Gregory M. Heestand, MD

All Publications

• Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2. Current problems in cancer Dao, V., Heestand, G. 2023; 47 (4): 100960

  Abstract

  The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.

  View details for DOI 10.1016/j.currproblcancer.2023.100960

  View details for PubMedID 37285606

• Single-molecule methylation profiles of cell-free DNA in cancer with nanopore sequencing. Genome medicine Lau, B. T., Almeda, A., Schauer, M., McNamara, M., Bai, X., Meng, Q., Partha, M., Grimes, S. M., Lee, H., Heestand, G. M., Ji, H. P. 2023; 15 (1): 33

  Abstract

  Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to 200 million reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.

  View details for DOI 10.1186/s13073-023-01178-3

  View details for PubMedID 37138315

  View details for PubMedCentralID 1283450

• Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer. Journal of patient-reported outcomes Generalova, O., Roy, M., Hall, E., Shah, S. A., Cunanan, K., Fardeen, T., Velazquez, B., Chu, G., Bruzzone, B., Cabot, A., Fisher, G. A., Srinivas, S., Fan, A. C., Haraldsdottir, S., Wakelee, H. A., Neal, J. W., Padda, S. K., Johnson, T., Heestand, G. M., Hsieh, R. W., Ramchandran, K. 2021; 5 (1): 91

  Abstract

  BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

  View details for DOI 10.1186/s41687-021-00358-2

  View details for PubMedID 34524558

• Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR. The Journal of molecular diagnostics : JMD Wood-Bouwens, C. M., Haslem, D. n., Moulton, B. n., Almeda, A. F., Lee, H. n., Heestand, G. M., Nadauld, L. D., Ji, H. P. 2019

  Abstract

  As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, we developed and a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA). This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3,000 genome equivalents. The objective of this study was to validate the use of personalized dPCR mutation assays to monitor patients with metastatic cancer. We compared our digital PCR results to serum biomarkers indicating disease progression or response. Patients had metastatic colorectal, biliary, breast, lung and melanoma cancers. Mutations occurred in essential cancer drivers such as BRAF, KRAS and PIK3CA. We monitored patients over multiple cycles of treatment up to a year. All patients had detectable ctDNA mutations. Our results correlated with serum markers of metastatic cancer burden including CEA, CA-19-9, and CA-15-3, and qualitatively corresponding to imaging studies. We observed corresponding trends among these patients receiving active treatment with chemotherapy or targeted agents. For example, in one patient under active treatment, we detected increasing quantities of ctDNA molecules over time, indicating recurrence of tumor. Our study demonstrates that personalized digital PCR enables longitudinal monitoring of patients with metastatic cancer and maybe a useful indicator for treatment response.

  View details for DOI 10.1016/j.jmoldx.2019.10.008

  View details for PubMedID 31837432

• The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA. Molecular cancer therapeutics Riviere, P. n., Fanta, P. T., Ikeda, S. n., Baumgartner, J. n., Heestand, G. M., Kurzrock, R. n. 2018; 17 (1): 297–305

  Abstract

  We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N = 55; 26%), appendiceal adenocarcinoma (N = 46; 22%), hepatocellular carcinoma (N = 31; 15%), and pancreatic ductal adenocarcinoma (N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297-305. ©2017 AACR.

  View details for DOI 10.1158/1535-7163.MCT-17-0360

  View details for PubMedID 29133621

  View details for PubMedCentralID PMC5752585

• Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients. European journal of cancer (Oxford, England : 1990) Heestand, G. M., Schwaederle, M. n., Gatalica, Z. n., Arguello, D. n., Kurzrock, R. n. 2017; 83: 80–87

  Abstract

  Topoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well.We analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well.Overexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer.Our data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co-alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation.

  View details for DOI 10.1016/j.ejca.2017.06.019

  View details for PubMedID 28728050

• FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. Journal of translational medicine Shi, E., Chmielecki, J., Tang, C. M., Wang, K., Heinrich, M. C., Kang, G., Corless, C. L., Hong, D., Fero, K. E., Murphy, J. D., Fanta, P. T., Ali, S. M., De Siena, M., Burgoyne, A. M., Movva, S., Madlensky, L., Heestand, G. M., Trent, J. C., Kurzrock, R., Morosini, D., Ross, J. S., Harismendy, O., Sicklick, J. K. 2016; 14 (1): 339

  Abstract

  About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions.Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.

  View details for DOI 10.1186/s12967-016-1075-6

  View details for PubMedID 27974047

  View details for PubMedCentralID PMC5157084

• A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3 PLOS ONE Shultz, D. B., Pai, J., Chiu, W., Ng, K., Hellendag, M. G., Heestand, G., Chang, D. T., Tu, D., Moore, M. J., Parulekar, W. R., Koong, A. C. 2016; 11 (1)

  Abstract

  NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples.Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker.Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention.ClinicalTrials.gov NCT00040183.

