Should All Breast Cancer Patients Receive Genetic Testing?

In In The News by Barbara Jacoby

By: Jaime Rosenberg


Recent years have seen calls for genetic testing for all patients with breast cancer. A session at the 2020 San Antonio Breast Cancer Symposium reviewed the evidence for, and against, such testing.

In light of the 30th anniversary of Mary-Claire King, PhD, mapping BRCA1, a session on the last day of the 2020 San Antonio Breast Cancer Symposium (SABCS) begged the question: Should all women with breast cancer receive genetic testing?

Recent years have seen calls for genetic testing for all patients with breast cancer, most notably from the American Society of Breast Surgeons, which issued guidelines in February of last year urging genetic testing with a multi-gene panel for every person diagnosed with breast cancer. Published research has also supported population-based screening among those diagnosed with the disease, while other research has urged caution for such an approach.

Making the case for testing all patients

Mark Robson, MD, a medical oncologist and chief of Breast Medicine Service at Memorial Sloan Kettering Cancer Center, started the SABCS session off by outlining the benefits of testing all patients.

According to Robson, since criteria for genetic testing was first established, some of the assumptions previously used to asses risk have since been debunked. Something Robson says has become evident in recent years is that family history criteria are somewhat insensitive for detecting pathogenic variants (PVs).

For example, a 2018 study of nearly 1000 women with breast cancer found that National Comprehensive Cancer Network criteria were relatively insensitive, with nearly half of patients with a PV with clinically actionable and/or management guidelines in development being missed by current guidelines.1 Robson noted that in the study, the criteria was relatively sensitive for BRCA1/2 PVs, and that sensitivity dulled once expanded out beyond the BRCA PVs.

“So, why is diagnostic yield important?” queried Robson, who then offered several answers. “Certainly for BRCA1/2, we know that there is a substantial risk of contralateral breast cancer (CBC)—greater for BRCA1 than BRCA2 and probably greater for younger women than for older women, but nonetheless the risks are high enough that a woman would very much want to consider bilateral mastectomy as her local treatment even if she were otherwise eligible for breast conservation to mitigate this risk.

And while this decision is from a personal utility perspective, there is some research showing that contralateral prophylactic mastectomy might improve survival, said Robson.

Another factor that highlights the importance of diagnostic yield is that selection of BRCA1/2 carriers can identify those with metastatic disease who are eligible for Poly (ADP-ribose) polymerase (PARP) inhibitor therapy, which was demonstrated in both the OlympiAD2 and EMBRACA3 trials.

And this benefit might even extend beyond BRCA1/2, according to Robson, highlighting TBCRC 048, a phase 2 study looking at patients with breast cancer treated with olaparib who had PVs in other susceptible genes, which showed a dramatic benefit in patients who had PALB2 mutations.4

Diagnostic yield may also be leveraged as an opportunity to identify index patients with BRCA mutations or other PVs in other genes and use them as an entry point for cascade testing throughout the family, which “can more rapidly identify unaffected PV carriers, which is the greatest opportunity for reduction in risk of morbidity and mortality from inherited susceptibility,” said Robson.

Such testing may also help reduce racial and socioeconomic inequities in genetic testing access, as some research has shown that Black patients and those from higher poverty census are currently less likely to be tested.

Outside of a clinical perspective, some research has suggested that testing all patients may actually be cost effective. A 2019 study published in JAMA Oncology5 found that testing all patients at diagnosis was extremely cost-effective compared with testing based on clinical criteria or family history at the usual willingness to pay threshold of $100,000 (incremental cost-effectiveness ratio $65,661/quality-adjusted life year [QALY] from the payer perspective or $61,618/QALY from the societal perspective). This cost effectiveness remained for up to $2432 per test from a payer perspective and for up to $2679 from a societal perspective.

An emphasis on risk stratification

According to Susan Domchek, MD; director, MacDonald Women’s Cancer Risk Evaluation Center; executive director, the Basser Center for BRCA; and Basser Professor in Oncology at Penn Medicine; there is also evidence supporting the use of risk stratification through factors like family history and phenotype rather than testing all patients.

For example, data from the CARRIERS study presented at last year’s SABCS meeting found that 5% of patients with breast cancer had PVs, approximately half of which were BRCA1/2/PALB2 compared with 1.63% of unaffected women, 0.47% of which had BRCA1/2/PALB2 PVs. Looking deeper into the cohorts, the researchers saw that having a first-degree relative, such as a parent or sibling, with breast cancer carried a significantly higher risk of having a PV (8.29% vs 4.18%) and having a BRCA1/2/PALB2 PV specifically (5.19% vs 1.96%).

Phenotype was also shown to matter, with patients with ER+ disease having a much lower risk of a PV overall compared with those that had ER- disease or triple-negative breast cancer (4.23% vs 8.18% vs 10.05%, respectively) and for having a BRCA1/2/PALB2 PV specifically (1.85% vs 6.26% vs 8.13%, respectively).

Looking at age, the study also showed that younger age was associated with a higher risk of having a PV. In a JAMA 2019 study,6 patients who were over the age of 65 were found to have approximately a 1% risk of having a BRCA1/2 mutation.

According to Domchek, a recent has been made that suggests all women under the age of 60 should be tested and then should be risk stratified from there.



1. Beitsch P, Whitworth P, Hughes K, et al. Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2018;37(6):453-460.

2. Robson M, Im S, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017; 377:523-533.

3. Litton J, Rugo H, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. New Engl J Med. 2018; 379:753-763.

4. Tung N, Robson M, Vents S, et al. TBCRC 048L Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. Published online October 29, 2020. doi:10.1200/JCO.20.02151

5. Sun L, Brentnall A, Patel S, et al. A cost-effectiveness analysis of multigene testing for all patients with breast cancer. JAMA Oncol. 2019;5(12):1718-1730.

6. Kurian A, Bernhisel R, Larson, et al. Prevalence of pathogenic variants in cancer susceptibility genes among women with postmenopausal breast cancer. JAMA. 2020;323(10):995-997.