Jacqueline Aredo

All Publications

• Phase II Trial of Regorafenib and Oral Methotrexate in Previously Treated Advanced <i>KRAS</i>-Mutant NSCLC JTO CLINICAL AND RESEARCH REPORTS Aredo, J., Wakelee, H. A., Ramchandran, K. J., Neal, J. W., Diehn, M., Hui, A., Salahudeen, A., Kwong, B., Berry, G. J., Guo, H., Cunanan, K., Vali, S., Pancirer, D., Tsang, V., Hwang, G., Loza, M., Johnson, B., Blanchard, I., Padda, S. K. 2024; 5 (12)

  View details for DOI 10.1016/j.jtocrr.2024.100741

  View details for Web of Science ID 001358515100001

• Consolidation ALK Tyrosine Kinase Inhibitors versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK+ Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Nassar, A. H., Jayakrishnan, R., Feng, J., Shepherd, F., Adib, E., Cheung, J. M., Lin, J. J., Liu, Y., Lin, S. H., Parikh, K., Sridhar, A., Shakya, P., Dilling, T. J., Kaldas, D., Gray, J. E., Lobachov, A., Bar, J., Luders, H., Grohe, C., Gupta, S., Leal, T., Fitzgerald, B., Crowley, F., Fujiwara, Y., Marron, T. U., Wilgucki, M., Reuss, J., Chen, L., Sankar, K., Aredo, J. V., Neal, J. W., Wakelee, H. A., Thummalapalli, R., Yu, H., Whitaker, R., Velazquez, A., Ragavan, M., Cortellini, A., Kwiatkowski, D. J., Naqash, A. R., Goldberg, S. B., Kim, S. Y. 2024

  Abstract

  Patients with advanced ALK-positive non-small cell lung cancer (NSCLC) typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation (cCRT).We conducted a retrospective study using a multi-center study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015-2022 were included. Patients received ALK TKI, durvalumab, or observation after cCRT. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAE) were classified by Common Terminology Criteria for Adverse Events v5.0. Outcomes were assessed by multivariable Cox regression analysis.Sixty-seven patients were included, of whom 39 (58%) were female. Median age was 57 years (IQR: 49-67). Fifteen received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the 3 groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached [NR], 95% CI 22.7-NR) versus durvalumab (11.3 months, 95% CI 8.9-18.5, hazard ratio [HR]=0.12, 95% CI: 0.026-0.5, p-adjusted=0.006) or observation (7.2 months, 95% CI 3.4-10.6, HR=0.04, 95% CI: 0.009-0.2, p-adjusted<0.0001). Durvalumab significantly improved median rwPFS compared to observation (HR=0.37, 95% CI: 0.19-0.71, p-adj = 0.002, p-adjusted=0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared to patients on observation (ALK TKI-observation: p=0.04; durvalumab-observation: p=0.03). TrAE of any grade occurred in 8 (53%) and 11 (37%) patients treated with ALK-TKI and durvalumab, respectively. Grade ≥3 trAEs occurred in 27% (n=4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes seen with either durvalumab or observation. While both ALK TKI therapy and durvalumab offer an extension in OS compared to observation alone, it appears that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.

  View details for DOI 10.1016/j.jtho.2024.09.1379

  View details for PubMedID 39260522

• Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Blakely, C. M., Urisman, A., Gubens, M. A., Mulvey, C. K., Allen, G. M., Shiboski, S. C., Rotow, J. K., Chakrabarti, T., Kerr, D. L., Aredo, J. V., Bacaltos, B., Gee, M., Tan, L., Jones, K. D., Devine, W. P., Doebele, R. C., Aisner, D. L., Patil, T., Schenk, E. L., Bivona, T. G., Riess, J. W., Coleman, M., Kratz, J. R., Jablons, D. M. 2024: JCO2400071

  Abstract

  To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC).This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling.A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%).Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

  View details for DOI 10.1200/JCO.24.00071

  View details for PubMedID 39028931

• Mindfulness in Facilitating Pelvic Floor Botulinum Toxin Injection in Women with Chronic Pelvic Pain. Toxins Aredo, J. V., Tandon, H. K., Panahi, S., Phan, V. T., Ameli, R., Karp, B. I., Stratton, P. 2024; 16 (5)

  Abstract

  Botulinum toxin (BoNT) injection can safely be done as an office-based procedure, but can be painful itself, especially when injecting pelvic floor muscles to treat chronic pelvic pain (CPP). Mindfulness interventions may reduce procedure-associated acute anxiety and pain. We applied mindfulness techniques to increase the tolerability of office-based pelvic floor BoNT injections in women with CPP. Women enrolled in a clinical trial of BoNT for endometriosis-associated CPP were offered a brief, guided mindfulness session before and/or after transvaginal injection. Anxiety, pain, and dysphoria were rated on a 0-10 numerical rating scale (NRS) before and after each mindfulness session. Eight women underwent mindfulness sessions. Five participants had a session before and two after the transvaginal injection. One participant had two sessions: one before and one after separate injections. All six women completing a session prior to injection had at least moderate anxiety, which lessened after the mindfulness session (median NRS change: -3.3/10). All three women reporting injection-associated pain experienced less intense pain following the post-injection session (median NRS change: -3/10). Three women experiencing dysphoria improved after the session (median NRS change: -3/10). A brief, guided mindfulness session may lessen acute pain, anxiety, and dysphoria associated with office-based transvaginal BoNT injection.

  View details for DOI 10.3390/toxins16050216

  View details for PubMedID 38787068

  View details for PubMedCentralID PMC11126137

• Top advances of the year: Perioperative therapy for lung cancer. Cancer Aredo, J. V., Wakelee, H. A. 2024

  Abstract

  Emerging data supporting the rise of perioperative immune checkpoint inhibitors (ICIs) as a standard of care in the treatment of early stage, surgically resectable non-small cell lung cancer (NSCLC) dominated the NSCLC news in 2023. Adjuvant pembrolizumab became the second adjuvant ICI to receive US Food and Drug Administration approval in early 2023 after the 2021 approval of adjuvant atezolizumab and the 2022 approval of neoadjuvant nivolumab with chemotherapy. Subsequently in 2023, multiple phase 3 trials examining perioperative ICIs were positive and demonstrated clinically meaningful outcomes by prolonging event-free survival, improving pathologic complete response rates, and trending toward improved overall survival in most. Perioperative pembrolizumab became the first ICI to attain US Food and Drug Administration approval in this setting through the KEYNOTE-671 trial (ClinicalTrials.gov identifier NCT03425643), which also demonstrated a definitive overall survival benefit in the entire study population. However, questions remain regarding patient selection for either approach and how we can optimize biomarkers to determine who needs adjuvant therapy after surgery.

