Editor’s Note: Among breast cancer patients, 5% to 10% have definite genetic mutations, with gBRCA1/2 mutations accounting for 15% of these cases. Individuals with gBRCA1 mutations have a higher risk of contralateral breast cancer recurrence, making the decision to undergo contralateral prophylactic mastectomy (CPM) a hot topic of discussion. At the 2024 North-South Summit, Professor Jia Wang from The Second Affiliated Hospital of Dalian Medical University delivered a report titled “gBRCA-Mutated Breast Cancer: Should Contralateral Prophylactic Mastectomy Be Considered?” This article reviews the content of the lecture.
Clinical Significance of gBRCA-Mutated Breast Cancer
Professor Jia Wang first introduced the characteristics of individuals with germline BRCA (gBRCA) mutations. She noted that if a patient has already been diagnosed with breast cancer, the average probability of developing cancer in the contralateral breast is 2.5%. However, if the patient carries a gBRCA mutation, the probability increases to 15% to 17%. This significant increase underscores the heightened risk of contralateral breast cancer in gBRCA-mutated breast cancer patients.
Professor Wang then discussed the populations that should undergo gBRCA mutation testing. Clinically, breast cancer patients are tested for gBRCA mutations if they exhibit high-risk characteristics such as diagnosis at ≤45 years old, a high-risk family history, triple-negative breast cancer (TNBC), a history of ovarian, prostate, or pancreatic cancer, or male breast cancer. Different ethnic groups have different gBRCA mutation sites, and not all mutations are pathogenic. Classification systems from the International Agency for Research on Cancer (IARC), the American College of Medical Genetics and Genomics (ACMG), and the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) categorize gBRCA1/2 variants based on risk levels, from pathogenic (class 5, >0.990 probability of being pathogenic) to benign (class 1, <0.001 probability of being pathogenic). The focus is on “pathogenic” mutations, as carriers have a high risk of breast cancer, particularly those under 40 years old. Additionally, gBRCA1 carriers have a higher risk of contralateral breast cancer compared to gBRCA2 carriers.
The Pros and Cons of Contralateral Prophylactic Mastectomy
For carriers of gBRCA1/2 pathogenic mutations, two main issues arise in surgical decision-making: the choice of surgery for the affected breast and whether to remove the contralateral breast prophylactically. Although patients with gBRCA1/2 pathogenic mutations who undergo breast-conserving surgery (BCS) have a higher local recurrence rate than those who undergo mastectomy, their survival is not inferior. The decision regarding the contralateral breast involves weighing the benefits and drawbacks. Tumor-related and non-tumor-related factors influence this decision.
Tumor-Related Factors
Tumor-related factors include the risk of developing breast cancer in the contralateral breast and the impact of contralateral mastectomy on survival. Carriers of gBRCA pathogenic mutations have a 4-5 times higher risk of contralateral breast cancer compared to non-carriers, but individual variations exist. Studies have shown that if the contralateral breast is retained and subsequently develops cancer, even with standardized surgery and adjuvant therapy, the recurrence-free survival is significantly worse than in non-gBRCA mutation carriers. Prophylactic contralateral mastectomy can reduce the breast cancer risk for gBRCA1/2 mutation carriers. However, long-term prospective and retrospective studies have shown inconsistent results regarding the impact on overall survival or disease-free survival.
According to the 2023 SABCS report, prophylactic bilateral mastectomy did not significantly reduce mortality in breast cancer patients with gBRCA1 pathogenic mutations. However, patients who did not undergo prophylactic contralateral mastectomy and later developed contralateral breast cancer had a twofold increased risk of death, with very poor long-term survival.
Non-Tumor-Related Factors
Non-tumor-related factors include the impact of contralateral mastectomy on surgical complications and cosmetic outcomes. Previous studies have found that bilateral breast reconstruction, whether using autologous tissue or implants, has a higher risk of complications compared to unilateral reconstruction. Additionally, surgical complications can delay the start of adjuvant treatments, such as radiation therapy.
In clinical practice, the proportion of bilateral reconstruction surgeries is increasing both domestically and internationally. Studies have shown that contralateral prophylactic mastectomy combined with bilateral breast reconstruction is not highly difficult or risky and that patients generally report high satisfaction with the cosmetic appearance, physical, and psychological outcomes, which can alleviate anxiety and depression.
International and Domestic Guideline Consensus
At the 2021 St. Gallen Conference, 85% of experts recommended prophylactic mastectomy for young gBRCA1/2 mutation carriers. Various guidelines and consensus statements, including the Chinese Expert Consensus on BRCA1/2 Genetic Testing and Clinical Application in Breast Cancer Patients (2018 Edition) and the Consensus Statement of the American Society of Breast Surgeons, indicate a high level of evidence for prophylactic contralateral mastectomy in breast cancer patients with gBRCA mutations. However, the Chinese consensus has certain conditions: for healthy BRCA mutation carriers, prophylactic mastectomy can reduce cancer risk, and bilateral prophylactic mastectomy may be considered (evidence level 3). For breast cancer patients with BRCA mutations, prophylactic contralateral mastectomy may be considered if they have high histological grade and negative hormone receptor status (evidence level 2B). For high-risk young patients under 50, early prophylactic bilateral salpingo-oophorectomy is recommended for maximum benefit (evidence level 2B).
To precisely identify patients with a high risk of contralateral breast cancer recurrence among gBRCA1/2 pathogenic mutation carriers, Professor Jie Yuntao’s team from Peking University Cancer Hospital developed a predictive model incorporating factors such as youth, high-risk family history, specific mutation sites, and endocrine therapy. The research was published in JCO (IF 51), suggesting the model can predict risk.
Current Challenges
Currently, there are several challenges regarding gBRCA mutation carriers. The high cost of gBRCA testing, low patient awareness, and limited accessibility result in insufficient clinical data to guide treatment decisions. Future efforts should aim to include gBRCA testing costs in health insurance coverage. Additionally, determining the optimal timing for gBRCA testing in young breast cancer patients or those with a family history and making appropriate treatment decisions are crucial considerations. More comprehensive predictive models are needed to accurately identify high-risk patients for contralateral breast cancer recurrence, minimizing unnecessary procedures while not missing any high-risk patients.
Professor Jia Wang Chief Physician, Professor, Master’s Supervisor, Medical Doctor, Postdoctoral Researcher Deputy Director of the Department of Breast Surgery, Second Affiliated Hospital of Dalian Medical University Member of the Breast Group of the Oncology Branch of the Chinese Medical Association Young Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Standing Member of the Breast Surgery Branch of the Liaoning Medical Association Deputy Director of the Precision Treatment and Clinical Research Committee for Breast Tumors of the Liaoning Cell Biology Association Deputy Director of the Young Committee of the Minimally Invasive Diagnosis and Treatment Committee for Breast Diseases of the Liaoning Life Sciences Society
Professor Wang has led six Japan and national-level provincial science funds, authored the Clinical Practice Guidelines for Local Treatment of Primary IV Breast Cancer (2022 Edition) of the Chinese Medical Association, and co-authored the Guidelines for the Diagnosis and Treatment of Breast Cancer (2021 and 2022 Editions) of the Chinese Anti-Cancer Association. She has published over 20 SCI articles as the first or corresponding author, with an impact factor exceeding 200. She holds one patent and has co-authored four books. She has received the 2021 Liaoning Provincial Science and Technology Progress Award (Second Prize), the 2021 First Prize in the Dalian Youth Science and Technology Innovation Competition, and the 2021 First Prize in the Dalian Women’s Research Project Achievements.
