Skip to main content
Premium Trial:

Request an Annual Quote

SABCS Studies Explore Germline Mutations' Varied Effects on Breast Cancer Risk, Survival Outcomes

SABCS 2023-2

SAN ANTONIO – A collection of studies presented at the San Antonio Breast Cancer Symposium on Thursday illustrated the wide-ranging effect of germline genetic mutations on breast cancer risk and survival across tumor subtypes and with different treatment approaches.

Researchers explored the somatic mutation landscape of breast cancers with germline mutations for clues about treatment strategies and to better understand why patient with these mutations have poor outcomes. Experts also assessed the risk of developing another cancer in the opposite breast after surgery and the risk of developing breast cancer in unaffected BRCA1/2 mutation carriers who use contraceptives.

Interplay of somatic and germline mutations

In one study presented at SABCS, researchers aimed to characterize the somatic mutational profiles for breast cancer patients harboring germline mutations compared to those with non-hereditary, or sporadic, breast cancer. The retrospective analysis included 7,500 patients, among which about 5 percent harbored germline pathogenic variants in the cancer-associated genes BRCA1/2, PALB2, ATM, or CHEK2.

The study reaffirmed that certain breast cancer subtypes are more common among patients with pathogenic variants in these genes. For example, there was a higher incidence of triple-negative breast cancer among patients with germline mutations in BRCA1, BRCA2, and PALB2, compared to patients with sporadic cancers without these germline mutations.

Researchers further found that certain somatic mutations were enriched among patients with hereditary cancer. In germline BRCA2-mutant cancers, there were fewer somatic PIK3CA and CCND1 mutations than seen in sporadic cancer. Meanwhile, somatic TP53 alterations were enriched in germline BRCA1-mutant cancers but depleted in germline ATM- and CHEK2-mutant cancers, the study showed, and somatic ESR1 mutations were enriched in germline ATM-mutated cancers.

"There are significant differences in the somatic mutation profile between incidental hereditary and sporadic breast cancer, which highlights the unique tumor biology of germline variant carriers," said Siddhartha Yadav, assistant professor of oncology within Mayo Clinic's College of Medicine, who presented the research. He added these somatic mutation profiles could help oncologists select treatments for their patients.

In discussing this study at the meeting, Banu Arun, a professor in the department of breast medical oncology at MD Anderson Cancer Center, agreed that these somatic mutation findings may have clinical implications for patients with hereditary breast cancer.

Patients with germline BRCA2 mutations in whom somatic PIK3CA mutations are rare may not do well on PI3K-targeted therapies, for example. Patients with germline ATM mutations who are more likely to have somatic ESR1 mutations, meanwhile, may be good candidates for Menarini's selective estrogen receptor degrader Orserdu (elacestrant). That drug was recently approved in the US for treating estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced breast cancer, Arun noted.

However, these potential implications need to be explored prospectively, she said, adding that "the interplay between germline and somatic mutations in breast cancer is very interesting and exciting because, although germline mutations carriers are rare, we are going into personalized therapy [for these patients]."

In another large population study exploring the landscape of germline mutations in breast cancer, also presented by Yadav, researchers found certain groups with these mutations had worse overall survival, including African American patients and patients with ER-positive tumors.

Researchers analyzed data from 16,000 breast cancer patients in the CARRIERS study to better understand how germline mutations affect survival outcomes. After adjusting for a number of factors, including age and menopausal status at diagnosis, race and ethnicity, tumor ER status, type of breast surgery, prophylactic oophorectomy, and use of radiation, chemotherapy, and endocrine agents, researchers found that BRCA1/2 mutation carriers with ER-positive breast cancer may have worse overall survival compared to non-carriers. ATM and CHEK2 mutation carriers, however, had similar overall survival than non-carriers. Among African American women in the study, those who harbored a PALB2 germline mutation had "threefold worse" overall survival compared to non-carriers, Yadav reported.

Contralateral breast cancer risk with surgery

An international study presented at SABCS on Thursday explored the risk of contralateral breast cancer, defined as a second tumor in the opposite breast more than six months after initial breast cancer diagnosis, and breast cancer-specific mortality in patients harboring a BRCA1 mutation according to the different surgical procedures they received. Researchers considered patients who underwent breast-conserving surgery, unilateral mastectomy, or bilateral mastectomy.

Across the cohort of 2,482 patients, 11.5 percent were diagnosed with contralateral breast cancer. Of those who underwent bilateral mastectomy, less than 1 percent were diagnosed with contralateral breast cancer, compared to 11 percent of patients who had unilateral mastectomies and 11 percent of those who underwent breast-conserving surgeries.

The researchers also tracked how many patients with BRCA1-mutant breast cancer died from the disease. In the entire cohort, 11.5 percent of patients died from their breast cancer, but those who had unilateral mastectomies had the lowest 15-year survival, at 78.7 percent, compared to 88.7 percent for patients who had bilateral mastectomies and 86.2 percent for breast-conserving surgery patients.

"Women with a BRCA1 pathogenic variant who elect for bilateral mastectomy are significantly less likely to develop a contralateral breast cancer," said Kelly Metcalfe, a senior scientist at the Women's College Research Institute in Toronto, who presented the research. "And women with a BRCA1 mutation who develop a contralateral breast cancer are twice as likely to die from cancer."

She added that the research does raise questions about surgery options for patients with BRCA1-mutant breast cancer, especially as new treatments come to the market, such as Merck and AstraZeneca's PARP inhibitor Lynparza (olaparib) for early-stage breast cancer patients with BRCA1/2 mutations.

Further research is needed to explore how other factors affect the risk of contralateral breast cancer and overall survival, such as the impact of oophorectomy and the role of other mutations in PALB2 or TP53.

Increased risk with contraception

Another analysis presented at SABCS evaluated whether hormonal contraception use affects cancer risk in patients with germline BRCA1/2 mutations. Kelly-Anne Phillips, co-lead of breast medical oncology at the Peter MacCallum Cancer Center in Melbourne, Australia, presented the analysis, which included data from four prospective studies.

Patients included in the analysis could not have a personal history of breast cancer or a bilateral mastectomy at the time of cohort entry. The prospective studies tracked whether a patient had exposure to a contraceptive and whether they later developed invasive breast cancer or ductal carcinoma in situ (DCIS).

Among 3,882 BRCA1 mutation carriers in the analysis, there were 488 cases of breast cancer, and among the 1,509 BRCA2 mutation carriers, there were 191 breast cancer cases.

"Use of hormonal contraception was statistically significantly associated with increased breast cancer risk for BRCA1 carriers," Phillips said. "There was a risk increase of 3 percent per year of use. For BRCA2, there were no statistically significant associations seen."

She added that physicians needed to weigh the potential increase in breast cancer risk when deciding to prescribe hormonal contraceptives for women with a BRCA1 mutation.

However, Arun, who was not involved with the study, noted that this research needed further confirmation.

"Many studies [in this area] are retrospective, though the current study by Phillips [and colleagues] is prospective and might have a little bit more weight," she said. "It appears from the literature review and from this study that mutation carriers in BRCA2 are not at increased risk. But for BRCA1 carriers, we need to be a little bit more careful when we do the discussions with them [about contraceptives], especially considering that oral contraceptives can reduce ovarian cancer risk."