Neil Osterweil

October 19, 2017

ORLANDO — Using cancer status instead of family history to assess whether a person should undergo testing for breast cancer susceptibility genes is more effective and cheaper, new research shows.

In our study, if the decision to test had been made on the basis of family history, mutations in more than 5% of patients would have been missed, said Nazneen Rahman, MD, PhD, from the Institute of Cancer Research in London.

"We've been able to do BRCA testing for over 20 years, but studies have universally shown that we are not as effective at it as we would like," Dr Rahman said here at the American Society of Human Genetics 2017 Annual Meeting.

The health authorities in most countries recommend that people with a risk for BRCA mutations above 10% be offered genetic testing. In most systems, this involves complex, time-consuming, and costly counseling sessions and referrals, and access to testing can be limited by financial and staffing constraints, she explained.

"There have been many lost opportunities for optimizing the management of cancer patients, and for cancer prevention in well individuals," she said.

Dr Rahman and her colleagues wanted to develop a simpler and more effective way to test patients diagnosed with breast cancer for predisposition.

The team began by identifying five categories of high-risk breast cancer: onset before age 40; bilateral breast cancer before age 60; triple-negative breast cancer (estrogen-, progesterone-, and HER2-receptor-negative disease) at any age; breast and ovarian cancer at any age; and breast cancer in a male.

They then used the TruSight cancer gene panel, from Illumina, to test for BRCA mutations and to calculate mutation detection rates. They also looked at the rate of mutation detection for eight other breast cancer predisposition genes the panel tested for.

BRCA1 and/or BRCA2 mutations were detected in 110 (10.8%) of the 1020 breast cancer patients who met the criteria for a high-risk category and underwent testing. If the decision to test had been made on the basis of family history, mutations in 56 (5.5%) patients would have been missed.

And for each individual category, the mutation detection rate was above 10%.

Table. Mutation Detection Rate in the High-risk Five Categories

Cancer Status Detection Rate, %
Onset before age 40 12.1
Bilateral breast cancer before age 60 13.6
Triple-negative breast cancer at any age 10.2
Breast and ovarian cancer at any age 27.8
Breast cancer in a male 11.5


To confirm these findings, Dr Rahman's team then conducted a retrospective study of 2036 patients recruited for the Breast and Ovarian Cancer Susceptibility study.

For every category but male breast cancer, the mutation detection rate ranged from 11.0% to 13.2%. The detection rate for men with breast cancer was just 3.2%, but the sample size too small — only 31 patients — to determine an accurate rate, Dr Rahman reported.

The researchers then used two BRCA mutation risk scores to assess the accuracy of family history as an indicator.

When a Manchester score of at least 15 was set as the threshold, only 53 of the 110 (48.2%) patients with mutations were identified. And when a Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score of at least 10% was used, only 42 (38.2%) of the mutation carriers were identified.

With these risk models, "more than 50% of mutation carriers would not have been eligible for testing based on family history," Dr Rahman said.

When 368 patients with cancer who did not fall into any of the high-risk categories but who had a family history of cancer were assessed, the rate of mutations was 5.4% for patients with a moderate family history, and 7.0% for patients with a strong family history.

The take-home message from this study is that "once cancer-based testing has been done, current family history criteria are not good at predicting the likelihood of having a mutation," Dr Rahman explained.

Pound Wise

In addition, a financial analysis showed that use of the high-risk categories to identify candidates for genetic testing, rather than family history, would save a total of £3,063,681 (US$4,035,480) by preventing 1157 cancers and 222 deaths from breast or ovarian cancer each year.

This strategy appears to offer advantages over family history as a basis for test eligibility, said Ian Campbell, PhD, from the Peter MacCallum Cancer Centre in Melbourne, Australia.

"People's recollection of family history is notoriously bad," he told Medscape Medical News, noting that some people are not always aware of cancers in first-degree relatives. And others might overestimate risk because a more distant female relative died from breast cancer at an advanced age.

If implemented, such a system might reduce the use of pretesting genetic counseling, said Aisha Furqan, a genetic counselor at St. Agnes Medical Center in Fresno, California.

"You might be cutting some costs and time, but really, counseling is invaluable for individuals who don't have preconceived ideas about what genetic testing can or can't do," she said after the presentation.

Women have come to my office and declined genetic testing after counseling because, at that point in their treatment or in their family lives, they just weren't ready for it, she told Medscape Medical News. But they might be interested at another time, she added.

The study was supported by the Wellcome Trust and The National Institute for Health Research. Dr Rahman reports serving on the board of directors of AstraZenca. Dr Campbell and Ms Furqan have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2017 Annual Meeting: Abstract 65. Presented October 18, 2017.

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