  View details for DOI 10.1002/cncr.35357

  View details for PubMedID 38717993

• Consolidation Osimertinib versus Durvalumab versus Observation following Concurrent Chemoradiation in Unresectable EGFR-Mutant Non-Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Nassar, A. H., Kim, S. Y., Aredo, J. V., Feng, J., Shepherd, F., Xu, C., Kaldas, D., Gray, J. E., Dilling, T. J., Neal, J. W., Wakelee, H. A., Liu, Y., Lin, S. H., Abuali, T., Amini, A., Nie, Y., Patil, T., Lobachov, A., Bar, J., Fitzgerald, B., Fujiwara, Y., Marron, T. U., Thummalapalli, R., Yu, H., Owen, D. H., Sharp, J., Farid, S., Rocha, P., Arriola, E., D'Aiello, A., Cheng, H., Whitaker, R., Parikh, K., Ashara, Y., Chen, L., Sankar, K., Harris, J. P., Nagasaka, M., Ayanambakkam, A., Manana, A. I., Ragavan, M., Lin, J. J., Piotrowska, Z., Wilgucki, M., Reuss, J., Luders, H., Grohe, C., Espinar, J. B., Feiner, E., Punekar, S. R., Gupta, S., Leal, T., Kwiatkowski, D. J., Mak, R. H., Adib, E., Naqash, A. R., Goldberg, S. B. 2024

  Abstract

  Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. However, the optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.In this multi-institutional international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary endpoint) and overall survival (OS, secondary endpoint). Treatment-related adverse events (trAE) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Multivariable Cox regression analysis was used.Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 received observation alone. Baseline characteristics were similar across the 3 cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (Inter-quartile range [IQR]: NR-NR) and was 5.5 (IQR:2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those in the durvalumab or observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p<0.001 for both comparisons). There was no difference in rwPFS between durvalumab and the observation cohort. No significant difference in OS across the 3 cohorts was detected, possibly due to the limited follow-up. Any grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors (TKIs). Of these, 14 (38%) patients developed trAEs including 5 pneumonitis (14%; 2 [5.4%] grade ≥3) and 5 diarrhea (14%; 1 [2.7%] grade ≥3).This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with significantly longer rwPFS than durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

  View details for DOI 10.1016/j.jtho.2024.01.012

  View details for PubMedID 38278303

• Second Primary Lung Cancer Among Lung Cancer Survivors Who Never Smoked. JAMA network open Choi, E., Su, C. C., Wu, J. T., Aredo, J. V., Neal, J. W., Leung, A. N., Backhus, L. M., Lui, N. S., Le Marchand, L., Stram, D. O., Liang, S. Y., Cheng, I., Wakelee, H. A., Han, S. S. 2023; 6 (11): e2343278

  Abstract

  Lung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC.To estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked.This population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years and had complete smoking data at baseline. These participants were followed up for IPLC and further SPLC development through the Surveillance, Epidemiology, and End Results registry. The data were analyzed from July 1, 2022, to January 31, 2023.Never-smoking vs ever-smoking exposure at MEC enrollment.The study had 2 primary outcomes: (1) 10-year cumulative incidence of IPLC in the entire study cohort and 10-year cumulative incidence of SPLC among patients with IPLC and (2) standardized incidence ratio (SIR) (calculated as the SPLC incidence divided by the IPLC incidence) by smoking history.Among 211 414 MEC participants, 7161 (3.96%) developed IPLC over 4 038 007 person-years, and 163 (2.28%) developed SPLC over 16 470 person-years. Of the participants with IPLC, the mean (SD) age at cohort enrollment was 63.6 (7.7) years, 4031 (56.3%) were male, and 3131 (43.7%) were female. The 10-year cumulative IPLC incidence was 2.40% (95% CI, 2.31%-2.49%) among ever-smokers, which was 7 times higher than never-smokers (0.34%; 95% CI, 0.30%-0.37%). However, the 10-year cumulative SPLC incidence following IPLC was as high among never-smokers (2.84%; 95% CI, 1.50%-4.18%) as ever-smokers (2.72%; 95% CI, 2.24%-3.20%), which led to a substantially higher SIR for never-smokers (14.50; 95% CI, 8.73-22.65) vs ever-smokers (3.50; 95% CI, 2.95-4.12).The findings indicate that SPLC risk among lung cancer survivors who never smoked is as high as among those with IPLC who ever-smoked, highlighting the need to identify risk factors for SPLC among patients who never smoked and to develop a targeted surveillance strategy.

  View details for DOI 10.1001/jamanetworkopen.2023.43278

  View details for PubMedID 37966839

• Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US. JAMA oncology Choi, E., Ding, V. Y., Luo, S. J., Ten Haaf, K., Wu, J. T., Aredo, J. V., Wilkens, L. R., Freedman, N. D., Backhus, L. M., Leung, A. N., Meza, R., Lui, N. S., Haiman, C. A., Park, S. L., Le Marchand, L., Neal, J. W., Cheng, I., Wakelee, H. A., Tammemägi, M. C., Han, S. S. 2023

  Abstract

  The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity.To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria.In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included.The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines.Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer).Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%).The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.

  View details for DOI 10.1001/jamaoncol.2023.4447

  View details for PubMedID 37883107

• Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model. Cancer Choi, E., Luo, S. J., Ding, V. Y., Wu, J. T., Kumar, A. V., Wampfler, J., Tammemägi, M. C., Wilkens, L. R., Aredo, J. V., Backhus, L. M., Neal, J. W., Leung, A. N., Freedman, N. D., Hung, R. J., Amos, C. I., Le Marchand, L., Cheng, I., Wakelee, H. A., Yang, P., Han, S. S. 2023

  Abstract

  Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors.The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines.Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202).In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance.Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.

