Association of Genetic Testing Results With Mortality Among Women With Breast Cancer or Ovarian Cancer

Allison W. Kurian, MD, MSc; Paul Abrahamse, MA; Irina Bondarenko, MS; Ann S. Hamilton, PhD; Dennis Deapen, DrPH; Scarlett L. Gomez, PhD; Monica Morrow, MD; Jonathan S. Berek, MD, MMSc; Timothy P. Hofer, MD, MSc; Steven J. Katz, MD, MPH; Kevin C. Ward, PhD, MPH


J Natl Cancer Inst. 2022;114(2):245-253. 

In This Article

Abstract and Introduction


Background: Breast cancer and ovarian cancer patients increasingly undergo germline genetic testing. However, little is known about cancer-specific mortality among carriers of a pathogenic variant (PV) in BRCA1/2 or other genes in a population-based setting.

Methods: Georgia and California Surveillance Epidemiology and End Results (SEER) registry records were linked to clinical genetic testing results. Women were included who had stages I-IV breast cancer or ovarian cancer diagnosed in 2013–2017, received chemotherapy, and were linked to genetic testing results. Multivariable Cox proportional hazard models were used to examine the association of genetic results with cancer-specific mortality.

Results: 22 495 breast cancer and 4320 ovarian cancer patients were analyzed, with a median follow-up of 41 months. PVs were present in 12.7% of breast cancer patients with estrogen and/or progesterone receptor-positive, HER2-negative cancer, 9.8% with HER2-positive cancer, 16.8% with triple-negative breast cancer, and 17.2% with ovarian cancer. Among triple-negative breast cancer patients, cancer-specific mortality was lower with BRCA1 (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.35 to 0.69) and BRCA2 PVs (HR = 0.60, 95% CI = 0.41 to 0.89), and equivalent with PVs in other genes (HR = 0.65, 95% CI = 0.37 to 1.13), vs noncarriers. Among ovarian cancer patients, cancer-specific mortality was lower with PVs in BRCA2 (HR = 0.35, 95% CI = 0.25 to 0.49) and genes other than BRCA1/2 (HR = 0.47, 95% CI = 0.32 to 0.69). No PV was associated with higher cancer-specific mortality.

Conclusions: Among breast cancer and ovarian cancer patients treated with chemotherapy in the community, BRCA1/2 and other gene PV carriers had equivalent or lower short-term cancer-specific mortality than noncarriers. These results may reassure newly diagnosed patients, and longer follow-up is ongoing.


Genetic testing for inherited pathogenic variants (PVs) in cancer susceptibility genes has an established role in cancer treatment[1] and is relevant for secondary cancer risk reduction and testing of relatives.[2] We and others reported that patients diagnosed with breast and/or ovarian cancer increasingly undergo germline sequencing of many genes.[3–6] In this context, patients may experience a positive genetic test result as a worrisome second diagnosis[7,8] and wonder whether having a PV increases their chance of dying from their cancer. It is important to know whether cancer mortality is associated with germline PVs to inform treatment decision-making and how clinicians counsel p atients about prognosis.

Prior studies have investigated breast and ovarian cancer-specific mortality among carriers of PVs in BRCA1 and/or BRCA2 (BRCA1/2), with mixed results. Some showed lower cancer-specific mortality in BRCA1/2 PV carriers, particularly among cohorts treated with chemotherapy, which may reflect a greater chemosensitivity of BRCA1/2 PV carriers vs noncarriers due to dysfunctional DNA repair.[9–12] Additional studies showed higher cancer-specific mortality in BRCA1/2 PV carriers,[13–16] whereas others showed no difference from patients who tested negative.[17–23] Several prior studies were from single institutions or academic networks, which may introduce selection bias. Few studies analyzed results according to breast cancer subtypes or looked beyond BRCA1/2 to consider the many other genes now evaluated in clinical practice.

We studied cancer-specific mortality among a population-based cohort comprising all women diagnosed with breast cancer or ovarian cancer in Georgia or California and reported to statewide Surveillance Epidemiology and End Results (SEER) cancer registries from 2013 to 2017, together with their results of clinical germline genetic sequencing provided by testing laboratories. Given concerns that SEER underreports chemotherapy,[24] we excluded patients with no chemotherapy reported, because of uncertainty about their actual treatment history; thus, we limited the study to patients with documented chemotherapy receipt. Based on studies suggesting high chemosensitivity in BRCA1/2 PV carriers,[9–11,13,22,25] our hypothesis was that patients with a PV in BRCA1/2 or another cancer susceptibility gene would have lower cancer-specific mortality than patients having negative or uncertain genetic testing results.