7 mRNA ISH.Of 863 patients, 551 (63.9%) were male and median age was 58 years (interquartile range, 51-68 years). Among 240 OPSCCs, 144 (60%) were p16 positive (p16+), 115 (48%) were HPV16 DNA ISH positive (ISH16+), and 134 (56%) were positive for any oncogenic HPV type (ISH+). From 1995 to 2012, the proportion of p16+ OPSCC increased significantly among women (from 29% to 77%; P = .005 for trend) and men (36% to 72%; P < .001 for trend), as well as among whites (39% to 86%; P < .001 for trend) and nonwhites (32% to 62%; P = .02 for trend). Similar results were observed for ISH+ OPSCC (P ≤ .01 for all). Among 623 non-OP HNSCCs, a higher proportion were p16+ compared with ISH positive (62 [10%] vs 30 [5%]; P = .001). A high proportion (26 of 62 [42%]) of these p16+ non-OP HNSCCs were found in sites adjacent to the oropharynx. The proportion of p16+ and ISH+ non-OP HNSCCs were similar by sex. Over time, the proportion of non-OP HNSCCs that were p16+ (or ISH+) increased among whites (P = .04 for trend) but not among nonwhites (each P > .51 for trend). Among OPSCCs, p16 had high sensitivity (100%), specificity (91%), and positive (93%) and negative predictive value (100%) for ISH positivity. In non-OP HNSCCs, p16 had lower sensitivity (83%) and positive predictive value (40%) but high specificity (94%) and negative predictive value (99%) for ISH positivity.During 1995 through 2012, the proportion of OPSCCs caused by HPV has increased significantly. This increase was not restricted to white men but was a consistent trend for women and men, as well as for white and nonwhite racial groups. Few non-OP HNSCCs were HPV related. P16 positivity was a good surrogate for ISH+ tumor status among OPSCC, but not a good surrogate for non-OP HNSCC.

  View details for DOI 10.1001/jamaoncol.2016.3067

  View details for PubMedID 27930766

  View details for PubMedCentralID PMC7286346

• Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Kang, H., Tan, M., Bishop, J. A., Jones, S., Sausen, M., Ha, P. K., Agrawal, N. 2017; 23 (1): 283-288

  Abstract

  Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (P = 0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of MEC. Clin Cancer Res; 23(1); 283-8. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-0720

  View details for PubMedID 27340278

  View details for PubMedCentralID PMC5182193

• Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Chow, L. Q., Haddad, R., Gupta, S., Mahipal, A., Mehra, R., Tahara, M., Berger, R., Eder, J. P., Burtness, B., Lee, S. H., Keam, B., Kang, H., Muro, K., Weiss, J., Geva, R., Lin, C. C., Chung, H. C., Meister, A., Dolled-Filhart, M., Pathiraja, K., Cheng, J. D., Seiwert, T. Y. 2016; 34 (32): 3838-3845

  Abstract

  Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.

  View details for DOI 10.1200/JCO.2016.68.1478

  View details for PubMedID 27646946

  View details for PubMedCentralID PMC6804896

• Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study JOURNAL OF CLINICAL ONCOLOGY Nanda, R., Chow, L. M., Dees, E., Berger, R., Gupta, S., Geva, R., Pusztai, L., Pathiraja, K., Aktan, G., Cheng, J. D., Karantza, V., Buisseret, L. 2016; 34 (21): 2460-+

  Abstract

  Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.

  View details for DOI 10.1200/JCO.2015.64.8931

  View details for Web of Science ID 000381497000005

  View details for PubMedID 27646946

  View details for PubMedCentralID PMC6804896

• Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC). Bauml, J., Seiwert, T. Y., Pfister, D. G., Worden, F. P., Liu, S. V., Gilbert, J., Saba, N. F., Weiss, J., Wirth, L. J., Sukari, A., Kang, H., Gibson, M. K., Massarelli, E., Powell, S., Meister, A., Shu, X., Cheng, J. D., Haddad, R. I. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.6011

  View details for Web of Science ID 000404711502139

• Analysis of chemotherapy selection for locally advanced squamous cell carcinoma of head and neck (SCCHN) in a commercially insured population in the United States. Kang, H., Gourin, C., Kiess, A., Forastiere, A. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.6066

