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

Qiting Wan; Liming Su; Tao Ouyang; Jinfeng Li; Tianfeng Wang; Zhaoqing Fan; Tie Fan; Benyao Lin; Yuntao Xie

doi:10.1001/jamanetworkopen.2021.6259

. 2021 Apr 23;4(4):e216259. doi: 10.1001/jamanetworkopen.2021.6259

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

Qiting Wan ¹, Liming Su ¹, Tao Ouyang ¹, Jinfeng Li ¹, Tianfeng Wang ¹, Zhaoqing Fan ¹, Tie Fan ¹, Benyao Lin ¹, Yuntao Xie ^1,^✉

PMCID: PMC8065382 PMID: 33890992

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.

Abstract

Importance

Whether patients with breast cancer who carry a BRCA1/2 variant can safely undergo breast-conserving therapy (BCT) remains controversial.

Objective

To compare survival rates after BCT vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer.

Design, Setting, and Participants

In this cohort study, a large consecutive series of 8396 unselected patients with primary breast cancer underwent either BCT, mastectomy with radiotherapy, or mastectomy alone from October 1, 2003, to May 31, 2015, at the Breast Center of Peking University Cancer Hospital in China. All patients were assessed for BRCA1/2 germline variant status. Statistical analysis was performed from May 1 to September 30, 2020.

Main Outcomes and Measures

The primary outcomes were breast cancer–specific survival (BCSS) and overall survival (OS); secondary outcomes included recurrence-free survival, distant recurrence–free survival, and ipsilateral breast tumor recurrence.

Results

Of these 8396 Chinese patients (8378 women [99.8% women]; mean [SD] age, 50.8 [11.4] years; 187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers), 3135 (37.3%) received BCT, 1511 (18.0%) received mastectomy with radiotherapy, and 3750 (44.7%) received mastectomy alone. After a median follow-up of 7.5 years (range, 0.3-16.6 years), both BRCA1 and BRCA2 variant carriers treated with BCT had similar rates of survival compared with those treated with mastectomy with radiotherapy (BCSS: hazard ratio [HR] for BRCA1, 0.58 [95% CI, 0.16-2.10]; P = .41; HR for BRCA2, 0.46 [95% CI, 0.15-1.41]; P = .17; OS: HR for BRCA1, 0.61 [95% CI, 0.18-2.12]; P = .44; HR for BRCA2, 0.72 [95% CI, 0.26-1.96]; P = .52) or mastectomy alone (BCSS: HR for BRCA1, 0.70 [95% CI, 0.22-2.20]; P = .54; HR for BRCA2, 0.59 [95% CI, 0.18-1.93]; P = .39; OS: HR for BRCA1, 0.77 [95% CI, 0.27-2.21]; P = .63; HR for BRCA2, 0.62 [95% CI, 0.22-1.73]; P = .37) after adjusting for clinicopathologic factors and adjuvant therapy. For noncarriers, patients receiving BCT had significantly better survival than those receiving mastectomy with radiotherapy (BCSS: HR, 0.45 [95% CI, 0.36-0.57]; P < .001; OS: HR, 0.46 [95% CI, 0.37-0.58]; P < .001) or mastectomy alone (BCSS: HR, 0.71 [95% CI, 0.57-0.89]; P = .003; OS: HR, 0.71 [95% CI, 0.58-0.87]; P < .001) in multivariable analyses.

Conclusions and Relevance

This study suggests that BRCA1/2 variant carriers treated with BCT have survival rates at least comparable to those treated with mastectomy with radiotherapy or mastectomy alone and that BCT could be an option for BRCA1/2 variant carriers when the tumor is clinically appropriate for BCT.

This cohort study compares survival rates after breast-conserving therapy vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer.