  View details for DOI 10.1002/cncr.35069

  View details for PubMedID 37877788

• EGFR tyrosine kinase inhibitors (TKIs) versus durvalumab (durva) following concurrent chemoradiation (CRT) in unresectable EGFR-mutant non-small-cell lung cancer (NSCLC) Nassar, A., Adib, E., Feng, J., Aredo, J. V., Parikh, K., Harris, J., Manana, A., Ragavan, M., Lin, J., Piotrowska, Z., Fitzgerald, B., Grohe, C., Sankar, K., Neal, J. W., Wakelee, H. A., Shepherd, F. A., Herbst, R. S., Naqash, A., Goldberg, S. B., Kim, S. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003642

• Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC. Cancer discovery Negrao, M. V., Araujo, H. A., Lamberti, G., Cooper, A. J., Akhave, N. S., Zhou, T., Delasos, L., Hicks, J. K., Aldea, M., Minuti, G., Hines, J., Aredo, J. V., Dennis, M. J., Chakrabarti, T., Scott, S. C., Bironzo, P., Scheffler, M., Christopoulos, P., Stenzinger, A., Riess, J. W., Kim, S. Y., Goldberg, S. B., Li, M., Wang, Q., Qing, Y., Ni, Y., Do, M. T., Lee, R., Ricciuti, B., Alessi, J. V., Wang, J., Resuli, B., Landi, L., Tseng, S. C., Nishino, M., Digumarthy, S. R., Rinsurongkawong, W., Rinsurongkawong, V., Vaporciyan, A. A., Blumenschein, G. R., Zhang, J., Owen, D. H., Blakely, C. M., Mountzios, G., Shu, C. A., Bestvina, C. M., Garassino, M. C., Marrone, K. A., Gray, J. E., Patel, S. P., Cummings, A. L., Wakelee, H. A., Wolf, J., Scagliotti, G. V., Cappuzzo, F., Barlesi, F., Patil, P. D., Drusbosky, L., Gibbons, D. L., Meric-Bernstam, F., Lee, J. J., Heymach, J. V., Hong, D. S., Heist, R. S., Awad, M. M., Skoulidis, F. 2023

  Abstract

  Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

  View details for DOI 10.1158/2159-8290.CD-22-1420

  View details for PubMedID 37068173

• Efficacy of osimertinib in patients with lung cancer positive for uncommon EGFR exon 19 deletion mutations. Clinical cancer research : an official journal of the American Association for Cancer Research Grant, M. J., Aredo, J. V., Starrett, J. H., Stockhammer, P., van Alderwerelt van Rosenburgh, I. K., Wurtz, A., Piper-Valillo, A. J., Piotrowska, Z., Falcon, C., Yu, H. A., Aggarwal, C., Scholes, D., Patil, T., Nguyen, C., Phadke, M., Li, F. Y., Neal, J., Lemmon, M. A., Walther, Z., Politi, K., Goldberg, S. B. 2023

  Abstract

  The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared to the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) harboring L747_A750>P and other uncommon ex19dels is not known.The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multi-center retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L).Ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institution cohort (N=200), E746_A750del was associated with significantly prolonged progression free survival (PFS) with 1L osimertinib vs. L747_A750>P (median 21.3 months [95% CI 17.0-31.7] vs. 11.7 months [10.8-29.4], adjusted hazard ratio [HR] 0.52 [0.28-0.98] p=0.043). Osimertinib efficacy in patients with other uncommon ex19dels varied based on the specific mutation present.The ex19del L747_A750>P is associated with inferior PFS compared to the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del.

  View details for DOI 10.1158/1078-0432.CCR-22-3497

  View details for PubMedID 36913537

• Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study. JTO clinical and research reports Ji, J., Aredo, J. V., Piper-Vallillo, A., Huppert, L., Rotow, J. K., Husain, H., Stewart, S., Cobb, R., Wakelee, H. A., Blakely, C. M., Wong, M. L., Gubens, M. A., Madani, M. H., Digumarthy, S. R., McCoach, C., Piotrowska, Z., Neal, J. W., Riess, J. W. 2023; 4 (3): 100459

  Abstract

  Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion ofexon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n= 18), G719X (28%, n= 14), and exon 20 insertion (14%, n= 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n= 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

  View details for DOI 10.1016/j.jtocrr.2022.100459

  View details for PubMedID 36879929

• Implementation and evaluation of an elective quality improvement curriculum for preclinical students: a prospective controlled study. BMC medical education Aredo, J. V., Ding, J. B., Lai, C. H., Trimble, R., Bromley-Dulfano, R. A., Popat, R. A., Shieh, L. 2023; 23 (1): 66

  Abstract

  BACKGROUND: Quality improvement (QI) is a systematic approach to improving healthcare delivery with applications across all fields of medicine. However, exposure to QI is minimal in early medical education. We evaluated the effectiveness of an elective QI curriculum in teaching preclinical health professional students foundational QI concepts.METHODS: This prospective controlled cohort study was conducted at a single academic institution. The elective QI curriculum consisted of web-based video didactics and exercises, supplemented with in-person classroom discussions. An optional hospital-based QI project was offered. Assessments included pre- and post-intervention surveys evaluating QI skills and beliefs and attitudes, quizzes, and Quality Improvement Knowledge Application Tool-Revised (QIKAT-R) cases. Within-group pre-post and between-group comparisons were performed using descriptive statistics.RESULTS: Overall, 57 preclinical medical or physician assistant students participated under the QI curriculum group (N=27) or control group (N=30). Twenty-three (85%) curriculum students completed a QI project. Mean quiz scores were significantly improved in the curriculum group from pre- to post-assessment (Quiz 1: 2.0, P<0.001; Quiz 2: 1.7, P=0.002), and the mean differences significantly differed from those in the control group (Quiz 1: P<0.001; Quiz 2: P=0.010). QIKAT-R scores also significantly differed among the curriculum group versus controls (P=0.012). In the curriculum group, students had improvements in their confidence with all 10 QI skills assessed, including 8 that were significantly improved from pre- to post-assessment, and 4 with significant between-group differences compared with controls. Students in both groups agreed that their medical education would be incomplete without a QI component and that they are likely to be involved in QI projects throughout their medical training and practice.CONCLUSIONS: The elective QI curriculum was effective in guiding preclinical students to develop their QI knowledge base and skillset. Preclinical students value QI as an integral component of their medical training. Future directions involve evaluating the impact of this curriculum on clinical clerkship performance and across other academic institutions.

