
Editor’s Note: With the ongoing advancements in breast cancer research, BRCA gene mutations, as a significant genetic risk factor for breast cancer, have attracted increasing attention. In this article, Dr. Songqing Ye from Fujian Provincial Hospital will provide a detailed discussion on the prognosis and treatment advances for BRCA-mutated breast cancer patients, covering the association between BRCA genes and breast cancer, the impact of genetic mutations on prognosis, treatment options, and a comprehensive review of the latest clinical research findings.
Breast cancer is the most common malignancy among women globally and the second most common malignancy among women in China. The incidence continues to rise at a rate of 1% annually. Approximately 5.3% of breast cancer patients carry BRCA1/2 mutations (1.8% for BRCA1, 3.5% for BRCA2). Among these, about 17% of triple-negative breast cancer (TNBC) patients carry BRCA mutations, 6% of HR+ breast cancer patients carry BRCA mutations, and about 2% of HER2+ breast cancer patients carry BRCA mutations.
BRCA1/2 genes are known as breast cancer susceptibility genes and are closely related to tumor suppressor genes and hereditary breast cancer. Younger breast cancer patients tend to have more genetic predispositions. A large non-selective cohort study found that, compared to non-carriers (average age of diagnosis 51.4 years), BRCA1 carriers (average age of diagnosis 44.8 years) and BRCA2 carriers (average age of diagnosis 47.8 years) were diagnosed with breast cancer at significantly younger ages. Studies show that the incidence of BRCA mutations is higher in younger breast cancer patients, and these mutations can be inherited in a dominant manner, leading to a significantly increased risk of breast cancer and ovarian cancer in family members. There is also an increased risk of prostate cancer, pancreatic cancer, and other cancers.
Does Genetic Mutation Affect Overall Survival for Breast Cancer Patients? The Controversy and Debate on the Prognosis of BRCA Mutations
A preclinical study involving 68 BRCA1/2-mutated breast cancer patients analyzed 75 tumor samples and found that the grading of BRCA1 and BRCA2 tumors was significantly higher than that of sporadic tumors, with 90% of BRCA1 tumors being grade 3, compared to 47% in sporadic tumors. BRCA-related breast cancer has a higher incidence of contralateral breast cancer and second primary cancers compared to sporadic breast cancer. A large cohort study in China showed that, compared to non-carriers, the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers was significantly increased by 4.52 times and 5.54 times, respectively. Another cohort analysis also indicated that BRCA1 or BRCA2-mutated breast cancer patients had a higher risk of developing second primary cancers. Specifically, the incidence of second primary cancers was 19.0% in BRCA1-mutated patients, 21.0% in BRCA2-mutated patients, and only 5.9% in BRCA wild-type patients. Early studies suggested that BRCA mutations were associated with poorer prognosis. For example, a meta-analysis published in Medicine in 2016 (n=105220) showed that BRCA mutation carriers had worse overall survival (OS) compared to non-carriers. A 2018 cohort study published in BMC Cancer involving 480 high-risk patients with hereditary breast cancer found that the 5-year disease-free survival (DFS) rate for BRCA mutation carriers was 73.3%, compared to 91.1% for non-carriers. The 5-year distant metastasis-free survival (DMFS) rate for BRCA mutation carriers was 79.7%, compared to 94.2% for non-carriers, with race being an important factor. Chinese patients seemed to be more adversely affected by BRCA mutations. Some studies have reported that germline CHEK2 1100delC mutations in breast cancer patients are linked to poorer prognosis.
However, more recent studies have indicated that BRCA mutation status does not significantly impact survival prognosis. The prospective POSH study showed similar 2, 5, and 10-year OS rates for BRCA mutation carriers and non-carriers. In TNBC patients, BRCA mutation carriers had a higher 2-year OS rate than non-carriers, but the 5- and 10-year OS rates showed no statistically significant differences, suggesting that BRCA mutation patients may have an early survival advantage in TNBC. A 2018 prospective randomized controlled study published in Lancet Oncology (n=2733) showed similar survival rates for young breast cancer patients (≤40 years) with or without BRCA mutations. A 2019 domestic study published in Int J Cancer (n=2769) showed that, compared to non-carriers, BRCA1 mutation carriers had a significantly lower disease-free survival (DFS), while OS showed no statistical difference. A 2021 meta-analysis published in Breast Cancer Research and Treatment included 35,972 patients (32,308 BRCA wild-type patients and 3,402 BRCA mutation carriers). Eight studies were prospective cohort studies, and 22 studies were retrospective cohort studies, with an average age of 45.6 years. The analysis showed: 1) For BRCA1 mutation patients, OS was worse compared to wild-type patients, but no significant differences were found in DFS, BCSS, and DMFS. 2) For BRCA2 mutation patients, DFS and BCSS were worse compared to wild-type patients, but no significant differences were found in OS and DMFS.
