Disclosures: The NIH and Breast Cancer Research Foundation supported the CARRIERS Consortium study. The European Union Horizon 2020 research and innovation programs BRIDGES and B-CAST, the Wellcome Trust and Cancer Research UK supported the Breast Cancer Association Consortium study. Couch reports no relevant financial disclosures. Easton reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
January 26, 2021
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Several genetic mutations linked to breast cancer risk among women in general population

Disclosures: The NIH and Breast Cancer Research Foundation supported the CARRIERS Consortium study. The European Union Horizon 2020 research and innovation programs BRIDGES and B-CAST, the Wellcome Trust and Cancer Research UK supported the Breast Cancer Association Consortium study. Couch reports no relevant financial disclosures. Easton reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Certain genetic mutations in breast cancer predisposition genes could inform screening and improve management of women at low risk for the disease, according to results of two studies published in The New England Journal of Medicine.

“Traditionally, genetic testing of inherited breast cancer genes has focused on women at high risk who have a strong family history of breast cancer or those who were diagnosed at an early age, such as under 45 years,” Fergus J. Couch, PhD, pathologist at Mayo Clinic in Rochester, Minnesota, and an author on one of the studies, said in a press release. “The risk for developing breast cancer is generally lower for women without a family history of the disease. When we looked at all women, we found that 30% of breast cancer mutations occurred in women who are not high risk.”

Genetic researcher Adobe
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In another study, Douglas F. Easton, PhD, director of the Center for Cancer Genetic Epidemiology at University of Cambridge in the U.K., and colleagues identified specific genetic mutations that appeared most clinically useful for inclusion on panels for prediction of breast cancer risk. The researchers also provided estimates of risk associated with protein-truncating variants that could further guide genetic counseling.

Douglas F. Easton, PhD
Douglas F. Easton

“We have known for a long time that inheritance of genetic variants in certain genes is associated with an increased risk for breast cancer,” Easton told Healio. “Some of these genes, such as BRCA1 and BRCA2, are well-established, but for many other genes, their involvement is less clear and the level of risk is unclear. In recent years, genetic testing has become widespread, both within health care services and through private companies. The aim of our study was to define which genes have clear evidence of breast cancer risk and could be useful for genetic counseling.”

CARRIERS Consortium

In the first study, Couch and colleagues used a custom multigene amplicon-based panel to perform sequencing and identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (cases) and 32,544 women without breast cancer (controls) from population-based studies included in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. The consortium aims to provide a better understanding of genetic and environmental risk factors for breast cancer with the use of data from 17 large U.S. epidemiology studies focused on women in the general population who develop breast cancer.

Women in the case group had a slightly higher mean age (62.07 years vs. 61.22 years) and were more likely to be white (78.9% vs. 76.2%) than those in the control group.

Researchers detected pathogenic variants in 12 established breast cancer-predisposition genes among 5.03% (95% CI, 4.79-5.27) of women with breast cancer and 1.63% (95% CI, 1.5-1.78) of controls. These included variants in ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53.

Pathogenic variants associated with high risk for breast cancer included those in BRCA1 (OR = 7.62; 95% CI, 5.33-11.27) and BRCA2 (OR = 5.23; 95% CI, 4.09-6.77) whereas variants in PALB2 appeared associated with moderate risk (OR =3.83; 95% CI, 2.68-5.63).

Researchers also observed associations between pathogenic variants in BARD1, RAD51C and RAD51D and increased risk for ER-negative and triple-negative breast cancers. Women who harbored variants in ATM, CDH1 and CHEK2 appeared to be at increased risk for ER-positive breast cancer.

Pathogenic variants in 16 candidate breast cancer-predisposition genes, including c.657_661del5 founder variant in NBN, did not appear to be associated with increased breast cancer risk, according to the researchers.

“We anticipate that the estimates from the population-based CARRIERS analysis will inform cancer screening and other risk-management strategies for women with pathogenic variants in cancer-predisposition genes in the general population,” the researchers wrote.

They noted several limitations of the study, including the fact that enrollment was limited to women aged 50 years or older in certain population-based studies in the CARRIERS Consortium, which may have influenced the generalizability of the aggregate estimates of the prevalence of variants in BRCA1 and BRCA2 to younger women.

Breast Cancer Association Consortium

Easton and colleagues used a panel of 34 putative susceptibility genes to perform genetic sequencing on samples from 60,466 women with breast cancer (cases) and 53,461 women without breast cancer (controls) who participated in 44 studies of the Breast Cancer Association Consortium.

They performed separate analyses for protein-truncating variants and rare missense variants among these genes to estimate ORs for breast cancer, as well as tumor subtypes. Missense-variant associations were assessed according to domain and classification of pathogenicity.

Among the 34 genes analyzed, nine mutations — BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, RAD51C, RAD51D and TP53 — showed clear evidence of breast cancer risk, according to Easton.

“Certain other genes may also be associated, but importantly, for more than half of the genes we tested, we were able to exclude a more than twofold risk,” Easton said.

In addition, an overall risk for breast cancer was associated with protein-truncating variants in seven genetic mutations, including BARD1 (OR = 2.09; 95% CI, 1.35-3.23), RAD51C (OR = 1.93; 95% CI, 1.2-3.11), RAD51D (OR = 1.8; 95% CI, 1.11-2.93), PTEN (OR = 2.23; 95% CI, 0.85-6), NF1 (OR = 1.76; 95% CI, 0.96-3.21), TP53 (OR = 3.06; 95% CI, 0.63-14.91) and MSH6 (OR = 1.96; 95% CI, 1.15-3.33).

Researchers also found significantly stronger associations between ATM (OR = 2.33; 95% CI, 1.87-2.91) and CHEK2 (OR = 2.67; 95% CI, 2.3-3.11) and risk for ER-positive vs. ER-negative breast cancer.

“We found that the type of breast cancer differs by gene, in most cases the mutations tend to predispose to [hormone receptor]-negative breast cancer, with the main exceptions being ATM and CHEK2, where mutations tend to give rise to ER-positive breast cancer,” Easton said.

“These data will help to determine breast cancer risks and therefore offer appropriate advice regarding screening and potentially risk-reducing medication or surgery,” he added. “In addition to the family history setting, genetic testing is becoming more widespread in the oncology setting, such as through tumor sequencing, and this type of information will help provide appropriate advice to relatives of [patients with cancer] found to have mutations in these genes.”

It is important to emphasize that although these genes are important, cancer risk is determined by other genetic and lifestyle factors, Easton added.

“Best estimates for breast cancer risk are provided by combining all of these factors, which can be done by using the BOADICEA model, for example, which is available to clinicians for this purpose,” Easton said.

References:

Breast Cancer Association Consortium. N Engl J Med. 2021;doi:10.1056/NEJMoa1913948.
Hu C, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2005936.

For more information:

Douglas F. Easton, PhD, can be reached at the University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom; email: dfe20@medschl.cam.ac.uk.