  View details for DOI 10.1186/s12909-023-04047-0

  View details for PubMedID 36703204

• Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Hui, A. B., Padda, S. K., Joshi, N. D., Guo, H. H., Chaudhuri, A., Diehn, M., Loo, B. W., Neal, J. W. 2022; 33: 100659

  Abstract

  INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

  View details for DOI 10.1016/j.ctarc.2022.100659

  View details for PubMedID 36427429

• Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients Choi, E., Lam, V. T., Aredo, J. A., Kumar, A. V., Wampfler, J., Wu, J. T., Christiani, D. C., Cheng, I., Amos, C. I., Hung, R. J., Backhus, L. M., Neal, J. W., Wakelee, H. A., Yang, P., Han, S. S. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509507119

• High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience. JTO clinical and research reports Piper-Vallillo, A. J., Rotow, J. K., Aredo, J. V., Shaverdashvili, K., Luo, J., Carlisle, J. W., Husain, H., Muzikansky, A., Heist, R. S., Rangachari, D., Ramalingam, S. S., Wakelee, H. A., Yu, H. A., Sequist, L. V., Bauml, J. M., Neal, J. W., Piotrowska, Z. 2022; 3 (6): 100328

  Abstract

  This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR-mutant NSCLC.Retrospective review identified 105 patients from eight institutions with advanced EGFR-mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg.Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects.Among patients with EGFR-mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression.

  View details for DOI 10.1016/j.jtocrr.2022.100328

  View details for PubMedID 35637759

  View details for PubMedCentralID PMC9142556

• Efficacy of osimertinib in patients with EGFR mutant lung cancer harboring the uncommon exon 19 deletion, L747_A750>P. Grant, M. J., Aredo, J. V., Starrett, J., Wurtz, A., Piotrowska, Z., Piper-Vallillo, A., Yu, H., Falcon, C., Patil, T., Nguyen, C., Aggarwal, C., Scholes, D. G., Li, F., Phadke, M., Neal, J. W., Walther, Z., Politi, K. A., Goldberg, S. B. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304358

• Racial and Ethnic Disparities in Lung Cancer Screening by the 2021 USPSTF Guidelines Versus Risk-Based Criteria: The Multiethnic Cohort Study. JNCI cancer spectrum Aredo, J. V., Choi, E., Ding, V. Y., Tammemagi, M. C., Ten Haaf, K., Luo, S. J., Freedman, N. D., Wilkens, L. R., Le Marchand, L., Wakelee, H. A., Meza, R., Park, S. L., Cheng, I., Han, S. S. 2022; 6 (3)

  Abstract

  BACKGROUND: In 2021, the US Preventive Services Task Force (USPSTF) revised its lung cancer screening guidelines to expand screening eligibility. We evaluated screening sensitivities and racial and ethnic disparities under the 2021 USPSTF criteria vs alternative risk-based criteria in a racially and ethnically diverse population.METHODS: In the Multiethnic Cohort, we evaluated the proportion of ever-smoking lung cancer cases eligible for screening (ie, screening sensitivity) under the 2021 USPSTF criteria and under risk-based criteria through the PLCOm2012 model (6-year risk≥1.51%). We also calculated the screening disparity (ie, absolute sensitivity difference) for each of 4 racial or ethnic groups (African American, Japanese American, Latino, Native Hawaiian) vs White cases.RESULTS: Among 5900 lung cancer cases, 43.3% were screen eligible under the 2021 USPSTF criteria. Screening sensitivities varied by race and ethnicity, with Native Hawaiian (56.7%) and White (49.6%) cases attaining the highest sensitivities and Latino (37.3%), African American (38.4%), and Japanese American (40.0%) cases attaining the lowest. Latino cases had the greatest screening disparity vs White cases at 12.4%, followed by African American (11.2%) and Japanese American (9.6%) cases. Under risk-based screening, the overall screening sensitivity increased to 75.7%, and all racial and ethnic groups had increased sensitivities (54.5%-91.9%). Whereas the screening disparity decreased to 5.1% for African American cases, it increased to 28.6% for Latino cases and 12.8% for Japanese American cases.CONCLUSIONS: In the Multiethnic Cohort, racial and ethnic disparities decreased but persisted under the 2021 USPSTF lung cancer screening guidelines. Risk-based screening through PLCOm2012 may increase screening sensitivities and help to reduce disparities in some, but not all, racial and ethnic groups. Further optimization of risk-based screening strategies across diverse populations is needed.

  View details for DOI 10.1093/jncics/pkac033

  View details for PubMedID 35642317

• Afatinib After Progression on Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Neal, J. W., Padda, S. K. 1800; 30: 100497

  Abstract

  INTRODUCTION: After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown.METHODS: We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib.RESULTS: After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017).CONCLUSION: Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.

  View details for DOI 10.1016/j.ctarc.2021.100497

  View details for PubMedID 34920242

• Consolidation Durvalumab Should Not Be Administered to Patients With Stage III EGFR-Mutant NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Hellyer, J. A., Neal, J. W., Wakelee, H. A. 2021; 16 (12): 1994-1998

  View details for DOI 10.1016/j.jtho.2021.07.033

  View details for PubMedID 34809803

• Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer. JCO precision oncology Padda, S. K., Aredo, J. V., Vali, S., Singh, N. K., Vasista, S. M., Kumar, A., Neal, J. W., Abbasi, T., Wakelee, H. A. 2021; 5: 153-162

  Abstract

  KRAS-mutated (KRASMUT) non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among KRASMUT NSCLC molecular subgroups.In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with KRASMUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers).Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: KRASMUT/TP53MUT, KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, KRASMUT/KEAP1MUT, KRASMUT/STK11MUT/KEAP1MUT, KRASMUT/PIK3CAMUT, KRAS MUT/ATMMUT, and KRASMUT without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the KRASMUT/TP53MUT, KRASMUT/PIK3CAMUT, and KRASMUT alone subgroups and resistance in the KEAP1MUT containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, and KRASMUT/ATMMUT subgroups. In an exploratory clinical cohort of 34 patients with advanced KRASMUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival (r = 0.80, P < .001).CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRASMUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.

  View details for DOI 10.1200/PO.20.00172

  View details for PubMedID 34994595

• Smoking Cessation After Lung Cancer Diagnosis and the Risk of Second Primary Lung Cancer: The Multiethnic Cohort Study. JNCI cancer spectrum Luo, S. J., Choi, E., Aredo, J. V., Wilkens, L. R., Tammemagi, M. C., Le Marchand, L., Cheng, I., Wakelee, H. A., Han, S. S. 2021; 5 (5): pkab076