Introduction

Early randomized clinical trials have demonstrated that breast-conserving therapy (BCT) with radiotherapy is equivalent to mastectomy in overall survival (OS) and breast cancer–specific survival (BCSS) among patients with early-stage breast cancer.^1,2,3,4,5 Since then, BCT has been widely used for patients with early-stage breast cancer worldwide for more than 2 decades. Recent analyses based on population or registry studies involving many patients showed that BCT is associated with even better OS than mastectomy among patients with early-stage breast cancer.^{6,7,8,9,10,11,12,13,14,15} By contrast, it is still debated whether BCT could be safely used for BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variant carriers with breast cancer. It is well documented that women carrying a germline variant in BRCA1/2 genes not only have a high risk of breast cancer but are also at increased risk of developing a second primary breast cancer, particularly in the contralateral breast.^{16,17,18,19,20,21,22,23,24,25,26} Although the results are not fully in concordance, many studies showed that BRCA1/2 variant carriers receiving BCT experienced a higher rate of ipsilateral breast cancer recurrence (especially second primary tumor) than did noncarriers.^{17,18,23,25,26} Therefore, the potential high risk of local recurrence after BCT and other unique features in BRCA1/2 variant carriers with breast cancer raised concerns about whether BCT is associated with survival compared with mastectomy.

Several studies have addressed this issue and found no significant difference in survival rates between BRCA1/2 variant carriers who underwent BCT and those who underwent mastectomy.^27,28,29,30 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.

Methods

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 study included 8396 Chinese patients with operable primary invasive breast cancer (stages I-III) (eFigure 1 in the Supplement).

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.

BRCA1/2 Variant

Germline DNA extracted from peripheral blood samples was tested for the BRCA1/2 variant with multigene panel sequencing³¹ and/or Sanger sequencing³² or multiplex ligation–dependent probe amplification³³ as described in previous studies. Only variants with definite pathogenicity were included. Of these 8396 patients, 187 (2.2%) carried a BRCA1 variant, 304 (3.6%) carried a BRCA2 variant, and 7905 (94.2%) were noncarriers.

Statistical Analysis

Statistical analysis was performed from May 1 to September 30, 2020. The common clinicopathologic characteristics and the types of adjuvant therapy were compared among BRCA1 variant carriers, BRCA2 variant carriers, and noncarriers receiving different types of surgery. Continuous variables were compared using a t test, and categorical variables were compared using the Pearson χ² test.

Follow-up started at the time of pathologic diagnosis from core needle biopsy or surgery. The primary outcomes included BCSS and OS, and the secondary outcomes were recurrence-free survival (RFS) and distant recurrence–free survival (DRFS). Breast cancer–specific survival was defined as the time from the date of diagnosis to death from breast cancer. Overall survival was calculated from the date of diagnosis to death from any cause. Recurrence-free survival was defined as the time from the date of pathologic diagnosis to the date of ipsilateral, regional, or distant recurrence or death from any cause but not including contralateral breast cancer. Distant recurrence–free survival was calculated from the date of diagnosis to distant recurrence or death from any cause. For patients who are alive, the latest date of follow-up was the last time they visited the physician or received a telephone call from the follow-up office of Peking University Cancer Hospital. Survival analyses were conducted using the Kaplan-Meier method, and the log-rank test was used to test differences between survival curves. Univariate and multivariable Cox proportional hazards regression models were used to assess the association between surgery procedures and survival. Multivariable adjustments were conducted for common clinicopathologic characteristics that are clinically relevant, including age at first breast cancer diagnosis; family history of breast and ovarian cancer; year of diagnosis; estrogen receptor, progesterone receptor, and ERBB2 status; nodal status; tumor size and grade; and adjuvant therapy.

Other secondary end points included ipsilateral breast tumor recurrence (IBTR) and contralateral breast cancer. Ipsilateral breast tumor recurrence was defined as a recurrence in the ipsilateral breast or chest wall no matter whether it was true tumor recurrence or a second primary tumor. Contralateral breast cancer was defined as developing invasive breast cancer or ductal carcinoma in situ in the contralateral breast at least 3 months after the primary breast cancer.

Tests were considered statistically significant at a 2-sided P < .05. All statistical analyses were completed in SPSS, version 23.0 software (SPSS Inc).

Results

Cohort Description

A total of 8396 patients (mean [SD] age, 50.8 [11.4] years) with primary invasive breast cancer (stages I-III), including 491 BRCA1/2 variant carriers (5.8%) (187 BRCA1 carriers [2.2%] and 304 BRCA2 carriers [3.6%]) and 7905 noncarriers (94.2%), were included in the final analyses. The detailed clinicopathologic characteristics and treatment information are presented in Table 1.