  View details for Web of Science ID 000404711502193

• FDG PET/CT in Patients With Head and Neck Squamous Cell Carcinoma After Primary Surgical Resection With or Without Chemoradiation Therapy. AJR. American journal of roentgenology Taghipour, M., Sheikhbahaei, S., Wray, R., Agrawal, N., Richmon, J., Kang, H., Subramaniam, R. M. 2016; 206 (5): 1093-100

  Abstract

  The purpose of this study was to assess the value of posttreatment FDG PET/CT in patients with squamous cell carcinoma of the head and neck (HNSCC) treated with primary surgical resection with or without adjuvant concurrent chemoradiotherapy.A total of 98 HNSCC patients were treated with primary surgical resection and had undergone PET/CT within 6 months of treatment completion. The accuracy of the scans and the added value to clinical assessment and impact on management were established based on the clinical information before and after each scan. Overall survival of patients was estimated with Kaplan-Meier curves.Of the total 98 scans, 25 (25.5%) were interpreted as positive and 73 (74.5%) as negative. The sensitivity of posttreatment PET/CT was 80.0%; specificity, 89.5%; positive predictive value, 66.7%; negative predictive value, 94.4%; and accuracy, 87.5%. These scans were helpful in excluding tumor in 31.8% of patients with clinical suspicion of residual disease and identifying suspected residual disease in 13.2% of patients with no prior clinical suspicion. Multivariate regression analysis showed that tumor size, grade (p = 0.041), scan type (p = 0.002), and scan result (p = 0.005) were independent covariates associated with overall survival. Kaplan-Meier analysis showed a significant difference and association in overall survival between patients with a positive versus a negative posttherapy PET/CT scan result (hazard ratio, 5.65; 95% CI, 2.48-12.83; log rank Mantel-Cox p < 0.001).Posttreatment FDG PET/CT results had a high negative predictive value, added value to clinical assessment of 35% of patients, influenced subsequent management, and were associated with survival outcome of HNSCC patients treated with primary surgical resection.

  View details for DOI 10.2214/AJR.15.15604

  View details for PubMedID 26999264

• A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral oncology Chung, C. H., Rudek, M. A., Kang, H., Marur, S., John, P., Tsottles, N., Bonerigo, S., Veasey, A., Kiess, A., Quon, H., Cmelak, A., Murphy, B. A., Gilbert, J. 2016; 53: 54-9

  Abstract

  Afatinib is an ErbB family receptor inhibitor with efficacy in head and neck squamous cell carcinoma (HNSCC). A phase I trial was conducted to determine the maximally tolerated dose (MTD) of afatinib in combination with carboplatin and paclitaxel as induction chemotherapy (IC).Patients with newly diagnosed, locally advanced HPV-negative or HPV-positive HNSCC with a significant smoking history were enrolled. Afatinib alone was given daily for two weeks as lead-in and subsequently given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) every 21days as IC. Afatinib was started at a dose of 20mg daily and dose escalated using a modified Fibonacci design. After completion of IC, afatinib was discontinued and patients received concurrent cisplatin 40mg/m(2) weekly and standard radiation. Toxicity was assessed using CTCAE version 4.0.Seven of nine patients completed afatinib lead-in and IC. Five patients had partial response and two patients had stable disease after IC. Dose level 1 (afatinib 20mg) was well tolerated with one grade 3 (ALT elevation) and one grade 4 (neutropenia) toxicities. However, dose level 2 (afatinib 30mg) was not well tolerated with nine grade 3 (pneumonia, abdominal pain, diarrhea, pancytopenia, and UTI), two grade 4 (sepsis) and one grade 5 (death) toxicities.The MTD of afatinib given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) is 20mg daily. Combination of afatinib at doses higher than 20mg with carboplatin and paclitaxel should be administered with caution due to the toxicities.

