CORRECTION February 4, 2020 // Editor's note: The original headline of this article incorrectly stated that breast cancer gene mutations were found in 30% of all women in a study. The mutations were found in 30% of women with breast cancer who were not at high risk of developing the disease.

New findings of breast cancer gene mutations in women who have no family history of the disease offer a new way of estimating risk and may change the way in which these women are advised on risk management.

The findings come from two large studies, both published on January 20 in The New England Journal of Medicine.

The two articles are "extraordinary" for broadening and validating the genomic panel to help screen women at risk for breast cancer in the future, commented Eric Topol, MD, professor of molecular medicine, Scripps Research, La Jolla, California, and Medscape editor-in-chief.

"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," commented the lead investigator of one of studies, Fergus Couch, PhD, pathologist at the Mayo Clinic, Rochester, Minnesota.

"[Although] the risk of 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," he said.

In both studies, mutations or variants in eight genes BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were found to be significantly associated with breast cancer risk.

However, the distribution of mutations among women with breast cancer differed from the distribution among unaffected women, notes Steven Narod, MD, from the Women's College Research Institute, Toronto, Ontario, Canada, in an accompanying editorial.

"What this means to clinicians, now that we are expanding the use of gene-panel testing to include unaffected women with a moderate risk of breast cancer in the family history, is that our time will increasingly be spent counseling women with CHEK2 and ATM mutations," he writes. Currently these two are "clumped in with 'other genes'.... [M]ost of the pretest discussion is currently focused on the implications of finding a BRCA1 or BRCA2 mutation."

The new findings may lead to new risk management strategies, he suggests. "Most breast cancers that occur in women with a mutation in ATM or CHEK2 are estrogen receptor positive, so these women may be candidates for anti-estrogen therapies such as tamoxifen, raloxifene, or aromatase inhibitors," he writes.

Narod observes that for now, the management of most women with either mutation will consist of screening alone, starting with MRI at age 40 years.

The medical community is not ready yet to expand genetic screening to the general population, cautions Walton Taylor, MD, past president of the American Society of Breast Surgeons (ASBrS).

The ASBrS currently recommends that all patients with breast cancer as well as those at high risk for breast cancer be offered genetic testing. "All women at risk should be tested, and all patients with pathogenic variants need to be managed appropriately it saves lives," Taylor emphasized.

However, "unaffected people with no family history do not need genetic testing at this time," he told Medscape Medical News.

As to what physicians might do to better manage patients with mutations that predispose to breast cancer, Taylor said, "It's surprisingly easy."

Every genetic testing company provides genetic counselors to guide patients through next steps, Taylor pointed out, and most cancer patients have nurse navigators who make sure patients get tested and followed appropriately.

Members of the ASBrS follow the National Comprehensive Cancer Network guidelines when they identify carriers of a pathogenic variant. Taylor says these are very useful guidelines for virtually all mutations identified thus far.

"This research is not necessarily new, but it is confirmatory for what we are doing, and that helps us make sure we are going down the right pathway," Taylor said. "It confirms that what we think is right is right and that matters," he reaffirmed.

The study led by Mayo's Couch was carried out by the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. It involved analyzing data from 17 epidemiology studies that focused on women in the general population who develop breast cancer. For the studies, which were conducted in the United States, pathogenic variants in 28 cancer-predisposition genes were sequenced from 32,247 women with breast cancer (case patients) and 32,544 unaffected women (control persons).

In the overall CARRIERS analysis, the prevalence of pathogenic variants in 12 clinically actionable genes was 5.03% among case patients and 1.63% among control persons. The prevalence was similar in non-Hispanic White women, non-Hispanic Black women, and Hispanic case patients, as well as control persons, they add. The prevalence of pathogenic variants among Asian American case patients was lower, at only 1.64%, they note.

Among patients who had breast cancer, the most common pathogenic variants included BRCA2, which occurred in 1.29% of case patients, followed by CHEK2, at a prevalence of 1.08%, and BRCA1, at a prevalence of 0.85%.

Mutations in BRCA1 increased the risk for breast cancer more than 7.5-fold; mutations in BRCA2 increased that risk more than fivefold, the investigators state.

Mutations in PALB2 increased the risk of breast cancer approximately fourfold, they add.

Prevalence rates for both BRCA1 and BRCA2 among breast cancer patients declined rapidly after the age of 40. The decline in other variants, including ATM, CHEK2, and PALB2, was limited with increasing age.

Indeed, mutations in all five of these genes were associated with a lifetime absolute risk for breast cancer greater than 20% by the age of 85 among non-Hispanic Whites.

Pathogenic variants in BRCA1 or BRCA2 yielded a lifetime risk for breast cancer of approximately 50%. Mutations in PALB2 yielded a lifetime breast cancer risk of approximately 32%.

The risk of having a mutation in specific genes varied depending on the type of breast cancer. For example, mutations in BARD1, RAD51C, and RAD51d increased the risk for estrogen receptor (ER)negative breast cancer as well as triple-negative breast cancer, the authors note, whereas mutations in ATM, CDH1, and CHEK2 increased the risk for ER-positive breast cancer.

"These refined estimates of the prevalences of pathogenic variants among women with breast cancer in the overall population, as opposed to selected high-risk patients, may inform ongoing discussions regarding testing in patients with breast cancer," the BCAC authors observe.

"The risks of breast cancer associated with pathogenic variants in the genes evaluated in the population-based CARRIERS analysis also provide important information for risk assessment and counselling of women with breast cancer who do not meet high-risk selection criteria," they suggest.

The second study was conducted by the Breast Cancer Association Consortium (BCAC) under lead author Leila Dorling, PhD, University of Cambridge, United Kingdom. This group sequenced 34 susceptibility genes from 60,466 women with breast cancer and 53,461 unaffected control persons.

"Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) were associated with a significant risk of breast cancer overall (P < .0001)," the BCAC members report. "For these genes, odds ratios ranged from 2.10 to 10.57," they add.

The association between overall breast cancer risk and mutations in seven other genes was more modest, conferring approximately twice the risk for breast cancer overall, although that risk was threefold higher for the TP53 mutation.

For the 12 genes the consortium singled out as being associated with either a significant or a more modest risk for breast cancer, the effect size did not vary significantly between European and Asian women, the authors note. Again, the risk forER-positive breast cancer was over two times greater for those who had either the ATM or the CHEK2 mutation. Having mutations in BARD1, BRCA1, BRCA1, PALB2, RAD51C, and RAD51D conferred a higher risk for ER-negative disease than for ER-positive disease.

There was also an association between rare missense variants in six genes CHEK2, ATM, TP53, BRCA1, CDH1, and RECQL and overall breast cancer risk, with the clearest evidence being for CHEK2.

"The absolute risk estimates place protein-truncating variants in BRCA1, BRCA2, and PALB2 in the high-risk category and place protein-truncating variants in ATM, BARD1, CHEK2, RAD51CC, and RAD51D in the moderate-risk category," Dorling and colleagues reaffirm.

"These results may guide screening as well as prevention with risk-reducing surgery or medication, in accordance with national guidelines," the authors suggest.

The CARRIERS study was supported by the National Institutes of Health. The study by Dorling and colleagues was supported by the European Union Horizon 2020 research and innovation programs, among others. Narod has disclosed no relevant financial relationships.

New Eng J Med. Published online January 20, 2021. Couch et al, Abstract; BCAC study, Full text; Editorial

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Breast Cancer Gene Mutations Found in 30% of All Women - Medscape