  Abstract

  Background: Smoking cessation reduces lung cancer mortality. However, little is known about whether diagnosis of lung cancer impacts changes in smoking behaviors. Furthermore, the effects of smoking cessation on the risk of second primary lung cancer (SPLC) have not been established yet. This study aims to examine smoking behavior changes after initial primary lung cancer (IPLC) diagnosis and estimate the effect of smoking cessation on SPLC risk following IPLC diagnosis.Methods: The study cohort consisted of 986 participants in the Multiethnic Cohort Study who were free of lung cancer and active smokers at baseline (1993-1996), provided 10-year follow-up smoking data (2003-2008), and were diagnosed with IPLC in 1993-2017. The primary outcome was a change in smoking status from "current" at baseline to "former" at 10-year follow-up (ie, smoking cessation), analyzed using logistic regression. The second outcome was SPLC incidence after smoking cessation, estimated using cause-specific Cox regression. All statistical tests were 2-sided.Results: Among 986 current smokers at baseline, 51.1% reported smoking cessation at 10-year follow-up. The smoking cessation rate was statistically significantly higher (80.6%) for those diagnosed with IPLC between baseline and 10-year follow-up vs those without IPLC diagnosis (45.4%) during the 10-year period (adjusted odds ratio = 5.12, 95% confidence interval [CI] = 3.38 to 7.98; P<.001). Incidence of SPLC was statistically significantly lower among the 504 participants who reported smoking cessation at follow-up compared with those without smoking cessation (adjusted hazard ratio = 0.31, 95% CI = 0.14 to 0.67; P=.003).Conclusion: Lung cancer diagnosis has a statistically significant impact on smoking cessation. Quitting smoking after IPLC diagnosis may reduce the risk of developing a subsequent malignancy in the lungs.

  View details for DOI 10.1093/jncics/pkab076

  View details for PubMedID 34611582

• RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF BOTULINUM TOXIN FOR ENDOMETRIOSIS-RELATED CHRONIC PELVIC PAIN. Stratton, P., Tandon, H. K., Vy Phan, Aredo, J. V., Sinaii, N., Shah, J., Karp, B. I. ELSEVIER SCIENCE INC. 2021: E52

  View details for Web of Science ID 000699951500121

• A Moving Target: Integration of Smoking Cessation Into Screening for Second Primary Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Wakelee, H. A., Han, S. S. 2021; 16 (8): e59-e60

  View details for DOI 10.1016/j.jtho.2021.05.008

  View details for PubMedID 34304856

• EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy. Clinical lung cancer Shah, M. P., Aredo, J. V., Padda, S. K., Ramchandran, K. J., Wakelee, H. A., Das, M. S., Neal, J. W. 2021

  Abstract

  INTRODUCTION: In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described.STUDY DESIGN: A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method.RESULTS: Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N=17, 94%) and second-line settings (N=1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR).CONCLUSIONS: The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.

  View details for DOI 10.1016/j.cllc.2021.07.001

  View details for PubMedID 34391686

• Development and Validation of a Risk Prediction Tool for Second Primary Lung Cancer. Journal of the National Cancer Institute Choi, E., Sanyal, N., Ding, V. Y., Gardner, R. M., Aredo, J. V., Lee, J., Wu, J. T., Hickey, T. P., Barrett, B., Riley, T. L., Wilkens, L. R., Leung, A. N., Le Marchand, L., Tammemagi, M. C., Hung, R. J., Amos, C. I., Freedman, N. D., Cheng, I., Wakelee, H. A., Han, S. S. 2021

  Abstract

  BACKGROUND: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. While mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction tool available for clinical use to identify high-risk LC survivors for SPLC.METHODS: Using data from 6,325 ever-smokers in the Multiethnic Cohort (MEC) diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using two population-based data, PLCO and NLST, that included 2,963 and 2,844 IPLC (101 and 93 SPLC cases), respectively.RESULTS: Over 14,063 person-years, 145 (2.3%) developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4-3.3) and discrimination (AUC = 81.9%, 95% CI=78.2%-85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th versus 1st quartile (9.5% versus 0.2%; P<.001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit versus hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI=74.6%-82.9%) and 72.7% (95% CI=67.7%-77.7%), respectively.CONCLUSIONS: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction tool can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision-making for SPLC surveillance and screening.

  View details for DOI 10.1093/jnci/djab138

  View details for PubMedID 34255071

• Randomized, Placebo-Controlled Trial of Botulinum Toxin for Endometriosis-Associated Chronic Pelvic Pain: A Longitudinal Assessment. Stratton, P., Tandon, H. K., Phan, V., Aredo, J. V., Sinaii, N., Shah, J. P., Karp, B. I. SPRINGER HEIDELBERG. 2021: 54A-55A

  View details for Web of Science ID 000675441000017

• The Survival Impact of Second Primary Lung Cancer in Patients with Lung Cancer Choi, E., Luo, S., Aredo, J., Wilkens, L., Leung, A., Le Marchand, L., Cheng, I., Wakelee, H., Han, S. AMER THORACIC SOC. 2021

  View details for Web of Science ID 000685468904797

• Metabolomic profiling for second primary lung cancer: A pilot case-control study. Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Purington, N., Su, L., Luo, S. J., Diao, N., Christiani, D. C., Wakelee, H. A., Han, S. S. 2021; 155: 61–67

  Abstract

  OBJECTIVES: Lung cancer survivors have a high risk of developing a second primary lung cancer (SPLC). While national screening guidelines have been established for initial primary lung cancer (IPLC), no consensus guidelines exist for SPLC. Furthermore, the factors that contribute to SPLC risk have not been established. This study examines the potential for using serum metabolomics to identify metabolite biomarkers that differ between SPLC cases and IPLC controls.MATERIAL AND METHODS: In this pilot case-control study, we applied an untargeted metabolomics approach based on ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) to serum samples of 82 SPLC cases and 82 frequency matched IPLC controls enrolled in the Boston Lung Cancer Study. Random forest and unconditional logistic regression models identified metabolites associated with SPLC. Candidate metabolites were integrated into a SPLC risk prediction model and the model performance was evaluated through a risk stratification approach.RESULTS: The untargeted analysis detected 1008 named and 316 unnamed metabolites among all study participants. Metabolites that were significantly associated with SPLC (False Discovery Rate q-value < 0.2) included 5-methylthioadenosine (odds ratio [OR] = 2.04, 95 % confidence interval [CI] 1.39-3.01; P = 2.8 * 10-4) and phenylacetylglutamine (OR = 2.65, 95 % CI 1.56-4.51; P = 3.2 * 10-4), each exhibiting approximately 1.5-fold increased levels among SPLC cases versus IPLC controls. In stratifying the study participants across quartiles of estimated SPLC risk, the risk prediction model identified a significantly higher proportion of SPLC cases in the fourth compared to the first quartile (68.3 % versus 39.0 %; P = 0.044).CONCLUSION: SPLC cases may have distinct metabolomic profiles compared to those in IPLC patients without SPLC. A risk stratification approach integrating metabolomics may be useful for distinguishing patients based on SPLC risk. Prospective validation studies are needed to further evaluate the potential for leveraging metabolomics in SPLC surveillance and screening.

