Patients With Breast Cancer and BRCA1, BRCA2, CHEK2, or PALB2 Germline Pathogenic Variants May Benefit From Enhanced Surveillance

Siddhartha Yadav, MD, MBBS

Women with a breast cancer with known germline pathogenic variants (PV) in BRCA1, BRCA2, CHEK2, or PALB2 may benefit from enhanced surveillance, such as supplemental MRI in addition to mammograms, and other risk-reduction strategies, according to a prospective analysis of 15,104 women which was published in the Journal of Clinical Oncology.¹

The study showed that women carrying a germline BRCA1, BRCA2, or CHEK2 PV were at a significantly elevated risk of contralateral breast cancer (CBC; HR > 1.9). For patients with estrogen receptor (ER)-negative breast cancer, only PALB2 carriers had an elevated risk (HR, 2.9; 95% CI, 1.4-6.4; P = .006). Of note, ATM PV carriers did not demonstrate a significantly increased CBC risk (HR, 1.2; 95% CI, 0.6-2.6; P = .56)—this was true in both the overall and ER-positive populations.

In the premenopausal population, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers for patients with ER-negative breast cancer. In the postmenopausal population, the rates were estimated to be 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.

“Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer and PALB2 PV carriers with ER-negative breast cancer are at significantly increased risk of CBC,” Siddhartha Yadav, MD, MBBS, a medical oncologist wat Mayo Clinic, and co-investigators, wrote in the study. “Premenopausal PV carriers of these 4 genes are at a higher risk of CBC compared with postmenopausal carriers, whereas the CBC risk in PV carriers among women over age 65 years appears to be similar to noncarriers.”

“Among African American women, the risk of CBC also appears to be elevated in BRCA1, BRCA2, CHEK2, and PALB2 PV carriers,” they added. “Germline PVs in ATM are not associated with a significantly increased risk of CBC in this study regardless of age at diagnosis, menopausal status, or race/ethnicity.”

There are no well-established thresholds for recommending contralateral prophylactic mastectomy (CPM) based on CBC risk, according to study authors, and it is therefore unclear whether premenopausal breast cancer survivors with PVs in CHEK2 or PALB2 will derive benefit from CPM. The role of CPM in improving survival is considered controversial even for those carrying BRCA2 or BRCA2.^2-5 In light of this, the decision to recommend CPM for PV carriers should be individualized across multiple factors, and study authors believe that these findings may aid in this decision making.

“The present study provides clinically valuable estimates of CBC risk in PV carriers on the basis of several of these factors, which will aid in decision making on CPM and surveillance strategies,” authors wrote.¹

The study prospectively assessed women who had received ipsilateral surgery for invasive breast cancer as part of the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium.1,5 Investigators assessed their risk of CBC by PV carriers in each gene. The median age at diagnosis for the initial breast cancer was 62 years old. The study had a median follow-up time of 11 years. Approximately 66% of participants were non-Hispanic White and 15% were African American. Notably, compared with the ER–positive population, patients who had ER–negative disease were also more likely to be African American, younger, and premenopausal at initial diagnosis.

The primary analysis characterized the overall cohort compared with women in the general population. The secondary analysis looked at associations by race and ethnicity, age at the time of primary breast cancer diagnosis, menopausal status, and tumor ER status.

In the all-population sample, the frequency of germline PVs—including ATM, BRCA1, BCRA2, CHEK2, or PALB2, was 4.4%. In the ER-positive and ER-negative subsets, the rates of germline PVs were 3.7% and 7.4%. Study authors noted that the study population was similar to the overall CARRIERs study in the following domains: median age at diagnosis, proportion of ER-negative tumors, and frequency of germline PVs. However, the proportion of Black, Hispanic, and Asian women was higher in the current study than in CARRIERS.⁵

Investigators reported a total of 801 CBC events throughout the time of follow-up, including 90 events (11.2%) among ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs. In the adjusted analysis, those with germline PVs in BRCA1, BRCA2, and CHEK2 demonstrated an elevated risk of CBC compared with women without PVs.¹

Specifically, BRCA1 PV carriers had a 2.7-fold increase in their CBC risk (HR, 2.7; 95% CI, 2.0-3.8; P < .001) and BRCA2 PV carriers had a 3.0-fold increased risk (HR, 3.0; 95% CI, 2.1-4.3; P < .001). Elevated risk with BRCA1 and BRCA2 were observed in both the ER-positive and ER-negative population.¹