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

Characteristic	No. (N = 8396)	No. (%)			P value
Characteristic	No. (N = 8396)	BRCA1 carriers (n = 187 [2.2%])	BRCA2 carriers (n =304 [3.6%])	Noncarriers (n = 7905 [94.2%])	BRCA1 carriers vs noncarriers	BRCA2 carriers vs noncarriers	BRCA1 carriers vs BRCA2 carriers
Surgery
BCT	3135	73 (39.0)	106 (34.9)	2956 (37.4)	.79	.18	.25
Mastectomy plus RT	1511	30 (16.0)	67 (22.0)	1414 (17.9)
Mastectomy alone	3750	84 (44.9)	131 (43.1)	3535 (44.7)
Follow-up, y
Mean (SD)	8.1 (3.2)	8.1 (3.5)	7.9 (3.2)	8.1 (3.2)	.76	.50	.52
Median (range)	7.5 (0.3-16.6)	7.7 (0.8-15.6)	7.3 (0.4-16.0)	7.5 (0.3-16.6)
Age, y
Mean (SD)	50.8 (11.4)	44.8 (10.0)	47.6 (10.4)	51.0 (11.4)	<.001	<.001	.004
Median (range)	50 (19-90)	43 (27-81)	47 (21-75)	51 (19-90)
≤45	2913	110 (58.8)	130 (42.8)	2673 (33.8)	<.001	.001	.001
>45	5483	77 (41.2)	174 (57.2)	5232 (66.2)	<.001	.001	.001
Year of diagnosis
2003-2009	3480	87 (46.5)	111 (36.5)	3282 (41.5)	.17	.08	.03
2010-2015	4916	100 (53.5)	193 (63.5)	4623 (58.5)	.17	.08	.03
Family history of any cancer
Yes	2632	112 (59.9)	166 (54.6)	2354 (29.8)	<.001	<.001	<.001
No	5764	75 (40.1)	138 (45.4)	5551 (70.2)	<.001	<.001	<.001
Family history of breast and/or ovarian cancer
Yes	799	71 (38.0)	100 (32.9)	628 (7.9)	<.001	<.001	.25
No	7597	116 (62.0)	204 (67.1)	7277 (92.1)	<.001	<.001	.25
ER status^a
Positive	6071	59 (31.7)	242 (79.6)	5770 (73.0)	<.001	.01	<.001
Negative	2295	127 (68.3)	62 (20.4)	2106 (26.6)	<.001	.01	<.001
Unknown	30	1	0	29
PR status^a
Positive	5475	55 (29.6)	224 (73.7)	5196 (65.7)	<.001	.006	<.001
Negative	2886	131 (70.4)	80 (26.3)	2675 (33.8)	<.001	.006	<.001
Unknown	35	1	0	34
ERBB2 status^a
Positive	1986	13 (7.0)	35 (11.5)	1938 (24.6)	<.001	<.001	.10
Negative	6369	173 (93.0)	269 (88.5)	5927 (75.4)	<.001	<.001	.10
Unknown	41	1	0	40
Molecular type^a
ER positive, PR positive, and ERBB2 negative	5197	58 (31.2)	225 (74.0)	4914 (62.5)	<.001	<.001	<.001
ER negative, PR negative, and ERBB2 negative	1171	115 (61.8)	44 (14.5)	1012 (12.9)
ERBB2 positive	1986	13 (7.0)	35 (11.5)	1938 (24.6)
Unknown	42	1	0	41
Stage^a
I	2490	60 (32.4)	83 (27.8)	2347 (30.5)	.20	.22	.05
II	4664	110 (59.5)	169 (56.5)	4385 (57.0)
III	1027	15 (8.1)	47 (15.7)	965 (12.5)
Unknown	215	2	5	208
Grade^a
I and II	6170	104 (61.2)	221 (81.5)	5845 (84.8)	<.001	.15	<.001
III	1165	66 (38.8)	50 (18.5)	1049 (15.2)	<.001	.15	<.001
Unknown	1061	17	33	1011
Nodal status^a
0	5200	131 (70.1)	174 (57.8)	4895 (62.5)	.05	.10	.005
1-3	2182	44 (23.5)	82 (27.2)	2056 (26.3)
≥4	937	12 (6.4)	45 (15.0)	880 (11.2)
Unknown	77	0	3	74
Tumor size, cm^a,b
≤2	3647	74 (40.4)	137 (45.5)	3436 (44.5)	.29	.84	.55
>2 to 3	2626	67 (36.6)	93 (30.9)	2466 (31.9)
>3 to 5	1544	30 (16.4)	54 (17.9)	1460 (18.9)
>5	393	12 (6.6)	17 (5.6)	364 (4.7)
Unknown	186	4	3	179
Adjuvant therapy
Chemotherapy	1972	115 (61.5)	60 (19.7)	1797 (22.7)	<.001	.003	<.001
Endocrine therapy	2050	11 (5.9)	59 (19.4)	1980 (25.0)
Chemotherapy and endocrine therapy	4073	58 (31.0)	179 (58.9)	3836 (48.5)
None	301	3 (1.6)	6 (2.0)	292 (3.7)