  View details for DOI 10.1016/j.lungcan.2021.03.007

  View details for PubMedID 33743383

• Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer JCO PRECISION ONCOLOGY Padda, S. K., Aredo, J., Vali, S., Singh, N. K., Vasista, S. M., Kumar, A., Neal, J. W., Abbasi, T., Wakelee, H. A. 2021; 5: 153–62

  View details for DOI 10.1200/PO.20.00172

  View details for Web of Science ID 000636553300004

• Tobacco Smoking and Risk of Second Primary Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Luo, S. J., Gardner, R. M., Sanyal, N. n., Choi, E. n., Hickey, T. P., Riley, T. L., Huang, W. Y., Kurian, A. W., Leung, A. N., Wilkens, L. R., Robbins, H. A., Riboli, E. n., Kaaks, R. n., Tjønneland, A. n., Vermeulen, R. C., Panico, S. n., Le Marchand, L. n., Amos, C. I., Hung, R. J., Freedman, N. D., Johansson, M. n., Cheng, I. n., Wakelee, H. A., Han, S. S. 2021

  Abstract

  Lung cancer survivors are at high risk of a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined risk factors for SPLC across multiple epidemiologic cohorts and assessed the impact of smoking cessation on reducing SPLC risk.We analyzed data from 7,059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N=3,423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (EPIC, N=4,731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.Overall, 163 (2.3%) MEC cases developed a SPLC. Smoking pack-years (HR 1.18 per 10 pack-years; P<0.001) and smoking intensity (HR 1.30 per 10 cigarettes per day (CPD); P<0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's (USPSTF) screening criteria at IPLC diagnosis also had an increased SPLC risk (HR 1.92; P<0.001). Validation studies with PLCO and EPIC showed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (Pmeta<0.001), 1.25 per 10 CPD (Pmeta<0.001), and 1.99 (Pmeta<0.001) for meeting the USPSTF criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR 0.17; P<0.001).Tobacco smoking is a risk factor for SPLC. Smoking cessation after IPLC diagnosis may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.

  View details for DOI 10.1016/j.jtho.2021.02.024

  View details for PubMedID 33722709

• The Survival Impact of Second Primary Lung Cancer in Patients with Lung Cancer. Journal of the National Cancer Institute Choi, E., Luo, S. J., Aredo, J. V., Backhus, L. M., Wilkens, L. R., Su, C. C., Neal, J. W., Le Marchand, L., Cheng, I., Wakelee, H. A., Han, S. S. 2021

  Abstract

  Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis.We analyzed data from 138,969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988-2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (N = 1,540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided.A total of 12,115 (8.7%) patients developed SPLC in SEER over 700,421 person-years of follow up. Compared to patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio [HR]=2.12, 95% confidence interval [CI] = 2.06-2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early-stage IPLC vs. advanced-stage IPLC (HR = 2.14 [95% CI = 2.08-2.20] vs. 1.43 [95% CI = 1.21-1.70], respectively; Pinteraction <0.001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs. those who formerly or never smoked (HR = 2.31 [95% CI = 1.48-3.61] vs. 1.41 [95% CI = 0.98-2.03], respectively; Pinteraction=0.04).SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early-stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.

  View details for DOI 10.1093/jnci/djab224

  View details for PubMedID 34893871

• Brief Report: Role of Consolidation Durvalumab in patients with EGFR and HER2 Mutant Unresectable Stage III NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Hellyer, J. A., Aredo, J. V., Das, M. n., Ramchandran, K. n., Padda, S. K., Neal, J. W., Wakelee, H. A. 2021

  Abstract

  Despite the recent advance of consolidation durvalumab in the treatment of unresectable stage III non-small cell lung cancer (NSCLC), not every patient benefits from durvalumab and predictive markers of response have been difficult to identify.We performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab following definitive chemoradiation from January 2018 to March 2020.Thirty-six patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Fourteen of these patients had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be non-smokers; otherwise the two groups were similar in age, sex, PD-L1 expression and type of prior chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease free survival compared to the EGFR/ERBB2 wildtype cohort (7.5 months vs NR, p= 0.04).Consolidation durvalumab appears to be less efficacious in patients with ERBB2/EGFR mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.

  View details for DOI 10.1016/j.jtho.2020.12.020

  View details for PubMedID 33539970

• Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Mambetsariev, I. n., Hellyer, J. A., Amini, A. n., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Naidoo, J. n., Abuali, T. n., Salgia, R. n., Loo, B. W., Diehn, M. n., Han, S. S., Wakelee, H. A. 2021

  Abstract

  In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.

  View details for DOI 10.1016/j.jtho.2021.01.1628

  View details for PubMedID 33588109

• Is smoking a risk factor for second primary lung cancer Aredo, J., Luo, S. J., Gardner, R., Hickey, T. P., Riley, T. L., Wilkens, L. R., Le Marchand, L., Amos, C., Hung, R. J., Johansson, M., Cheng, I., Wakelee, H. A., Han, S. S. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-2298

  View details for Web of Science ID 000590059304293

• Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study. Ji, J., Aredo, J., Piper-Vallillo, A., Huppert, L., Rotow, J. K., Husain, H., Stewart, S. L., Cobb, R., Wakelee, H. A., Blakely, C., Wong, M. L., Gubens, M. A., Chen, J., Oxnard, G. R., McCoach, C., Piotrowska, Z., Neal, J. W., Riess, J. W. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303469

• High-dose osimertinib for CNS progression in EGFR plus non-small cell lung cancer (NSCLC): A multi-institutional experience. Piper-Vallillo, A., Rotow, J. K., Aredo, J., Shaverdashvili, K., Luo, J., Carlisle, J. W., Husain, H., Muzikansky, A., Heist, R., Rangachari, D., Ramalingam, S. S., Wakelee, H. A., Yu, H., Sequist, L., Bauml, J., Neal, J. W., Piotrowska, Z. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303485

• Targeted Treatment of Multiple Primary Lung Cancers Harboring Distinct EGFR or RET Alterations: A Case Report. Clinical lung cancer Aredo, J. V., Diehn, M. n., Berry, G. J., Wakelee, H. A. 2020

  View details for DOI 10.1016/j.cllc.2020.12.005

  View details for PubMedID 33451914

• Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: A cross-sectional study. European journal of pain (London, England) Phan, V. T., Stratton, P. n., Tandon, H. K., Sinaii, N. n., Aredo, J. V., Karp, B. I., Merideth, M. A., Shah, J. P. 2020