  View details for DOI 10.1016/j.oraloncology.2015.11.020

  View details for PubMedID 26705063

  View details for PubMedCentralID PMC4707116

• Intratherapy or Posttherapy FDG PET or FDG PET/CT for Patients With Head and Neck Cancer: A Systematic Review and Meta-analysis of Prognostic Studies. AJR. American journal of roentgenology Sheikhbahaei, S., Ahn, S. J., Moriarty, E., Kang, H., Fakhry, C., Subramaniam, R. M. 2015; 205 (5): 1102-13

  Abstract

  The objective of this study was to determine the predictive value of intra-therapy or posttherapy FDG PET or FDG PET/CT with regard to overall survival (OS) and event-free survival (EFS) outcomes for patients with head and neck cancer (HNC).A systematic search of the MEDLINE and EMBASE databases was performed. Studies in which PET/CT was performed during or after completion of primary therapy and for which survival outcomes were reported were included. OS and EFS were considered as outcomes. The pooled estimates of hazard ratios (HRs) and Mantel-Haenszel risk ratios (RRs) were generated for summary effects.Twenty-six studies were eligible for inclusion. The pooled HRs for OS (nine studies, 600 patients) and EFS (eight studies, 479 patients) were 3.55 (95% CI, 2.35-5.37) and 4.73 (95% CI, 2.61-8.56), respectively. Results from the RR analyses, including all 26 studies, showed that intratherapy or posttherapy PET/CT could significantly predict the 2-year and 3- to 5-year risk of death or disease progression. A positive PET result was associated with a more-than-sixfold increase in the risk of death within 2 years (2-year RR, 6.19 [95% CI, 3.04- 12.62]), which is attenuated--but remains significant--with longer follow-up (3- to 5-year RR, 2.42 [95% CI, 1.76-3.32]). The estimated pooled RRs for 2-year mortality were 8.31 (95% CI, 3.83-18.01) for posttherapy PET/CT versus 3.99 (95% CI, 1.43-11.10) for intratherapy PET/CT.Positive results of intratherapy or posttherapy PET/CT examinations strongly predict the risk of adverse events and death, particularly within 2 years but also up to 5 years, for patients with HNC.

  View details for DOI 10.2214/AJR.15.14647

  View details for PubMedID 26496559

• FDG PET/CT for Management and Assessing Outcomes of Squamous Cell Cancer of the Oral Cavity. AJR. American journal of roentgenology Pasha, M. A., Marcus, C., Fakhry, C., Kang, H., Kiess, A. P., Subramaniam, R. M. 2015; 205 (2): W150-61

  Abstract

  FDG PET/CT has excellent diagnostic accuracy for detecting locoregional nodal and distant metastases, can be used to assess therapeutic response, and provides valuable information about prognosis in patients with oral cavity cancer. The aim of this article is to summarize the value of FDG PET/CT in the treatment of patients with squamous cell cancer of the oral cavity.FDG PET/CT is a valuable imaging study in the management of oral squamous cell cancer and in predicting patient outcome.

  View details for DOI 10.2214/AJR.14.13830

  View details for PubMedID 26001119

• Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Science translational medicine Wang, Y., Springer, S., Mulvey, C. L., Silliman, N., Schaefer, J., Sausen, M., James, N., Rettig, E. M., Guo, T., Pickering, C. R., Bishop, J. A., Chung, C. H., Califano, J. A., Eisele, D. W., Fakhry, C., Gourin, C. G., Ha, P. K., Kang, H., Kiess, A., Koch, W. M., Myers, J. N., Quon, H., Richmon, J. D., Sidransky, D., Tufano, R. P., Westra, W. H., Bettegowda, C., Diaz, L. A., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Agrawal, N. 2015; 7 (293): 293ra104

  Abstract

  To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC.

  View details for DOI 10.1126/scitranslmed.aaa8507

  View details for PubMedID 26109104

  View details for PubMedCentralID PMC4587492

• Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. Annals of oncology : official journal of the European Society for Medical Oncology Chung, C. H., Guthrie, V. B., Masica, D. L., Tokheim, C., Kang, H., Richmon, J., Agrawal, N., Fakhry, C., Quon, H., Subramaniam, R. M., Zuo, Z., Seiwert, T., Chalmers, Z. R., Frampton, G. M., Ali, S. M., Yelensky, R., Stephens, P. J., Miller, V. A., Karchin, R., Bishop, J. A. 2015; 26 (6): 1216-1223

  Abstract

  To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies.DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison.Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles.The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.

