A Happy Medium?

Identification of germline pathogenic variants associated with increased cancer susceptibility is important for early detection and prevention of cancer.

In 2018, a study showed that a significant proportion of women with germline variants are not captured by the National Comprehensive Cancer Network (NCCN) guidelines (PMID: 30526229). In response, the American Society of Breast Surgeons (ASBrS) issued a statement in 2019 that genetic testing should be offered to all women with a personal history of breast cancer (PMID: 31342359).

The argument for universal testing has been further supported by a 2020 publication, which found that universal testing among patients with solid tumor cancer was associated with increased detection of inherited genetic variants over the predicted yield of guideline-based testing (PMID: 33126242).

While the approach of offering genetic testing to all women with breast cancer increases the detection of germline pathogenic variants, there are challenges associated with widespread screening.

Concerns regarding breast cancer population-wide testing include increased costs to the healthcare system, lack of clear management guidelines for genes with uncertain clinical relevance for breast cancer, as well as exacerbation of the nation-wide shortage of genetic providers.

Conflicting recommendations from the NCCN and ASBrS have created a debate about whether all women with breast cancer need to undergo germline genetic testing.

To compare the sensitivity and specificity of genetic testing criteria for hereditary breast cancer, women in a large breast cancer registry were evaluated for hereditary breast cancer susceptibility.

In this study, 3,907 women with a diagnosis of breast cancer were offered germline testing for pathogenic variants in nine breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN and TP53). Results show the NCCN guidelines effectively identify women who are more likely to carry a pathogenic variant than those who do not meet testing criteria.

However, the guidelines miss a substantial proportion of women with hereditary breast cancer susceptibility, thereby confirming that current NCCN criteria are not optimal for the selection of individuals for hereditary breast cancer genetic testing.

The study went on to explore alternative selection criteria by evaluating the results of genetic testing offered to all women diagnosed with breast cancer at or before 65 years of age. Their findings demonstrate that expansion of criteria improves sensitivity without requiring testing of all women with breast cancer. Specifically, it achieves over 90% sensitivity for the nine breast cancer predisposition genes and over 98% sensitivity for BRCA1 and BRCA2. Restricting testing to this age group reduces the proportion of women tested by 21%, which may help to address concerns regarding the allocation of scarce genetic resources.

Does modification of the NCCN guidelines sufficiently improve the sensitivity of selection criteria? Should women who have a low probability of carrying a pathogenic variant be excluded from widespread genetic testing in the name of cost reduction and resource preservation? Or does this defeat the purpose of universal screening, which is designed to capture as many pathogenic variant carriers as possible?

Many experts remain in favor of continued use of the NCCN guidelines to conserve genetic resources for individuals who are most likely to have a genetic predisposition to cancer. Yet numerous professionals advocate for offering testing to all women with breast cancer because of the irrefutable limitations of more restrictive guidelines.

Is expansion of the NCCN guidelines rather than universal testing of all women with breast cancer a reasonable compromise?

Or does the approach leave both parties (those in favor of the ASBrS statement and those in favor of NCCN criteria) dissatisfied?

As genetic advancements continue to lower the cost of testing and elevate the value of precision medicine, society moves closer to population-wide genetic screening.

Could adherence to the NCCN guidelines for genetic testing just be prolonging the inevitable opening of the floodgates?

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