  Abstract

  Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment.Characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain.Cross-sectional study of 30 women prior to participation in a clinical trial. Evaluation included pain-focused abdominopelvic gynaecologic examination with the identification of pelvic floor muscle spasm. Neuro-musculoskeletal examination assessed paraspinal allodynia and hyperalgesia bilaterally and myofascial trigger points in 13 paired muscles. Pressure-pain thresholds were measured over interspinous ligaments and trigger points. Women completed the body territories element of the Body Pain Index.All women had a pelvic floor muscle spasm that they self-identified as a major focus of pain. Twenty of 30 women described their pelvic pain as focal. However, all demonstrated widespread myofascial dysfunction with low pressure-pain thresholds and trigger points in over two-thirds of 26 assessed regions. Widespread spinal segmental sensitisation was present in 17/30, thoracic in 21/30 and lumbosacral/pelvic in 18/30. Cervical sensitisation manifested as low pressure-pain thresholds with 23/30 also reporting recurrent, severe headaches and 21/30 experiencing orofacial pain. Those reporting diffuse pelvic pain were more likely to have widespread (p = .024) and lumbosacral/pelvic (p = .036) sensitisation and report over 10 painful body areas (p = .009).Women with endometriosis-associated chronic pelvic pain often have myofascial dysfunction and sensitisation beyond the pelvic region that may be initiated or maintained by on-going pelvic floor spasm. These myofascial and nervous system manifestations warrant consideration when managing pain in this population. Clinicaltrials.gov identifier: NCT01553201.Women with endometriosis often have pelvic pain persisting after surgery despite hormonal therapies and these women have regional pelvic sensitisation and myofascial dysfunction. Pelvic floor muscle spasm is a major pain focus in this population. Sensitisation and myofascial dysfunction are widespread, beyond the pelvic region. On-going pelvic floor spasm may initiate or maintain sensitisation. Myofascial/sensitisation manifestations warrant consideration when managing pain in this population.

  View details for DOI 10.1002/ejp.1713

  View details for PubMedID 33326662

• Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study WORLD NEUROSURGERY Huang, Y., Chow, K. H., Aredo, J. V., Padda, S. K., Han, S. S., Kakusa, B. W., Gephart, M. 2019; 125: E487–E496

  View details for DOI 10.1016/j.wneu.2019.01.112

  View details for Web of Science ID 000466491700065

• EGFR mutation status confers survival benefit in non-small cell lung cancer patients undergoing surgical resection of brain metastases: a retrospective cohort study. World neurosurgery Huang, Y., Chow, K. K., Aredo, J. V., Padda, S. K., Han, S. S., Kakusa, B. W., Gephart, M. H. 2019

  Abstract

  BACKGROUND: Few prognostic markers are available for NSCLC patients undergoing neurosurgical resection of symptomatic brain metastases.OBJECTIVE: We investigated whether tumor mutation status (EGFR, KRAS, ALK, ROS1, BRAF) and treatment history were associated with survival after neurosurgery.METHODS: We reviewed the electronic health records of 104 NSCLC patients with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018. We used multivariate Cox proportional hazards regression models to evaluate the association between overall survival (OS) after neurosurgery and clinico-pathological factors including mutation status.RESULTS: Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval: 18-34). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR] 0.214 p = 0.029), independent of tyrosine kinase inhibitor (TKI) use. Presence of KRAS, ALK, ROS1 and BRAF alterations were not associated with survival (all p > 0.05). Conversely, older age (HR: 1.039; p=0.029), a history of multiple brain irradiation procedures (HR 9.197; p < 0.001) and presence of extracranial metastasis (HR 2.556; p = 0.016) resulted in increased risk of mortality.CONCLUSION: Patients requiring surgical resection of an EGFR mutated NSCLC brain metastasis had an associated improved survival compared to patients without this mutation, independent of TKI use. Decreased survival was associated with older age, multiple prior brain radiation therapies and extracranial metastasis.

  View details for PubMedID 30710723

• Response to comment on "Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes". Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.lungcan.2019.08.020

  View details for PubMedID 31492438

• Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019; 133: 144–50

  Abstract

  Concurrent genetic mutations are prevalent in KRAS-mutant non-small cell lung cancer (NSCLC) and may differentially influence patient outcomes. We sought to characterize the effects of KRAS mutation subtypes and concurrent pathogenic mutations on overall survival (OS) and PD-L1 expression, a predictive biomarker for anti-PD-1/PD-L1 immunotherapy.We retrospectively identified patients with KRAS-mutant NSCLC at a single institution and abstracted clinical, molecular, and pathologic data from electronic health records. Cox regression and multinomial logistic regression were used to determine how KRAS mutation subtypes and concurrent pathogenic mutations are associated with OS and tumor PD-L1 expression, respectively.A total 186 patients were included. Common KRAS mutation subtypes included G12C (35%) and G12D (17%). Concurrent pathogenic mutations were identified in TP53 (39%), STK11 (12%), KEAP1 (8%), and PIK3CA (4%). On multivariable analysis, KRAS G12D mutations were significantly associated with poor OS (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.15-5.16; P = 0.021), as were STK11 co-mutations (HR 2.95, 95% CI 1.27-6.88; P = 0.012). Compared to no (<1%) PD-L1 expression, KRAS G12C mutations were significantly associated with positive yet low (1-49%) PD-L1 expression (odds ratio [OR] 4.94, 95% CI 1.07-22.85; P = 0.041), and TP53 co-mutations with high (≥50%) PD-L1 expression (OR 6.36, 95% CI 1.84-22.02; P = 0.004).KRAS G12D and STK11 mutations confer poor prognoses for patients with KRAS-mutant NSCLC. KRAS G12C and TP53 mutations correlate with a biomarker that predicts benefit from immunotherapy. Concurrent mutations may represent distinct subsets of KRAS-mutant NSCLC; further investigation is warranted to elucidate their role in guiding treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.015

  View details for PubMedID 31200821

• Management of KRAS-Mutant Non-Small Cell Lung Cancer in the Era of Precision Medicine CURRENT TREATMENT OPTIONS IN ONCOLOGY Aredo, J. V., Padda, S. K. 2018; 19 (8)

  View details for DOI 10.1007/s11864-018-0557-6

  View details for Web of Science ID 000436782000002

• Management of KRAS-Mutant Non-Small Cell Lung Cancer in the Era of Precision Medicine. Current treatment options in oncology Aredo, J. V., Padda, S. K. 2018; 19 (8): 43

  Abstract

  OPINION STATEMENT: The discovery of genomic alterations that drive the development and progression of non-small cell lung cancer (NSCLC) has transformed how we treat metastatic disease. However, the promise of precision medicine remains elusive for the most commonly mutated oncogene in NSCLC, KRAS. This is perhaps due to the substantial heterogeneity within the broader genomic context of KRAS-mutant NSCLC. At this time, approaches for treating metastatic KRAS-mutant NSCLC mirror those for treating NSCLC that lacks a known driver mutation, including standard chemotherapeutic and immunotherapeutic approaches. Ongoing research aims to define further subgroups of KRAS-mutant NSCLC based on mutation subtype and co-occurring mutations. These efforts offer the potential to optimize standard-of-care regimens within these emerging subgroups and harness innovative strategies to realize precision medicine in this setting.