Prognosis may vary among different molecular subtypes of BRCA-mutated breast cancer. A study involving 4,709 BRCA patients from 78 centers worldwide found that HR+ patients had a higher rate of distant recurrence but a lower rate of second primary breast cancers. Compared to other subtypes, Luminal A patients had the worst long-term DFS. Current studies suggest that BRCA mutation patients may not have worse prognoses. The inconsistency in research conclusions may be attributed to the increasing focus on BRCA mutation patients, clinical research targeting these patients, and advances in treatment strategies such as improved chemotherapy regimens, PARP inhibitors, and prophylactic surgeries. Thanks to continuous improvements in precision treatments, the prognosis for BRCA mutation patients has been improving. More prospective studies are needed to clarify the relationship between BRCA mutations and breast cancer prognosis.
How to Choose Between Breast Conserving Surgery and Mastectomy for gBRCA1/2 Mutation Breast Cancer Patients? Is Prophylactic Contralateral Mastectomy Recommended?
There is no significant difference in local recurrence events between BRCA mutation patients and non-mutated patients, but differences in second malignancies and new tumors are statistically significant. Data from Peking University Cancer Hospital published in JAMA Network Open in 2021 (2003.10-2015.5; n=8396) showed that, after adjusting for clinical pathological factors and auxiliary treatments, the survival rate for breast-conserving surgery in BRCA1/2 mutation carriers was similar to that of mastectomy with or without radiation. In non-mutated patients, the survival rate for breast-conserving surgery was significantly higher than for mastectomy with or without radiation. For BRCA1/2 mutation patients, breast-conserving surgery is a viable option, and when the clinical evaluation of the tumor is appropriate, breast-conserving therapy can be selected.
A large international study presented at the 2024 SABCS conference, titled “Relationship Between Risk-Reducing Surgery and Survival in Young BRCA Carriers with Breast Cancer,” included over 5,200 young breast cancer patients carrying pathogenic or potentially pathogenic BRCA mutations from 109 centers in 33 countries. The study found that both risk-reducing mastectomy and salpingo-oophorectomy significantly improved overall survival, disease-free survival, and cancer recurrence intervals. Increasingly, international guidelines recommend these two surgeries for BRCA mutation breast cancer patients. However, based on China’s national conditions, the Chinese Clinical Practice Guidelines for Prophylactic Mastectomy in Hereditary Breast Cancer (2024 version) recommend that young hereditary breast cancer patients (diagnosed at ≤40 years old) with BRCA1/2, CHEK2, or TP53 mutations, or a history of chest radiation before the age of 30, may opt for contralateral prophylactic mastectomy (CPM). The team at Peking University Cancer Hospital, led by Xie Yuntao, has developed the BRCA-CRisk prediction model to assess the risk of contralateral breast cancer in Chinese BRCA1/2 mutation carriers, providing better recommendations for clinical decision-making and offering more precise risk simulations for contralateral breast cancer.
Adjuvant Therapy for Early BRCA Mutation Breast Cancer Patients
The OlympiA study is an international phase III clinical trial that enrolled 1,836 HER2-negative, high-risk early breast cancer patients carrying germline BRCA mutations. After completing neoadjuvant, adjuvant, and local treatments, patients were randomized to receive one year of olaparib or placebo. The median age was 42 years, with 81.5% having TNBC. At the 2024 SABCS conference, new data from the OlympiA study was presented, showing consistent iDFS and DDFS benefits across all predefined subgroups, including high-risk hormone receptor-positive patients, after an average follow-up of 6.1 years (with a maximum of 9.6 years).
