Moving breast cancer susceptibility gene testing into the mainstream

Timely delivery of results to guide index cancer treatment and greater equity of access are among the goals of broader testing

Testing for breast cancer susceptibility genes has evolved dramatically over the past three decades. BRCA1/2 genetic testing was introduced soon after the genes were identified in the mid‐1990s, but the process was labour‐intensive, expensive, and took many months to complete, making restrictive eligibility criteria necessary. Genetic counselling typically took place in hereditary cancer clinics in medical genetics departments, where women in families at high risk of breast cancer were offered risk assessment and genetic testing. But as women with breast cancer were treated in surgery and oncology departments, decoupling of genetic testing from the cancer care treatment pathway was typical. For those with pathogenic variants in breast cancer susceptibility genes, increased surveillance and prevention of subsequent cancers was the main motive for women and their families, as genetic testing results were seldom available in time to alter primary local or systemic therapy decisions.1 Next generation sequencing, together with legal decisions determining that human genes are not patentable, has expanded access to genetic testing, which is now more efficient, of greater capacity, and scalable. A variety of breast cancer susceptibility genes are assessed with multi‐gene panels, including not only BRCA1/2, but also PALB2, TP53, ATM, and CHEK2, among others. Commensurate with improved capacity for testing, the cancer genetics community has ushered in the era of “mainstream genetic testing”, whereby people with newly diagnosed cancer are offered access to genetic testing as part of a program of initial investigations with both prognostic and predictive potential.

The goals of mainstream genetic testing, distinguishing it from traditional testing models, are to streamline the delivery of results so that oncologists can use genetic information to guide index cancer treatment, and to improve equity by expanding breast cancer susceptibility gene testing to a larger proportion of patients. For women with pathogenic variants, mainstreaming aims to use the brief window of opportunity between diagnosis and initiation of therapy by using breast cancer gene test results to minimise the treatment‐related morbidity that might ensue, for example, were a woman with a BRCA1 pathogenic variant to undergo prophylactic mastectomy after initial surgery or radiotherapy.2 Failing to identify women with homologous recombination repair deficiency caused by pathogenic variants in BRCA1/2 or PALB2 (or, probably, BARD1 or RAD51C/D) would miss an opportunity for targeted therapies such as poly (ADP‐ribose) polymerase (PARP) inhibitors, which measurably improve survival.3,4,5 Surgical prevention of dangerous high‐grade serous tubo‐ovarian carcinoma would also be a key benefit of universal testing for pathogenic variants in women with breast cancer.6

The MAGIC study reported by De Silva and colleagues in this issue of the MJA was well positioned to examine both goals of mainstreaming.7 The authors offered universal genetic testing to 474 Australian women with newly diagnosed or recurrent breast cancer. A 19‐gene panel was used to identify germline pathogenic variants in 31 participants (6.5% of tested women), more than half of whom (eighteen) did not meet national genetic testing eligibility guidelines. After a median turnaround time of 44 days, clinical management was altered for 24 women with pathogenic variants (77%); fifteen were referred for consideration of bilateral or contralateral prophylactic mastectomy, eighteen for consideration of risk‐reducing salpingo‐oophorectomy. The high acceptability and low decision regret reported by the participants echo reports by similar mainstreaming initiatives elsewhere of uptake by as many as 98% of people with breast cancer offered testing at the time of diagnosis.8

Future challenges posed by mainstream genetic testing for breast cancer are related in part to testing capacity and the need to remodel old infrastructure and provide oncologists with the required knowledge and skills. While health care professionals uniformly regard genetic testing as valuable for breast cancer care,9 many specialists outside genetic medicine feel they lack the requisite expertise to discuss testing and interpret genetic test results with their patients, especially variants of uncertain significance.10 While this knowledge gap has begun to close for other rarer disease sites where oncology‐initiated genetic testing is now routine (eg, tubo‐ovarian carcinoma), the breast cancer community must follow suit with clear guidelines and pathways for the mainstreaming of testing. Clinicians and geneticists must also agree on who should be tested (and, perhaps, who should not be tested) and on what should be reported; while calls for universal testing stem from a reasonable desire to avoid missing the 50–60% of people with clinically actionable variants who do not meet guideline‐endorsed criteria for testing, the inappropriate use of risk‐reducing surgery in people with variants of uncertain significance should be a cautionary tale for advocates of mainstreaming.11