  View details for DOI 10.1093/annonc/mdv109

  View details for PubMedID 25712460

  View details for PubMedCentralID PMC4516044

• Emerging biomarkers in head and neck cancer in the era of genomics. Nature reviews. Clinical oncology Kang, H., Kiess, A., Chung, C. H. 2015; 12 (1): 11-26

  Abstract

  Head and neck cancer (HNC) broadly includes carcinomas arising from the mucosal epithelia of the head and neck region as well as various cell types of salivary glands and the thyroid. As reflected by the multiple sites and histologies of HNC, the molecular characteristics and clinical outcomes of this disease vary widely. In this Review, we focus on established and emerging biomarkers that are most relevant to nasopharyngeal carcinoma and head and neck squamous-cell carcinoma (HNSCC), which includes primary sites in the oral cavity, oropharynx, hypopharynx and larynx. Applications and limitations of currently established biomarkers are discussed along with examples of successful biomarker development. For emerging biomarkers, preclinical or retrospective data are also described in the context of recently completed comprehensive molecular analyses of HNSCC, which provide a broad genetic landscape and molecular classification beyond histology and clinical characteristics. We will highlight the ongoing effort that will see a shift from prognostic to predictive biomarker development in HNC with the goal of delivering individualized cancer therapy.

  View details for DOI 10.1038/nrclinonc.2014.192

  View details for PubMedID 25403939

• A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology Chung, C. H., Lee, J. W., Slebos, R. J., Howard, J. D., Perez, J., Kang, H., Fertig, E. J., Considine, M., Gilbert, J., Murphy, B. A., Nallur, S., Paranjape, T., Jordan, R. C., Garcia, J., Burtness, B., Forastiere, A. A., Weidhaas, J. B. 2014; 25 (11): 2230-2236

  Abstract

  A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.NCT00503997, NCT00425750, NCT00003809.

  View details for DOI 10.1093/annonc/mdu367

  View details for PubMedID 25081901

  View details for PubMedCentralID PMC4207729

• Head and neck PET/CT: therapy response interpretation criteria (Hopkins Criteria)-interreader reliability, accuracy, and survival outcomes. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Marcus, C., Ciarallo, A., Tahari, A. K., Mena, E., Koch, W., Wahl, R. L., Kiess, A. P., Kang, H., Subramaniam, R. M. 2014; 55 (9): 1411-6

  Abstract

  There has been no established qualitative system of interpretation for therapy response assessment using PET/CT for head and neck cancers. The objective of this study was to validate the Hopkins interpretation system to assess therapy response and survival outcome in head and neck squamous cell cancer patients (HNSCC).The study included 214 biopsy-proven HNSCC patients who underwent a posttherapy PET/CT study, between 5 and 24 wk after completion of treatment. The median follow-up was 27 mo. PET/CT studies were interpreted by 3 nuclear medicine physicians, independently. The studies were scored using a qualitative 5-point scale, for the primary tumor, for the right and left neck, and for overall assessment. Scores 1, 2, and 3 were considered negative for tumors, and scores 4 and 5 were considered positive for tumors. The Cohen κ coefficient (κ) was calculated to measure interreader agreement. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier plots with a Mantel-Cox log-rank test and Gehan Breslow Wilcoxon test for comparisons.Of the 214 patients, 175 were men and 39 were women. There was 85.98%, 95.33%, 93.46%, and 87.38% agreement between the readers for overall, left neck, right neck, and primary tumor site response scores, respectively. The corresponding κ coefficients for interreader agreement between readers were, 0.69-0.79, 0.68-0.83, 0.69-0.87, and 0.79-0.86 for overall, left neck, right neck, and primary tumor site response, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of the therapy assessment were 68.1%, 92.2%, 71.1%, 91.1%, and 86.9%, respectively. Cox multivariate regression analysis showed human papillomavirus (HPV) status and PET/CT interpretation were the only factors associated with PFS and OS. Among the HPV-positive patients (n = 123), there was a significant difference in PFS (hazard ratio [HR], 0.14; 95% confidence interval, 0.03-0.57; P = 0.0063) and OS (HR, 0.01; 95% confidence interval, 0.00-0.13; P = 0.0006) between the patients who had a score negative for residual tumor versus positive for residual tumor. A similar significant difference was observed in PFS and OS for all patients. There was also a significant difference in the PFS of patients with PET-avid residual disease in one site versus multiple sites in the neck (HR, 0.23; log-rank P = 0.004).The Hopkins 5-point qualitative therapy response interpretation criteria for head and neck PET/CT has substantial interreader agreement and excellent negative predictive value and predicts OS and PFS in patients with HPV-positive HNSCC.

