Avoid common mistakes on your manuscript.
Multigene panel germline testing is one of the most useful and cost-effective tools for counseling patients with a newly diagnosed breast cancer. Genetic testing provides relevant information regarding the risks of associated malignancies, informs family members of their potential risks, and identifies patients who may be candidates for specific systemic therapies. Moreover, multigene panel testing can provide patients with a unilateral breast cancer information about their risk of a contralateral breast cancer (CBC). This information can then be used to guide management of the contralateral breast.
The cumulative risk of CBC is relatively low (approximately 0.4% per year) among patients with unilateral breast cancer without known germline pathogenic variants (PVs).1 In contrast, the cumulative, 10-year risk of CBC is approximately 30% among patients with unilateral breast cancer and a BRCA1 or BRCA2 PV.2 Many choose to undergo contralateral prophylactic mastectomy (CPM) to reduce that risk. However, the risk of CBC among patients with PVs in moderate-risk genes, such as ATM, PALB2, and CHEK2, is less clear. Additionally, the use of CPM among these women is largely unknown.
The publication of the current study by Zhang et al., evaluating the association of moderate-risk breast cancer genes and CPM, is timely. In this retrospective, single-center study from the Memorial Sloan Kettering Cancer Center, the authors reported that the overall CPM rate among patients with ATM, PALB2, and CHEK2 gene mutations was 39%.3 For patients with PVs in these genes, the CPM rate was 54% compared with 30% for patients with variants of unknown significance (VUS). The authors did not report the use of CPM at their institution during this same time interval for women without genetic mutations or for those who did not undergo genetic testing. Importantly, the findings of this study from a renowned cancer center in New York City may not be generalizable to other breast cancer patients in the United States.
The use of CPM has dramatically increased in the United States and other countries over the past several decades.4,5 The most common reason cited by patients for CPM is fear and anxiety regarding a future CBC.6,7 Data regarding the cumulative risk of CBC for moderate-risk genetic mutations are just now emerging. Bilateral breast cancer was identified in 16% of patients in the study by Zhang et al. with pooling of data amongst the three moderate-risk genes (ATM, CHEK2, and PALB2).3 However, risks of CBC appear to differ depending on the gene involved, age at diagnosis, and primary tumor estrogen receptor status. In the CARRIERS consortium study of 15,104 women with unilateral breast cancer, CHEK2 PV carriers had a 10-year, cumulative CBC incidence of 7.9%.8 Patients with a PALB2 PV did not have a significantly overall increased risk of CBC; however, among patients with estrogen receptor-negative primary cancers, a PALB2 PV was significantly associated with increased risk of CBC, with a 10-year, cumulative incidence similar to that of BRCA1 PV carriers (20% vs. 23%). ATM PV carriers were not at significantly elevated risk of CBC with a 10-year, cumulative incidence of 4%. In a cohort of Dutch patients with CHEK2 PVs, the 10-year, cumulative incidence of CBC was 28.9%,9 which is markedly higher than that reported in the CARRIERS study. So, the data regarding CBC risk among patients with moderate-risk genetic mutations are still evolving.
Presently, there are no established thresholds of CBC risk for recommending CPM. The American Society of Breast Surgeons published a consensus statement in 2016 concluding that CPM should be “discouraged” for women with an average risk of CBC and that CPM “should be considered primarily for women at the highest risk for CBC,” including those with PVs in BRCA1 or BRCA2.10 Of note, the guideline also commented that there is insufficient evidence regarding CBC risk to recommend for or against CPM among patients with PVs in CHEK2, PALB2, or CDH1.
Given our limited information to date, how do physicians advise patients with unilateral breast cancer and moderate-risk genetic mutations about management strategies of the contralateral breast? First, physicians need to understand that the risk of CBC is not the same for all moderate-risk genetic mutations: e.g., the risk is for CHEK2 is considerably higher than for ATM. Additionally, physicians need to emphasize that CBC risk among patients with VUS is indeed unknown. A small proportion of VUS ultimately get reclassified; amongst those, the majority are reclassified as benign variants.11 Nevertheless, nearly a third of the patients with VUS in the cohort by Zhang et al. received CPM.3 Moreover, other factors, such as the estrogen receptor status of the primary tumor, age at diagnosis, and family history, also contribute to CBC risk. Patients should be advised that CPM is associated with increased postoperative complications and longer recovery, which can lead to delays in adjuvant therapy for the known cancer.12 Finally, whereas CPM likely reduces the risk of CBC for patients with moderate-risk PVs, the impact on disease-specific survival is probably minimal, although currently unknown. Shared decision-making with a thorough discussion of CBC risks versus CPM risks therefore can be challenging. More data to guide these discussions are needed.
References
Giannakeas V, Lim DW, Narod SA. The risk of contralateral breast cancer: a SEER-based analysis. Br J Cancer. 2021;125(4):601–10. https://doi.org/10.1038/s41416-021-01417-7. (Epub 2021 May 26 PMID: 34040177).
Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, Olopade OI, Eisen A, Weber B, McLennan J, Sun P, Foulkes WD, Narod SA. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22(12):2328–35. https://doi.org/10.1200/JCO.2004.04.033. (PMID: 15197194).
Zhang JQ, Dos Anjos CH, Sevilimedu V, Crown A, Amoroso KA, Pilewski ML, Robson ME, Gemignani ML, Association of moderate-risk breast cancer genes with contralateral prophylactic mastectomy and bilateral disease. Ann Surg Oncol. 2023. https://doi.org/10.1245/s10434-023-14141-8.
Tuttle TM, Habermann E, Grund E, Morris TJ, Virnig B. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol. 2007;25:5203–9.
Yao K, Stewart AK, Winchester DJ, Winchester DP. Trends in contralateral prophylactic mastectomy for unilateral cancer: a report from the National Cancer Data Base, 1998–2007. Ann Surg Oncol. 2010;17(10):2554–62. https://doi.org/10.1245/s10434-010-1091-3. (Epub 2010 May 12 PMID: 20461470).
Rosenberg SM, Sepucha K, Ruddy KJ, Tamimi RM, Gelber S, Meyer ME, Schapira L, Come SE, Borges VF, Golshan M, Winer EP, Partridge AH. Local therapy decision-making and contralateral prophylactic mastectomy in young women with early-stage breast cancer. Ann Surg Oncol. 2015;22(12):3809–15. https://doi.org/10.1245/s10434-015-4572-6. (Epub 2015 May 1 PMID: 25930247).
Covelli AM, Baxter NN, Fitch MI, McCready DR, Wright FC. ‘Taking control of cancer’: understanding women’s choice for mastectomy. Ann Surg Oncol. 2015;22(2):383–91. https://doi.org/10.1245/s10434-014-4033-7. (Epub 2014 Sep 5 PMID: 25190120).
Yadav S, Boddicker NJ, Na J, Polley EC, Hu C, Hart SN, Gnanaolivu RD, Larson N, Holtegaard S, Huang H, Dunn CA, Teras LR, Patel AV, Lacey JV, Neuhausen SL, Martinez E, Haiman C, Chen F, Ruddy KJ, Olson JE, John EM, Kurian AW, Sandler DP, O’Brien KM, Taylor JA, Weinberg CR, Anton-Culver H, Ziogas A, Zirpoli G, Goldgar DE, Palmer JR, Domchek SM, Weitzel JN, Nathanson KL, Kraft P, Couch FJ. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023;41(9):1703–13. https://doi.org/10.1200/JCO.22.01239. (PMID: 36623243).
Kriege M, Hollestelle A, Jager A, Huijts PE, Berns EM, Sieuwerts AM, Meijer-van Gelder ME, Collée JM, Devilee P, Hooning MJ, Martens JW, Seynaeve C. Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: Impact of adjuvant chemotherapy. Br J Cancer. 2014;111(5):1004–13. https://doi.org/10.1038/bjc.2014.306. (Epub 2014 Jun 10 PMID: 24918820).
Boughey JC, Attai DJ, Chen SL, Cody HS, Dietz JR, Feldman SM, Greenberg CC, Kass RB, Landercasper J, Lemaine V, MacNeill F, Song DH, Staley AC, Wilke LG, Willey SC, Yao KA, Margenthaler JA. Contralateral prophylactic mastectomy (CPM) Consensus Statement from the American Society of Breast Surgeons: Data on CPM outcomes and risks. Ann Surg Oncol. 2016;23(10):3100–5. https://doi.org/10.1245/s10434-016-5443-5. (Epub 2016 Jul 28 PMID: 27469117).
Makhnoon S, Levin B, Ensinger M, Mattie K, Volk RJ, Zhao Z, Mendoza T, Shete S, Samiian L, Grana G, Grainger A, Arun B, Shirts BH, Peterson SK. A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes. Cancer Med. 2023;12(3):2875–84. https://doi.org/10.1002/cam4.5202. (Epub 2022 Nov 24 PMID: 36426404).
Sharpe SM, Liederbach E, Czechura T, Pesce C, Winchester DJ, Yao K. Impact of bilateral versus unilateral mastectomy on short term outcomes and adjuvant therapy, 2003–2010: a report from the National Cancer Data Base. Ann Surg Oncol. 2014;21(9):2920–7. https://doi.org/10.1245/s10434-014-3687-5. (Epub 2014 Apr 12 PMID: 24728739).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosure
The authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tuttle, T.M., Hui, J.Y.C. Breast Cancer Genes and Contralateral Prophylactic Mastectomy: Beyond BRCA. Ann Surg Oncol 30, 6958–6959 (2023). https://doi.org/10.1245/s10434-023-14161-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-023-14161-4