Comparison of Survival After Breast-Conserving Therapy vs Mastectomy Among Patients With or Without the BRCA1/2 Variant in a Large Series of Unselected Chinese Patients With Breast Cancer

Key Points Question Can patients with breast cancer who carry a BRCA1/2 variant safely undergo breast-conserving therapy (BCT)? Findings In this cohort study, 8396 patients with operable primary breast cancer (187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers) underwent BCT, mastectomy with radiotherapy, or mastectomy alone. In multivariable analyses, patients with both the BRCA1 and BRCA2 variants who were treated with BCT had a survival rate at least comparable to those treated with mastectomy with radiotherapy or mastectomy alone. Meaning This study suggests that BCT may be an option for patients who carry a BRCA1/2 variant when the tumor is clinically appropriate for this procedure.

[29][30] These studies, in general, have been limited to a relatively small number of variant carriers, especially BRCA2 variant carriers.In this study, therefore, we compared the survival rates between patients who underwent BCT and patients who underwent mastectomy with or without radiotherapy from a relatively large number of BRCA1/2 variant carriers and noncarriers who were drawn from a large series of unselected patients with breast cancer.

Study Design
We conducted a retrospective cohort study to compare the survival rates of BRCA1/2 variant carriers and noncarriers who underwent BCT, mastectomy with radiotherapy, or mastectomy alone at the Breast Center of Peking University Cancer Hospital from October 1, 2003, to May 31, 2015, in a large consecutive series of patients with operable primary invasive breast cancer who were unselected for age at diagnosis and family history of breast cancer.We also investigated the risk of recurrence in the ipsilateral breast and the risk of contralateral breast cancer in BRCA1/2 variant carriers and noncarriers when they underwent different surgical procedures.Follow-up was censored on May 1, 2020.
Written informed consent was obtained from all participants whose blood samples could be used for research, including genetic testing.We detected BRCA1/2 germline variants for research purposes.
Therefore, the patients and physicians were unaware of the BRCA1/2 variant status when the patients were treated at the breast center.This study was approved by the research and ethics committee of Peking University Cancer Hospital.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Patients and Procedures
A total of 10 269 consecutive patients with primary breast cancer were treated at the breast center, among whom 9822 patients had sufficient and qualified genomic DNA for BRCA1/2 germline variant sequencing.The following patients were excluded from this study: patients with stage IV disease at diagnosis, follow-up time less than 3 months or loss of follow-up after surgery, distant metastasis within 3 months after primary diagnosis, noninvasive breast cancer, no operation was performed, patients receiving breast-conserving surgery who refused to receive radiotherapy, and whether radiotherapy was applied or not was unknown after surgery.The final sample for this retrospective

BRCA1/2 Variant
Germline DNA extracted from peripheral blood samples was tested for the BRCA1/2 variant with multigene panel sequencing 31 and/or Sanger sequencing 32 or multiplex ligation-dependent probe amplification 33

Statistical Analysis
Statistical analysis was performed from May 1 to September

Discussion
In this cohort study of a large, consecutive series of 8396 Chinese patients with primary invasive breast cancer in a single center, we investigated whether BRCA1/2 variant carriers could safely undergo BCT when the breast tumor was suitable for this procedure.We found that BRCA1/2 variant carriers receiving BCT exhibited survival rates at least comparable to that of patients receiving mastectomy with or without radiotherapy after adjusting for clinicopathologic characteristics and adjuvant therapy.As expected,  BCT was associated with significantly better survival than mastectomy with or without radiotherapy among noncarriers after adjusting for all confounding factors.
In this large, consecutive series of unselected patients with breast cancer, all of the patients and physicians were not aware of the BRCA1/2 variant status when they selected BCT or mastectomy, largely depending on the tumor characteristics per se and the preferences of patients and physicians.
Therefore, the percentage of patients who underwent BCT was similar throughout the subgroups (39.0% of BRCA1 carriers, 34.9% of BRCA2 carriers, and 37.4% of noncarriers).In addition, the BRCA1/2 variant status was assessed for all of the participants.All of these features largely decreased selection bias.Therefore, our data represent the real world of clinical practice.8][29][30] Our present study comprised a relatively large number of BRCA1/2 variant carriers to date, particularly BRCA2 variant carriers (304 cases).These advantages enabled us to analyze survival among the BRCA1 and BRCA2 subgroups in univariate and multivariable analyses.The results of our present study in combination with previous studies suggest that the survival rate among BRCA1/2 variant carriers who underwent BCT and the survival rate among BRCA1/2 variant carriers who underwent mastectomy were comparable.
On the other hand, we also noted that patients who received mastectomy with radiotherapy usually had a large tumor or more positive lymph nodes involved compared with those who received BCT or mastectomy alone.In the univariate analyses, we found that BCT showed significantly favorable survival compared with mastectomy with radiotherapy among BRCA1/2 variant carriers and noncarriers, but these differences in BRCA1/2 variant carriers did not reach significance in multivariable analyses.The main reason for these differences not reaching significance was the relatively small sample size of BRCA1/2 variant carriers when stratified by 3 subgroups, particularly for BRCA1 variant carriers.In contrast, BCT showed significantly favorable survival compared with mastectomy with radiotherapy among noncarriers after adjusting for clinicopathologic factors and adjuvant therapy.
We further performed an analysis among patients with clinical stage I and II disease (T3N0M0 excluded) who might be either suitable for BCT or mastectomy.We found that BCT showed a survival  In this study, the IBTR rates were relatively low among the groups in the entire cohort, and there was no significant difference in the BRCA1 variant carrier, BRCA2 variant carrier, and noncarrier groups among the patients who underwent BCT, although BRCA2 variant carriers exhibited a nonsignificantly higher rate than noncarriers (7.5% vs 3.9%).These findings are in line with those of previous studies [19][20][21][22]24,26,34 and indicate that the rates of IBTR were reasonably low among BRCA1/2 variant carriers treated with BCT.
In contrast to IBTR, the rate of contralateral breast cancer was significantly higher among BRCA1/2 variant carriers than among noncarriers regardless of BCT or mastectomy.The high risk of contralateral breast cancer may outweigh the benefits associated with BCT for BRCA1/2 variant carriers.Clinicians may discuss this issue with BRCA1/2 variant carriers who may face a high risk of contralateral breast cancer regardless of BCT or mastectomy.Therefore, a mastectomy and a contralateral prophylactic mastectomy with or without immediate reconstruction is an alternative option for BRCA1/2 variant carriers.