  View details for DOI 10.2967/jnumed.113.136796

  View details for PubMedID 24947059

  View details for PubMedCentralID PMC4390037

• FDG PET/CT in the management of nasopharyngeal carcinoma. AJR. American journal of roentgenology Mohandas, A., Marcus, C., Kang, H., Truong, M. T., Subramaniam, R. M. 2014; 203 (2): W146-57

  Abstract

  FDG PET/CT has a growing role in the diagnosis and management of nasopharyngeal carcinoma (NPC). FDG PET has greater efficacy for N and M staging than other modalities, which enables the treating oncologists to select the appropriate mode of treatment. FDG PET/CT helps in radiation therapy planning, provides valuable prognostic information, and is useful in the assessment of therapy response and in follow-up to detect recurrences.FDG PET/CT is a valuable imaging test in the management of NPC.

  View details for DOI 10.2214/AJR.13.12420

  View details for PubMedID 25055290

• Antitumor effect of IMGN289, an anti-EGFR antibody-drug conjugate (ADC), in preclinical models of head and neck squamous cell carcinomas (HNSCC) Kang, H., Thakar, M., Sen, R., Chung, C. H. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.e17046

  View details for Web of Science ID 000358613200949

• Long-term use of valproic acid in US veterans is associated with a reduced risk of smoking-related cases of head and neck cancer. Cancer Kang, H., Gillespie, T. W., Goodman, M., Brodie, S. A., Brandes, M., Ribeiro, M., Ramalingam, S. S., Shin, D. M., Khuri, F. R., Brandes, J. C. 2014; 120 (9): 1394-400

  Abstract

  Epigenetic events play a major role in the carcinogenesis of tobacco-related cancers. The authors conducted a retrospective cohort study to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers of the lung, head and neck, prostate, bladder, and colon.The study was based on the 2002 through 2008 National Veterans Affairs (VA) medical SAS data set linked to the VA Central Cancer Registry. The cohort was defined as subjects aged>40 years who were followed in the VA system for at least 1 year for 1 of 4 diagnoses for which a VPA indication exists (bipolar disorder, posttraumatic stress disorder, migraines, and seizures). Multivariable Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence.VPA use was associated with a significant reduction in the risk of cancers of the head and neck (HR, 0.66; 95% CI, 0.48-0.92). Additional associations were noted with the duration of treatment and median VPA drug levels. No significant differences in cancer incidence were observed for cancers of the lung (HR, 1.00; 95% CI, 0.84-1.19), bladder (HR, 0.86; 95% CI, 0.64-1.15), colon (HR, 0.95; 95% CI, 0.74-1.22), and prostate (HR, 0.96; 95% CI, 0.88-1.12).Use of VPA is associated with a lower risk of developing head and neck cancers.

  View details for DOI 10.1002/cncr.28479

  View details for PubMedID 24664792

  View details for PubMedCentralID PMC4102261

• Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer. Cancer prevention research (Philadelphia, Pa.) Brodie, S. A., Li, G., El-Kommos, A., Kang, H., Ramalingam, S. S., Behera, M., Gandhi, K., Kowalski, J., Sica, G. L., Khuri, F. R., Vertino, P. M., Brandes, J. C. 2014; 7 (3): 351-61

  Abstract

  DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention.

