Testing for Both Germline and Somatic Mutations in Prostate and Other Cancers: Impact on Treatment Decision Making 

By William Oh, MD

June 24, 2021

ORION by VieCure

Volume 2, Issue 1

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Paired Germline & Somatic Testing:  Rationale

There is a growing realization that pathogenic mutations can drive cancer growth and represent excellent targets for therapeutic intervention in cancer patients.  Driver mutations have been identified in many tumors and are considered somatic or acquired mutations that represent damage that occurs to an individual patient’s cells during her lifetime. These mutations are not inherited and are not present in every cell in the body.

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In contrast, germline mutations are typically less common and can cause hereditary cancer.  These account for 5-10% of all cancers, and >50 hereditary cancer syndromes have been described, including Lynch Syndrome and BRCA1 and BRCA2-Associated Hereditary Breast and Ovarian Cancer.

 

More recently, prostate cancer has been recognized to 

be associated with homologous recombination repair (HRR) genes including BRCA1 and BRCA2.  As it turns out, metastatic castration-resistant prostate cancer patients may harbor HRR mutations up to 20-25% of the time, divided equally between somatic and germline mutations.1  Such a high prevalence rate was a surprise initially but was likely due to the fact that across all stages of prostate cancer, both germline and somatic pathogenic mutations in HRR mutations are much lower and because testing for such mutations has been uncommon.

1 Lang SH, et al. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol 2019; 55:597-616.

In 2020, two PARP inhibitors received accelerated approval for the treatment of mCRPC after initial androgen-targeted therapy, if the patients demonstrated either HRR mutations (for Olaparib) or BRCA1/2 mutations (for Rucaparib). These approvals were based on studies that showed significant clinical benefit in such patients with those mutations, whether these were germline or somatic in nature. 

For instance, in the PROfound trial, 387 patients with disease progression on previous treatment with first-line AR-targeted therapy were randomly assigned 2:1 to receive olaparib (n = 256) or a second AR-targeted therapy (n = 131). Cohort A patients included 245 patients (162 in the olaparib group and 83 in the control group) with at least one alteration in BRCA1, BRCA2, or ATM.  In this cohort, median overall survival was 19.1 months in the olaparib group vs 14.7 months in the control group

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(hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.50–0.97, P = 0.02). In a sensitivity analysis adjusting for crossover to olaparib, the hazard ratio was 0.42 (95% CI = 0.19–0.91).2

2 Hussain M, et al.  Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020; 383:2345-2357

Paired & Germline Testing:  Challenges in Clinical Practice

Testing for both somatic and germline mutations in HRR genes is underutilized in one real-world evidence study of mCRPC patients prior to the approval of PARP inhibitors in 2020. Of 5213 patients with mCRPC (mean age = 73 years), only 674 (13%) had a documented test pre- or post-mCRPC diagnosis for one of the HRR genes of interest.  Receiving care in an academic oncology center (versus a community-based oncology center) was a strong predictor of documented testing for HRR gene alterations (hazard ratio = 2.41).  This study suggests the use of and access to genetic testing approval was suboptimal for mCRPC patients.3

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There are likely multiple challenges to implementation of more widespread testing...

Which lab should a clinician use? 

Are there issues for reimbursement? 

Do clinicians understand how to interpret reports? 

Is there a policy issue? 

Are there educational gaps for clinicians?

Paired & Germline Testing:  Considerations for Practice

So, what should the community oncologist consider in terms of paired somatic and germline testing?

  • For metastatic patients, consider offering comprehensive somatic tumor testing paired with germline hereditary cancer testing to have the most complete view of the drivers of cancer

  • Some testing companies offer certified genetic counseling services to the patient through telehealth so that the patient and his/her family is completely aware of the implications of the any positive hereditary cancer findings and recommendations regarding cascade testing in the family

  • The presence of a pathogenic mutation in either the tumor only (somatic) or the germline (inherited) both may respond to specific treatments such as PARP inhibitors in patients with metastatic castration-resistant prostate cancer

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  • If you do not search for these genetic cancer drivers, you cannot offer your patients such life-prolonging drugs

The future of precision oncology is here already, and it includes paired testing of both germline and somatic genes using state of the art genetic tests.  Overcoming some of the challenges in the community oncology setting to facilitate routine testing when clinically appropriate will require a concerted effort by leading decision bodies (e.g., NCCN, ASCO), the private sector, third-party payers and practices to optimize use and improve outcomes.

William Oh, MD
Clinical Professor of Medicine
Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
Chief Medical Science Officer, Sema4
Ex Officio Member, VieCure Clinical Advisory Council