Limitations and Strengths
There are 2 limitations in our study.First, this was a retrospective study, and patients were not randomly assigned to treatment groups.Second, although the size of the entire cohort was large and the number of BRCA1/2 variant carriers was relatively large, the number of variant carriers (ie, BRCA1)

Conclusions
In this study, we found that BRCA1/2 variant carriers treated with BCT have a survival rate comparable to that of those treated with mastectomy with radiotherapy or mastectomy alone after adjusting for clinicopathologic factors and adjuvant therapy in this large, consecutive series of unselected patients with breast cancer.We also demonstrated that, with regard to survival rates, BCT is significantly superior to mastectomy with radiotherapy or mastectomy alone among noncarriers.Nevertheless, our present study clearly shows that BCT could be an option for BRCA1/2 variant carriers when the breast tumor is clinically appropriate for the procedure.

Figure 3 .No
Figure 3. Survival of Noncarriers Receiving Breast-Conserving Therapy (BCT), Mastectomy With Radiotherapy (RT), or Mastectomy Alone Survival After Breast-Conserving Therapy Among Patients With the BRCA1/2 Variant Clear margins were required for BCT; a frozen section diagnosis was performed to judge whether the margins were clear.Patients who underwent BCT and those who underwent mastectomy who have a large tumor (ie, >5 cm) and/or 4 positive lymph nodes are referred for radiotherapy, whereas patients with 1 to 3 positive lymph nodes may receive radiotherapy if they have other high-risk factors.Patients may receive neoadjuvant or adjuvant chemotherapy or endocrine therapy depending on tumor clinicopathologic characteristics and clinical stage.
as described in previous studies.Only variants with definite pathogenicity were

Table 1 .
Clinicopathologic Characteristics of BRCA1 and BRCA2 Variant Carriers and Noncarriers in the Entire Cohort

Table 2 .
Univariate and Multivariable Analyses of Survival for BRCA1 and BRCA2 Variant Carriers and Noncarriers Receiving BCT, Mastectomy With RT, or Mastectomy Alone (positive vs negative), tumor size (>3 vs Յ3 cm), grade (III vs I and II; unknown vs I and II), and adjuvant therapy (chemotherapy vs endocrine therapy or no therapy).
Survival After Breast-Conserving Therapy Among Patients With the BRCA1/2 Variant in the subgroups was relatively small.Thus, caution should be taken when estimating the rate of IBTR amongr BRCA1/2 variant carriers.This study also has some strengths, including the relatively large number of BRCA1/2 variant carriers and the comprehensive information on clinicopathologic characteristics and adjuvant therapy.
JAMA Network Open.2021;4(4):e216259.doi:10.1001/jamanetworkopen.2021.6259(Reprinted) April 23, 2021 10/13 Downloaded From: https://jamanetwork.com/ on 09/22/2023 Clinicopathologic Characteristics for BRCA1 Variant Carriers Receiving Breast-Conserving Therapy, Mastectomy With Radiotherapy, or Mastectomy Alone eTable 2. Clinicopathologic Characteristics for BRCA2 Variant Carriers Receiving Breast-Conserving Therapy, Mastectomy With Radiotherapy, or Mastectomy Alone eTable 3. Clinicopathologic Characteristics for Noncarriers Receiving Breast-Conserving Therapy, Mastectomy With Radiotherapy, or Mastectomy Alone eTable 4. Comparison of Survival Between Breast-Conserving Therapy, Mastectomy With Radiotherapy, and Mastectomy Alone in BRCA1 and BRCA2 Variant Carriers, and Noncarriers Among the Patients with Early-Stage Disease (T3N0M0 Excluded) eTable 5. Risk of Ipsilateral Breast Tumor Recurrence for Patients Receiving Different Type of Surgery Within BRCA1 and BRCA2 Variant Carriers, and Noncarriers eTable 6. Risk of Ipsilateral Breast Tumor Recurrence for BRCA1 and BRCA2 Variant Carriers, and Noncarriers in Subgroups of Different Type of Surgery eTable 7. Risk of Contralateral Breast Cancer for Patients Receiving Different Type of Surgery Within BRCA1 and BRCA2 Variant Carriers, and Noncarriers eFigure 1. Flow Diagram of the Patients Included in This Cohort eFigure 2. Survival Between BRCA1 and BRCA2 Variant Carriers, and Noncarriers in This Cohort