Genetic Testing: Multigene Panel Testing Detects Hereditary Risk Variants in Metastatic Breast Cancer Patients

The clinical value of performing multigene panel for inherited cancer in patients with metastatic breast cancer has been the subject of considerable debate. Those who believe in the value of such testing can now point to a new report by researchers from Johns Hopkins University School of Medicine and the Vanderbilt Ingram Cancer Center as evidence that such testing may be beneficial for guiding treatment decisions in some metastatic breast cancer patients, particularly individuals carrying risky mutations in BRCA1 or BRCA2 who might be eligible to receive PARP inhibitor treatment. Here is an overview of the new study, which was reported in the Aug. 29, 2019 edition of JAMA Oncology.

What Is At Stake

Multigene panel testing for inherited cancer in patients with breast cancer is based on the prevalence of pathogenic/likely pathogenic (P/LP) variants. Recent studies show that the prevalence of P/LP variants is similar in patients with breast cancer regardless of whether they the National Comprehensive Cancer Network (NCCN) guidelines criteria for testing. However, most of the participants in these studies were patients with early stage breast cancer and many low-risk variants were identified, raising the question of clinical actionability.

The recent FDA approval of polyadenosine diphosphate–ribose polymerase (PARP) inhibitors for patients with metastatic human epidermal growth fact or receptor 2 (HER2/ERBB2)-negative breast cancer with germline BRCA1 and BRCA2 (BRCA) pathogenic variants suggests germline testing of patients with metastatic breast cancer could have therapeutic implications. Exhibit A: A recent study finding that 11.8% of otherwise unselected patients with metastatic prostate cancer harbored a P/LP germline variant, which led the NCCN to change its guidelines recommend germline testing for all patients with metastatic prostate cancer. However, the researchers were aware of no analogous studies to quantify the prevalence of P/LP variants among patients with metastatic breast cancer.

The Study

With that in mind, the research team used a multigene germline panel test from Silicon Valley-based Color (formerly known as Color Genomics) to prospectively search for pathogenic or likely pathogenic variants in 30 genes in 100 individuals with metastatic breast cancer, regardless of whether those individuals currently met the NCCN testing criteria. Along with information for family members, the researchers hypothesized that such testing might be beneficial for guiding treatment decisions in some metastatic breast cancer patients, particularly individuals carrying risky mutations in BRCA1 or BRCA2 who might be eligible to receive PARP inhibitor treatment. The findings:

  • Of the 100 individuals, 14 were found to have pathogenic or likely pathogenic variants;
  • Six of those 14 individuals did not meet NCCN testing guidelines; and
  • Conversely, two of the six metastatic breast cancer patients had not been tested in the past even though they carried risky BRCA1/2 mutations and met NCCN testing criteria.

In addition to the pathogenic and likely pathogenic changes found in cancer-related genes such as ATM, BRIP1, or CHEK2, the researchers found another 21 metastatic breast cancer patients who had variants of uncertain significance in one or more of the genes on the panel.

“[G]iven that many of the genes included on the multigene panel are involved in DNA repair,” the authors noted, “there is scientific rationale that some of these [pathogenic or likely pathogenic] variants (ATM, BRIP1, CHEK2) may also be predictive for response to PARP inhibitors, a hypothesis currently being tested in clinical trials.”

Takeaway: “[O]ur results provide evidence to support genetic testing for inherited cancer predisposition among all patients with metastatic breast cancer, because this group represents a population with a high prevalence of [pathogenic or likely pathogenic] variants that could have therapeutic implications,” wrote corresponding author Ben Ho Park, a hematology researcher at Vanderbilt, and his colleagues in the JAMA Oncology research letter.


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