  View details for PubMedID 29951788

• Prognostic impact of KRAS mutation subtype and concurrent genetic mutations in non-small cell lung cancer. Aredo, J., Padda, S., Kunder, C., Han, S. S., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.e21023

  View details for Web of Science ID 000442916006490

• Beneficial Effects of Dry Needling for Treatment of Chronic Myofascial Pain Persist for 6 Weeks After Treatment Completion. PM & R : the journal of injury, function, and rehabilitation Gerber, L. H., Sikdar, S., Aredo, J. V., Armstrong, K., Rosenberger, W. F., Shao, H., Shah, J. P. 2017; 9 (2): 105-112

  Abstract

  Dry needling is an effective treatment for reducing pain associated with active myofascial trigger points (a-MTrPs) in the short term. The duration of the benefits of this treatment have not been fully assessed.To determine whether the benefits of dry needling (DN) of a-MTrPs are sustained 6 weeks posttreatment.Follow-up of a prospective study.University.A total of 45 patients (13 male and 32 female) with cervical pain >3 months and a-MTrPs in the upper trapezius who completed 3 DN treatments and who were evaluated 6 weeks posttreatment.None.Primary outcomes were changes from baseline to follow-up in scores for the verbal analogue scale (VAS), Brief Pain Inventory (BPI), and MTrP status. MTrPs were rated as active (spontaneously painful), latent (painful only on compression), and nonpalpable nodule. Responders were patients whose MTrP status changed from active to latent or nonpalpable nodule (resolved). Secondary outcomes were pain pressure threshold (PPT), Profile of Mood States, Oswestry Disability Index (ODI), MOS 36-Item Short-Form Health Survey (SF-36), and cervical range of motion.Pain measures remained significantly improved 6 weeks posttreatment (P < .003), as did the SF-36 physical functioning score (0.01) and ODI (P = .002). Side bending and PPT for subjects with unilateral MTrPs had sustained improvement (P = .002). The number of subjects with sustained MTrP response at 6 weeks was significant (P < .001). Comparing responders to nonresponders, the changes in VAS and BPI were statistically significant (P = .006, P = .03) but the change in PPT was not. Patients with higher baseline VAS scores had a higher risk of not responding to DN; those with a greater drop in VAS score from baseline had a higher probability of sustained response. A 1-unit decrease in VAS at baseline resulted in a 6.3-fold increase in the odds of being a responder versus a nonresponder (P = .008).In this study, there was sustained reduction of pain scores after completion of DN, which is more likely with a greater drop in VAS score. Patients with higher baseline VAS scores are less likely to respond to DN. Early intervention toward significant pain reduction is likely to be associated with sustained clinical response.IV.

  View details for DOI 10.1016/j.pmrj.2016.06.006

  View details for PubMedID 27297448

  View details for PubMedCentralID PMC5149452

• Relating Chronic Pelvic Pain and Endometriosis to Signs of Sensitization and Myofascial Pain and Dysfunction. Seminars in reproductive medicine Aredo, J. V., Heyrana, K. J., Karp, B. I., Shah, J. P., Stratton, P. 2017; 35 (1): 88-97

  Abstract

  Chronic pelvic pain is a frustrating symptom for patients with endometriosis and is frequently refractory to hormonal and surgical management. While these therapies target ectopic endometrial lesions, they do not directly address pain due to central sensitization of the nervous system and myofascial dysfunction, which can continue to generate pain from myofascial trigger points even after traditional treatments are optimized. This article provides a background for understanding how endometriosis facilitates remodeling of neural networks, contributing to sensitization and generation of myofascial trigger points. A framework for evaluating such sensitization and myofascial trigger points in a clinical setting is presented. Treatments that specifically address myofascial pain secondary to spontaneously painful myofascial trigger points and their putative mechanisms of action are also reviewed, including physical therapy, dry needling, anesthetic injections, and botulinum toxin injections.

  View details for DOI 10.1055/s-0036-1597123

  View details for PubMedID 28049214

  View details for PubMedCentralID PMC5585080

• Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective. PM & R : the journal of injury, function, and rehabilitation Shah, J. P., Thaker, N., Heimur, J., Aredo, J. V., Sikdar, S., Gerber, L. 2015; 7 (7): 746-761

  Abstract

  The intent of this article is to discuss the evolving role of the myofascial trigger point (MTrP) in myofascial pain syndrome (MPS) from both a historical and scientific perspective. MTrPs are hard, discrete, palpable nodules in a taut band of skeletal muscle that may be spontaneously painful (i.e., active) or painful only on compression (i.e., latent). MPS is a term used to describe a pain condition that can be acute or, more commonly, chronic and involves the muscle and its surrounding connective tissue (e.g. fascia). According to Travell and Simons, MTrPs are central to the syndrome-but are they necessary? Although the clinical study of muscle pain and MTrPs has proliferated over the past two centuries, the scientific literature often seems disjointed and confusing. Unfortunately, much of the terminology, theories, concepts, and diagnostic criteria are inconsistent, incomplete, or controversial. To address these deficiencies, investigators have recently applied clinical, imaging (of skeletal muscle and brain), and biochemical analyses to systematically and objectively study the MTrP and its role in MPS. Data suggest that the soft tissue milieu around the MTrP, neurogenic inflammation, sensitization, and limbic system dysfunction may all play a role in the initiation, amplification, and perpetuation of MPS. The authors chronicle the advances that have led to the current understanding of MTrP pathophysiology and its relationship to MPS, and review the contributions of clinicians and researchers who have influenced and expanded our contemporary level of clinical knowledge and practice.

  View details for DOI 10.1016/j.pmrj.2015.01.024

  View details for PubMedID 25724849

  View details for PubMedCentralID PMC4508225