For those carrying a germline CHEK2 PV, the risk of CBC was elevated 1.9-fold (HR, 1.9; 95% CI, 1.1-3.3; P = .03); among those with ER-positive disease and a CHEK2 PV, the risk was elevated 2.0-fold (HR, 2.0; 95% CI, 1.1-3.5; P = .02). Similar findings were observed among women carrying a c.1100delC CHEK2 PV, although, a combined analysis of women with CHEK2 truncating variants, or missense variants predicted to be deleterious by functional assays (n = 24), showed a lower CBC risk (HR, 1.7; 95% CI, 0.9 -2.9; P = .08). In addition, the CHEK2 p.Ile157Thr (c.470T>C) variant was not shown to substantially elevate CBC risk in either the overall (HR, 1.3; 95% CI, 0.5-3.4; P = .60) or ER–positive populations (HR, 1.1; 95% CI, 0.3-3.3; P = .90).¹

Comparison With General Population

Investigators also assessed findings from 14,237 women with breast cancer from the general population vs those enrolled in CARRIERS. Overall, this population of patients were older and more likely to be postmenopausal. The estimated risk of CBC for those carrying PV in the general population were similar: BRCA1 had an HR of 2.1 (95% CI, 1.2-3.5; P = .05), BRCA2 had a HR of 2.5 (95% CI, 1.5-4.0; P < .001), CHEK2, in the ER-positive population, had an HR of 2.1 (95% CI, 1.1-4.1; P = .03), and PALB2-in the ER-negative population, had an HR of 3.1 (95% CI, 1.2-7.8; P = .02).¹

Varying Factors

Furthermore, in an analysis of race, menopausal, stats, and age, on CBC, investigators observed that, among African American women (n = 2249), the risk of subsequent CBC was increased 2-fold for BRCA1, BRCA2, CHEK2, and PALB2 PV carriers compared with noncarriers. ATM PV carriers did not exhibit significant increases in risk in either race. In terms of menopausal status, the frequencies of germline PVs in the 5 genes was 6.9% in the 4050 premenopausal patients and 3.7% among the 11,050postmenopausal patients.

In premenopausal women, carrying a BRCA1 or BRCA2 PV was not linked to an increased risk of CBC, regardless of ER status, whereas CHEK2 PVC were tied to an increase in the ER-positive population and PALB2 PVs with ER-negative breast cancer. Although the rate of PVs were similar in these 2 groups, the number of CBC events was lower among postmenopausal women, and BRCA2 was the only gene which demonstrated an elevated risk of CBC (HR, 3.0; 95% CI, 1.7-5.2; P < .001).

The frequency of a germline PV across ATM, BRCA1, BRCA2, CHEK2, and PALB2 was 2.6% among the 6010 women diagnoses with initial breast cancer at or above the age of 65 years. Across a median follow-up of 10 years, only 3 CBC events were observed in the group.

Cumulative Incidence

For women with no germline PVs, the cumulative incidence of CBC across a 5-year span was 2.2%. Across a 10-year and 15-year span this increased to 4.3% and 6.2%. The annualized cumulative incidence rate was 0.4% per year. In comparison, for those who carried either BRCA1, BRCA2, CHEK2, and PALB2 germline PVs, the 10-year incidence rates of CBC were 4.0%, 23.1%, 16.9%, 7.9%, and 7.9%, respectively. The 10-year CBC risk for patients with ER-negative disease carrying PALB2 PV was 19.7%.

The 5-year, 10-year, and 15-year cumulative incidence of CBC among PV carriers was consistent with what investigators and anticipated: these rates were generally higher among the premenopausal women although the confidence intervals wide. Moreover, according to study authors, it is important to underscore that the 15-year cumulative incidence of CBC across the premenopausal population, with PVs in BRCA1, BRCA2, CHEK2, and PALB2, was greater than 20%.

References

1. Yadav S, Boddicker NJ, Na J, et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. Published online January 9, 2023. doi:10.1200/JCO.22.01239
2. van Sprundel TC, Schmidt MK, Rookus MA, et al. Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J Cancer. 2005;93(3):287-292. doi:10.1038/sj.bjc.6602703
3. Metcalfe K, Gershman S, Ghadirian P, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: Retrospective analysis. BMJ.2014;348:g226. doi:10.1136/bmj.g226
4. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta-analysis and systematic review. Clin Cancer Res. 2016;22(15):3971-3981. doi:10.1158/1078-0432.CCR-15-1465
5. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440-451. doi:10.1056/NEJMoa2005936

Updated January 30, 2023