  View details for DOI 10.1158/1940-6207.CAPR-13-0254

  View details for PubMedID 24441677

  View details for PubMedCentralID PMC3955098

• Efficacy and safety of dual calcium channel blockade for the treatment of hypertension: a meta-analysis. American journal of hypertension Alviar, C. L., Devarapally, S., Nadkarni, G. N., Romero, J., Benjo, A. M., Javed, F., Doherty, B., Kang, H., Bangalore, S., Messerli, F. H. 2013; 26 (2): 287-97

  Abstract

  Dual calcium-channel blocker (CCB) with a dihydropyridine (DHP) and a nondihydropyridine (NDHP) has been proposed for hypertension treatment. However, the safety and efficacy of this approach is not well known.A MEDLINE/EMBASE/CENTRAL search for randomized clinical trials published on this topic from 1966 to February 2012 was performed. Efficacy outcomes of decrease in systolic (SBP) and diastolic (DBP) blood pressures from baseline, changes in heart rate (HR), and adverse effects were compared between dual CCB therapy vs. DHP or NDHP. SBP, DBP, and HR were expressed as weighted mean deviation (WMD).A total of 6 studies with 153 patients were included. Dual CCB produced a significantly greater reduction in SBP (21.6±9.2 mmHg) from baseline than DHP (10.3±6.3 mmHg (WMD = 10.9 mmHg, P < 0.0001)) or NDHP (8.9±4.2 mmHg (WMD = 14.1 mmHg, P = 0.002)). Dual CCB therapy reduced DBP from baseline more than either monotherapy (dual CCB = 17.5±10.2 mmHg vs. DHP = 11.6±8.7 mmHg, WMD = 5.5 mmHg, P < 0.001; and NDHP = 10.5±5.6 mmHg, WMD = 5.3 mmHg, P = 0.03). Dual CCB therapy had significantly lower HR compared to DHP (P < 0.001) but was comparable to NDHP (P = 0.12) (Delta change dual CCB = -4.0±3.5 vs. DHP = -2.0±1.5 and NDHP = -6.0±5.0 beats/min). Dual CCB therapy did not increase adverse effects.Dual CCB therapy lowers blood pressure significantly better than CCB monotherapy, without an increase in adverse events. However, given the lack of long-term outcome data on efficacy and safety, dual CCB therapy should be used with restraint, if at all. Large-scale long-term trials are needed to further evaluate such a strategy.

  View details for DOI 10.1093/ajh/hps009

  View details for PubMedID 23382415

• Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development. Endocrinology Kim, W. Y., Kim, M. J., Moon, H., Yuan, P., Kim, J. S., Woo, J. K., Zhang, G., Suh, Y. A., Feng, L., Behrens, C., Van Pelt, C. S., Kang, H., Lee, J. J., Hong, W. K., Wistuba, I. I., Lee, H. Y. 2011; 152 (6): 2164-73

  Abstract

  The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3(+/+)) mice, mice carrying heterozygous (BP3(+/-)) or homozygous (BP3(-/-)) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGF(Tg) mice with 50% of physiological IGFBP-3 (BP3(+/-); IGF(Tg)) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGF(Tg) mice with normal (BP3(+/+;) IGF(Tg)) or homozygous deletion of IGFBP-3 (BP3(-/-); IGF(Tg)). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.

  View details for DOI 10.1210/en.2010-0693

  View details for PubMedID 21447628

  View details for PubMedCentralID PMC3100627

• Chemotherapy in the treatment of metastatic gastric cancer: is there a global standard? Current treatment options in oncology Kang, H., Kauh, J. S. 2011; 12 (1): 96-106

  Abstract

  Gastric cancer remains one of the leading causes of cancer mortality worldwide even though its incidence has been decreasing in recent years. Despite remarkable advancements in chemotherapy, advanced gastric cancer has remained a therapeutic challenge for physicians as well as for patients. While early chemotherapeutic regimens succeeded in showing a modest but definite improvement over best supportive care, no single regimen stood out as superior. Most early trials failed to show survival benefit of combination regimens over single agent fluorouracil, but combination regimens were shown to have better response rates. Based on these data, the Japanese adopted single agent fluorouracil as a reference standard for further investigations, while the rest of the world used a doublet containing fluorouracil and platinum. As more clinical trials were conducted, the Japanese standard evolved into a doublet, while the Western countries adopted triplet combinations. There is no established global standard as yet, but with the introduction of newer targeted agents based on molecular assays and personalized approaches combined with conventional chemotherapy, multiple regimens are likely to emerge as global standards rather than one standard treatment for all.

