Molecular Testing With Universal Method Comparable to Traditional Method in Hereditary Solid Tumors

Ozge Ceyhan-Birsoy, PhD

In multiple solid malignancies, including breast, ovarian, colorectal, and pancreatic cancers, there is a subset of patients with a hereditary predisposition for these diseases, but the current testing criteria do not mention this subset. In an effort to provide more information of genetic testing in this population, a study of Memorial Sloan Kettering Cancer Center (MSKCC) patients was conducted to test the traditional guideline-based method of testing versus universal testing of a broad cancer patient population over a 5-year period.

A total of 7235 patients were included in the analysis and tested for 76 to 88 cancers. Through this study, investigators uncovered pathogenic and likely pathogenic (P/LP) variants in 7.5% (95% CI 6.6%- 8.4%) of 3,341 patients with breast cancer, 17.4% (95% CI, 14%- 21.6%) of 384 those with ovarian cancer, 13.5% (95% CI, 9.8%- 18%) of 252 patients with colorectal, and 8.8% (95% CI, 5.1%-14.8%) of 136 patients with pancreatic cancer.

Overall, the study found that testing with universal method was comparable to the guideline-based method, implying that universal testing can expand genetic testing to patient populations who are in need but are currently underserved.

In an interview with Targeted Oncology during the 2020 Association for Molecular Pathology (AMP) Annual Meeting, Ozge Ceyhan-Birsoy, PhD, assistant director of the Laboratory for Molecular Medicine, MSKCC, discussed genetic testing methods for patients with hereditary predisposition and the molecular research underway at MSKCC to improve testing in this patient population.

TARGTED ONCOLOGY: In recent years, what advances have we see in cancer genetics?

Ceyhan-Birsoy: There have been significant advances in the range of genetic testing options for cancer patients in recent years. More patients are now able to receive molecular testing on their tumors to identify optimal targeted therapies for their cancer and germline genetic testing to uncover hereditary cancer predisposition. A paired analysis of tumor and normal DNA is increasingly being adapted, which improves the interpretation of both somatic and germline mutations. Additionally, incorporation of RNA analysis has expanded the scope of mutations that can be detected and characterized. Finally, the use of cell-free DNA now allows us to profile a patient’s tumor using only their blood.

TARGETED ONCOLOGY: How can hereditary predisposition inform oncologist for care/treatment decisions?

Ceyhan-Birsoy: Identifying hereditary mutations that predispose patients to cancer has important implications for their treatment and management. There are established targeted therapies available now for certain germline defects. For instance, germline mutations in certain homologous recombination and mismatch repair genes can predict response to PARP inhibitor and immune-checkpoint inhibitor therapies, respectively. Some therapies may pose high risk for patients with particular gene mutations, such as radiation therapy risks for patients with germline TP53 mutations. In addition, identifying hereditary cancer predisposition is critical to allow timely surveillance and prophylactic interventions for future cancers that the patient may be at higher risk of developing. As germline mutations are heritable, this information provides the opportunity for early surveillance in the patient’s family members, as well.

TARGETED ONCOLOGY: Can you explain how this MSKCC study came about?

Ceyhan-Birsoy: Genetic testing for hereditary cancer predisposition is traditionally performed in a guideline-dependent and targeted manner. In current practice, only patients who meet established criteria from national and professional organizations receive genetic testing and typically get tested for a small number of genes selected based on their tumor type, age of onset, and family histories. MSKCC has been 1 of the first institutes to pilot a universal testing approach for cancer patients, providing comprehensive germline testing of all known cancer predisposition genes without pre-selection of patients based on traditional genetic testing criteria. We have been performing both targeted and universal testing for our patients since 2015.

In this study, we aimed to understand how the yields (positive rates) of these 2 testing approaches compare to each other in greater than 4000 patients who had traditional and more than 9,000 patients who had universal testing at MSKCC in the past 5 years. We also assessed whether universal testing identified additional findings that would have been missed in a targeted testing approach for any given patient.

TARGETED ONCOLOGY: What are the key results of this analysis?

Ceyhan-Birsoy: We saw that universal germline testing without preselection of patients based on current guidelines yielded comparable rates of positive results to traditional guideline-dependent testing approach, particularly in patients with breast, ovarian, and pancreatic cancers. In addition, universal testing uncovered mutations that predispose to other cancers in about 9% of patients in genes that are not routinely tested for their diagnosis. Approximately half of those conferred high to moderate risk to cancer and about 40% of them implicated early surveillance or prophylactic surgery recommendations to prevent other cancers.

TARGETED ONCOLOGY: What is a key takeaway from your AMP 2020 presentation and explain the implications of these findings?

Ceyhan-Birsoy: Our results suggest that the preselection of patients for genetic testing based on the current guidelines may not significantly increase the likelihood of identifying a germline mutation in certain patient populations. A universal and comprehensive testing approach further provides the benefit of identifying hereditary risk for other cancers, allowing early surveillance and prophylactic interventions.

TARGETED ONCOLOGY: How can this information be applied in oncology clinics?

Ceyhan-Birsoy: Our study underlies the advantages of universal and comprehensive testing for cancer patients. However, there are many challenges that may limit the application of this approach for all cancer patients, including the cost of testing, resources needed to provide pre-test and post-test genetic counseling to patients, and the potential to discover more variants of uncertain significance that may lead to higher number of inconclusive results. Future efforts should be dedicated to providing wider groups of cancer patients access to genetic testing, which can aid in their clinical care and in the care of their family members.