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Uncovering Insights in Pancreatic and Prostate Cancers

Most know a pancreatic cancer diagnosis is devastating. We’ve seen Patrick Swayze, Michael Landon, and Steve Jobs taken too soon by this terrible disease. We know survival is rare. Only 9 percent of patients live five years after diagnosis.1

Many may not realize, however, that prostate cancer can also be devastating, specifically when the disease metastasizes. Entertainer Merv Giffin and actor Dennis Hopper succumbed to the disease. In metastatic prostate cancer patients, the five-year survival rate is only 30 percent.2

Uncovering new insights to inform treatment decisions for both of these difficult-to-treat cancers remains imperative. Two recent studies, each the largest of their kind, reveal important new insights into improving care for these patients. The pancreatic cancer study, published in Gastroenterology and the prostate cancer study published in the Journal of Clinical Oncology Precision Oncology (JCO PO), evaluated the landscape of genomic alterations identified in each disease type by comprehensive genomic profiling (CGP), providing an in-depth view of possible targets for both treatment planning and future drug development. The study published in Gastroenterology found that nearly one in five patients with a type of pancreatic cancer called pancreatic ductal adenocarcinomas (PDAC) could be eligible for currently available therapies and almost 60 percent of prostate cancer patients could potentially be candidates for targeted therapies that are under investigation in this cancer type.

The studies support CGP as an effective tool for helping to optimize patient care in these subsets of pancreatic and prostate cancers. The large sample size of these studies allows identification of genomic markers that are more common in subpopulations of patients, potentially informing cancer care now, as well as inform the focus of future clinical trials.


Comprehensive Genomic Profiling Identifies Subgroup of Pancreatic Cancer Patients with Targetable Genomic Alterations

Gastroenterology Infogram 2

The pancreatic cancer study published in Gastroenterology was done in collaboration with researchers at the University of Pittsburgh Medical Center, and it evaluated more than 3,500 PDAC tumor samples, making it the largest study of its kind.

First and foremost, the study found that nearly one in five patients with PDAC may be candidates for existing therapies. These patients could be divided into two categories: 1) patients with alterations in kinases signaling, for which many targeted therapies are in development, or 2) patients with alterations in the DNA damage repair pathway, especially the BRCA family of genes, which confer sensitivity to approved chemotherapy regimens and PARP inhibitors. Interestingly, half of the BRCA alterations found were heritable, while the other half were not. The study authors concluded that, because of these findings, it is possible to explore therapies directed at BRCA in a pancreatic cancer setting and clinical trials are currently ongoing.3,4

The study also challenged long-held beliefs about the genomic makeup of pancreatic cancer, specifically the number of pancreatic cancer patients who have the KRAS gene mutation, for which there are no FDA approved targeted therapies.5 Researchers have long believed that more than 95 percent of pancreatic cancer patients carry the KRAS gene mutation, but the study found that the number of patients with this mutation is 88 percent.6 Of the 12 percent of patients who have a normal copy of the KRAS gene, a subset instead harbor kinase fusions, for which there are investigational treatments. Larotrectinib, for example, is approved for all tumors that carry the fusions of the genes NTRK1-3. Importantly, these types of alterations can be detected with the breadth and depth provided by CGP testing, as opposed to standard hotspot tests that only test for one or a few genetic mutations.7


Genomic Alterations - Enriched in Metastatic Prostate Cancer - Point towards Exploring Existing Therapies in Hard-to-Treat Setting

Gastroenterology Infogram

Nearly 3,500 prostate tumors were evaluated in the study led by scientists at the Huntsman Cancer Institute, University of Utah, and published on May 10, 2019 in the Journal of Clinical Oncology Precision Oncology. The researchers found that almost 60 percent of all prostate cancer patients harbored genomic alterations that could match them to investigational targeted therapies currently in clinical trials. Of note, this study was the largest of its kind and found different genomic signatures in primary versus metastatic prostate tumors, suggesting that different therapeutic approaches should be explored in the difficult-to-treat metastatic setting.

For tumors that have grown outside the prostate, hormone therapy is the first line of treatment.8 Some prostate cancer patients can grow resistant to hormone therapy and among these patients, 90 percent develop metastatic disease.9 The study found that mutations in the androgen (hormone) receptor were more common in metastatic disease and point to potential investigative approaches for treatment in the metastatic setting.

In addition to individual genomic alterations, genomic signatures – like microsatellite instability (MSI), tumor mutational burden (TMB), and genome-wide loss of heterozygosity (gLOH) which are ideally evaluated via CGP – also play an important role when exploring precision oncology options for patients. In the study, a high gLOH was found in 17 percent of patients while high MSI and TMB values constituted 3 percent of cases. Patients with these signatures may benefit from immunotherapy and PARP inhibitor therapy, respectively, and recent clinical trial results with PARP inhibitors in prostate cancer presented at ASCO GU 2019 are generating excitement in the community.10,11

The Powerful Potential of CGP Needs to Continue to be Harnessed

These studies demonstrate that CGP can make possible powerful insights into difficult-to-treat diseases such as pancreatic and metastatic prostate cancer while also providing important targets for future research. The importance of incorporating CGP into routine clinical care becomes even more evident when we consider that currently only approximately 15 percent of advanced cancer patients receive CGP testing and 60 percent of advanced cancer patients get no genomic testing at all. This alarming statistic means that many patients and the people involved in their treatment and care are currently missing out on potentially powerful insights that could inform their decision making. At Foundation Medicine we are committed to continue to bring the powerful potential of CGP to patients and their caregivers.

Notes

1 American Cancer Society. Survival Rates for Pancreatic Cancer. https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html. Accessed March 13, 2019.

2 Cancer.Net. Prostate Cancer: Statistics. https://www.cancer.net/cancer-types/prostate-cancer/statistics. Accessed March 13, 2019.

3 Lowery MA, Wong W, Jordan EJ, et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018;110(10):1067-1074.

4 Krantz BA, O'Reilly EM. Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality? Clin Cancer Res 2017.

5 McCormick F: KRAS as a Therapeutic Target. Clin Cancer Res. 2015;21(8): 1797–1801.

6 Huggett MT, Pereira SP. Diagnosing and managing pancreatic cancer. Practitioner. 2011;255(1742):21-5, 2-3.

7 My Cancer Genome. Types of Molecular Tumor Testing. https://www.mycancergenome.org/content/molecular-medicine/types-of-molecular-tumor-testing/. Accessed May 10, 2019

8 American Cancer Society. Initial Treatment of Prostate Cancer, by Stage. https://www.cancer.org/cancer/prostate-cancer/treating/by-stage.html. Accessed March 14, 2019

9 Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Can Urol Assoc J. 2010;4(6):380-4.

10 Smith M, Sandhu SK, Kelly WK, et al. Phase 2 study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD. Poster presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU); February 2019; San Francisco, CA. Abstract 202.

11 Abida W, Bryce AH, Vogelzang NJ et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Presented at the European Society of Medical Oncology (ESMO); October 2018; Madrid, Spain. Abstract 793PD.

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