  View details for DOI 10.1007/s11864-010-0135-z

  View details for PubMedID 21274667

• Green tea consumption and stomach cancer risk: a meta-analysis. Epidemiology and health Kang, H., Rha, S. Y., Oh, K. W., Nam, C. M. 2010; 32: e2010001

  Abstract

  Green tea has been suggested to have a chemopreventive effect against various cancers including stomach cancer. The aim of this study is to elucidate the relationship between green tea consumption and stomach cancer risk by meta-analysis.Eighteen observational studies were identified using MEDLINE, THE COCHRANE LIBRARY, RISS, and a manual search. Summary relative risks/odds ratios (RR/ORs) for the highest versus non/lowest green tea consumption levels were calculated on the basis of fixed and random effect models. Subgroup analyses were used to examine heterogeneity across the studies.The combined results indicate a reduced risk of stomach cancer with intake of green tea (RR/OR=0.86, 95% CI=0.74-1.00). Subgroup analysis with six studies that reported differences between the highest and lowest consumption levels equal to or greater than five cups/day revealed a statistically significant protective effect (RR/OR=0.68, 95% CI=0.53-0.87).Green tea appears to play a protective role against the development of stomach cancer. The results also suggest that a higher level of green tea consumption might be needed for a clear preventive effect to appear. This conclusion, however, should be interpreted with caution because various biases can affect the results of a meta-analysis.

  View details for DOI 10.4178/epih/e2010001

  View details for PubMedID 21191454

  View details for PubMedCentralID PMC2984861

• [The determinants of adolescent smoking by gender and type of school in Korea]. Journal of preventive medicine and public health = Yebang Uihakhoe chi Kim, H., Kim, E. K., Choi, E. S., Kim, Y. J., Lee, H. J., Kim, J. J., Jang, H. S., Shim, K. S., Jeon, S. N., Kang, Y. H., Kang, H., Oh, J., Cho, K. S., Kwon, S. 2006; 39 (5): 379-88

  Abstract

  This study assessed the influences of various factors that are related to youth smoking such as gender, age and type of school, and we wanted to provide supporting data for tailored and effective policy initiatives to reduce adolescent smoking.A self-report survey was conducted on 14,910 teen-age students who were selected based on the nationwide distribution of students in large and small cities and counties, the gender ratio of the students and the ratio of students attending various type of school at 38 middle and high schools in six representative areas of each province. The survey was handled and managed by a health education teacher at each school. Binary and multinomial logistic regression was used in the analyses.Smoking by adolescents was associated with gender, age and even height. Male high school students tended to smoke more than female high school students, but this differences was not significant for middle school students. The older the adolescents were, the more likely that they smoked, except for the female high school students. Height was meaningful for all adolescents, except for the boys at the vocational high schools. Monthly allowance was significant for all adolescents. School factors such as type of school and the students' school performance were also crucial factors. Attending a vocational high school was strongly related to smoking, especially for girls. Students' school performance and the perceived level of stress were strongly associated with smoking, especially for boys. Home factors such as the relationship with parents and conversation time with family members were closely related to smoking behavior. Knowledge about the health hazard of smoking was also found to be strongly related to adolescent smoking.In conclusion, demographic factors, school factors, home surroundings and the perception on the harmfulness of smoking are strongly related to adolescent smoking behavior, but these differ from gender and type of school.

  View details for PubMedID 17076178

• EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity. Clinical cancer research : an official journal of the American Association for Cancer Research Donato, N. J., Perez, M., Kang, H., Siddik, Z. H., Ling, Y. H., Perez-Soler, R. 2000; 6 (1): 193-202

  Abstract

  Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 approximately 80 ng/ml in cDDP sensitive (PT-S) to approximately 2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (approximately 30-fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME-180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.

  View details for PubMedID 10656450