Based on the preliminary results of the OlympiA study, olaparib has been recommended by authoritative domestic and international guidelines. Olaparib was officially approved in China on December 25, 2024, for the adjuvant treatment of adults with HER2-negative, high-risk early breast cancer carrying harmful or suspected harmful germline BRCA mutations (gBRCAm), after receiving neoadjuvant or adjuvant chemotherapy. This approval undoubtedly opens up a new era of precision treatment for high-risk early breast cancer patients with gBRCA1/2 mutations.
Does BRCA Mutation Affect the Treatment Efficacy in Breast Cancer?
In TNBC, the KEYNOTE-522 study enrolled 82% of patients without clear gBRCA status. Of the 54 known gBRCAm carriers, no subgroup analysis was possible due to the small sample size. In the monarchE study, about 3.5% of patients had gBRCA mutations. Despite the small number of patients, data presented at the 2024 ESMO conference indicated that abemaciclib adjuvant therapy showed clear benefits in the gBRCA-mutated subgroup. Both the KEYNOTE-522 and OlympiA studies showed survival benefits for high-risk TNBC patients with gBRCA1/2 mutations. Patients who did not achieve a pCR after neoadjuvant pembrolizumab can be considered for combination or sequential olaparib therapy. In the advanced TOPACIO study, no significant additive toxicity was found when combining pembrolizumab and niraparib.
For high-risk ER+/PR+/HER2- breast cancer patients with gBRCA1/2 mutations, combined abemaciclib and olaparib therapy may lead to more severe adverse reactions. For those with non-pCR after neoadjuvant treatment, sequential olaparib therapy can be considered. Preclinical studies suggest that PARP inhibitors may affect the inhibitory effect of CDK4/6 inhibitors on the cell cycle, so sequential use of PARP inhibitors and CDK4/6 inhibitors may be a promising option.
For patients with gBRCA1/2 mutations in TNBC undergoing neoadjuvant therapy, whether chemotherapy combined with immune therapy and PARP inhibitors is feasible is currently being investigated. Fudan University’s Shanghai Cancer Center is conducting research to explore the efficacy and safety of adding PARP inhibitors to existing treatments for patients with homologous recombination repair deficiencies or BRCA mutations.
The OlympiAD trial in germline BRCA1/2-mutated breast cancer patients showed that olaparib significantly prolonged progression-free survival (PFS), from 4.2 months to 7.0 months, with a 42% reduction in the risk of disease progression. Exploratory subgroup analysis showed that olaparib provided more OS benefits in first-line treatment compared to standard treatment.
CDK4/6 inhibitors have become the first-line standard treatment for HR+/HER2- advanced breast cancer. Real-world data indicate that CDK4/6i therapy for advanced breast cancer in gBRCA mutation carriers may not be as effective. In the MONALEESA trial, subgroup analysis showed that BRCA1/2 non-mutant patients had better PFS benefits compared to gBRCA mutation carriers. Data from the 2024 ESMO conference focusing on patients with HR+/HER2- metastatic breast cancer carrying pathogenic BRCA1, BRCA2, or PALB2 mutations showed that sequential use of CDK4/6 inhibitors followed by PARP inhibitors may extend OS, but further research is needed.
Somatic mutations in breast cancer are relatively rare, and there is limited data on this type of mutation. Studies like BROCADE3 and Olaparib have included a few patients with somatic BRCA mutations, showing that somatic BRCA mutation patients may also benefit from PARP inhibitors, although the benefits may not be as significant as in germline mutation patients.
Breast cancer has entered the era of genetic testing, which emphasizes precise risk prediction, early diagnosis, genetic counseling, and clinical treatment decisions. We look forward to more research advancements in the treatment of BRCA-mutated breast cancer patients to transform clinical practices and offer more treatment options for patients, ultimately improving overall prognosis. Additionally, we hope that more new drugs will be approved in China, providing more treatment choices and benefiting more patients.
Dr. Songqing Ye
Chief Physician, Breast Surgery, Fujian Provincial Hospital Deputy Director of the Department of Surgery (Responsible for Daily Work) Member of the Breast Cancer Professional Committee, Chinese Anti-Cancer Association Member of the Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO) Member of the Breast Cancer Group, Chinese Medical Doctor Association Vice Chairman of the Yangtze Academic Belt Breast Cancer Alliance Vice Chairman of the Breast Disease Branch, Fujian Medical Association Editorial Board Member of Gland Surgery Invited Editorial Board Member of Chinese Journal of Breast Diseases