  View details for DOI 10.1371/journal.pone.0147995

  View details for PubMedID 26808546

• Approach to Patients With Pancreatic Cancer Without Detectable Metastases JOURNAL OF CLINICAL ONCOLOGY Heestand, G. M., Murphy, J. D., Lowy, A. M. 2015; 33 (16): 1770-?

  Abstract

  The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis.

  View details for DOI 10.1200/JCO.2014.59.7930

  View details for Web of Science ID 000356062200008

  View details for PubMedID 25918279

• Molecular landscape of pancreatic cancer: implications for current clinical trials ONCOTARGET Heestand, G. M., Kurzrock, R. 2015; 6 (7): 4553-4561

  Abstract

  Despite recent improvements, overall survival for advanced adenocarcinoma of the pancreas continues to be poor. In comparison to other tumor types that have enjoyed marked survival benefit by targeting aberrant cell signaling pathways, standard of care treatment for pancreatic cancer is limited to conventional cytotoxic chemotherapy. Multiple pathway aberrations have been documented in pancreatic cancer. A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF. In the era of tumor profiling, these aberrations may provide an opportunity for new therapeutic approaches. Yet, searching clinicaltrials.gov for recent drug intervention trials for pancreatic adenocarcinoma, remarkably few (10 of 116 (8.6%)) new study protocols registered in the last three years included a molecular/biomarker stratification strategy. Enhanced efforts to target subsets of patients with pancreatic cancer in order to optimize therapy benefit are warranted.

  View details for Web of Science ID 000352792000002

  View details for PubMedID 25714017

• A novel biomarker panel examining response to gemcitabine (G) with or without erlotinib (E) for pancreatic cancer (PA) therapy in NCIC clinical trials group PA.3. Shultz, D., Pal, J., Graber, M., Heestand, G. M., Chang, D., Parulekar, W. R., Tu, D., Moore, M. J., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.4133

  View details for Web of Science ID 000358613203296

• A novel biomarker panel examining response to adjuvant pancreatic cancer therapy in RTOG 9704 Heestand, G. M., Murphy, J., Moughan, J., Regine, W., Luo, J., Graber, M., Kunz, P. L., Fisher, G. A., Guha, C., Lin, B., Mowat, R. B., Gaur, R., Buyyounouski, M. K., Chen, Y., Chang, D., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.3_suppl.176

  View details for Web of Science ID 000333682100180

• Racial Disparity in Consultation, Treatment, and the Impact on Survival in Metastatic Colorectal Cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Simpson, D. R., Martinez, M. E., Gupta, S., Hattangadi-Gluth, J., Mell, L. K., Heestand, G., Fanta, P., Ramamoorthy, S., Le, Q., Murphy, J. D. 2013; 105 (23): 1814-1820

  Abstract

  Black patients with metastatic colorectal cancer have inferior survival compared to white patients. The purpose of this study was to examine disparity in specialist consultation and multimodality treatment and the impact that treatment inequality has on survival.We identified 9935 non-Hispanic white and 1281 black patients with stage IV colorectal cancer aged 66 years and older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Logistic regression models identified race-based differences in consultation rates and subsequent treatment with surgery, chemotherapy, or radiation. Multivariable Cox regression models identified potential factors that explain race-based survival differences. All statistical tests were two-sided.Black patients had lower rates of consultation with surgery, medical oncology, and radiation oncology. Among patients seen in consultation, black patients received less surgery directed at the primary tumor, liver- or lung-directed surgery, chemotherapy, and radiotherapy. Unadjusted survival analysis found a 15% higher chance of dying for black patients compared with white patients (hazard ratio [HR] = 1.15; 95% confidence interval (CI) = 1.08 to 1.22; P < .001). Adjustment for patient, tumor, and demographic variables marginally reduced the risk of death (HR = 1.08; 95% CI = 1.01 to 1.15; P = .03). After adjustment for differences in treatment, the increased risk of death for black patients disappeared.Our study shows racial disparity in specialist consultation as well as subsequent treatment with multimodality therapy for metastatic colorectal cancer, and it suggests that inferior survival for black patients may stem from this treatment disparity. Further research into the underlying causes of this inequality will improve access to treatment and survival in metastatic colorectal cancer.

  View details for DOI 10.1093/jnci/djt318

  View details for Web of Science ID 000328370000011

  View details for PubMedID 24231453

• The Evolution of Modern Systemic Agents for Colorectal Cancer LOWER GASTROINTESTINAL MALIGNANCIES Heestand, G., Kunz, P., Fisher, G. A., Ben Josef, E., Koong, A. 2010; 1 (2): 249–60

  View details for DOI 10.5003/2151-4208.1.2.249

  View details for Web of Science ID 000281785700001