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Abbreviations: BCT, breast-conserving therapy; ER, estrogen receptor; PR, progesterone receptor; RT, radiotherapy.

^{^a}

Percentages calculated without unknown numbers included.

^{^b}

Tumor size is a continuous variable, so size categories overlap.

A total of 3135 patients (37.3%) received BCT, 1511 (18.0%) received mastectomy with radiotherapy, and 3750 (44.7%) received mastectomy alone. The percentages of patients who underwent BCT, mastectomy with radiotherapy, and mastectomy alone were similar among the BRCA1 variant carriers, BRCA2 variant carriers, and noncarriers (Table 1).

Comparison of Survival Among BRCA1 and BRCA2 Variant Carriers and Noncarriers in the Entire Cohort

After a median follow-up of 7.5 years (range, 0.3-16.6 years) in the entire cohort, there were no significant differences in BCSS among BRCA1 variant carriers (88.8%), BRCA2 variant carriers (92.1%), and noncarriers (92.4%; log-rank, P = .22; eFigure 2 in the Supplement). Among the 187 BRCA1 variant carriers, 73 (39.0%) underwent BCT, 30 (16.0%) underwent mastectomy with radiotherapy, and 84 (44.9%) underwent mastectomy alone; the clinicopathologic characteristics of the 3 groups are presented in eTable 1 in the Supplement. The Kaplan-Meier survival curves of RFS, DRFS, BCSS, and OS in the 3 treatment subgroups of BRCA1 variant carriers are presented in Figure 1. Multivariable analyses showed that BRCA1 variant carriers treated with BCT had similar survival compared with those treated with mastectomy with radiotherapy (BCSS: hazard ratio [HR], 0.58 [95% CI, 0.16-2.10]; P = .41; OS: HR, 0.61 [95% CI, 0.18-2.12]; P = .44) or mastectomy alone (BCSS: HR, 0.70 [95% CI, 0.22-2.20]; P = .54; OS: HR, 0.77 [95% CI, 0.27-2.21]; P = .63) after adjusting for age at diagnosis, family history of breast and ovarian cancer, year of diagnosis, tumor size, tumor grade, lymph node, estrogen receptor, progesterone receptor, ERBB2, and adjuvant therapy (Table 2). The detailed data of multivariable analyses regarding RFS and DRFS among BRCA1 variant carriers are presented in Table 2.

Table 2. Univariate and Multivariable Analyses of Survival for BRCA1 and BRCA2 Variant Carriers and Noncarriers Receiving BCT, Mastectomy With RT, or Mastectomy Alone.

Survival, Surgery	Univariate analysis		Multivariable analysis^a
Survival, Surgery	HR (95% CI)	P value	HR (95% CI)	P value
BRCA1 carriers
RFS
BCT vs mastectomy plus RT	0.41 (0.18-0.92)	.03	0.55 (0.21-1.44)	.23
BCT vs mastectomy alone	0.97 (0.45-2.07)	.94	1.04 (0.46-2.35)	.93
DRFS
BCT vs mastectomy plus RT	0.38 (0.17-0.86)	.02	0.59 (0.22-1.61)	.31
BCT vs mastectomy alone	1.20 (0.53-2.70)	.67	1.20 (0.50-2.89)	.68
BCSS
BCT vs mastectomy plus RT	0.43 (0.14-1.27)	.13	0.58 (0.16-2.10)	.41
BCT vs mastectomy alone	0.81 (0.29-2.28)	.69	0.70 (0.22-2.20)	.54
OS
BCT vs mastectomy plus RT	0.42 (0.15-1.15)	.09	0.61 (0.18-2.12)	.44
BCT vs mastectomy alone	0.87 (0.34-2.26)	.78	0.77 (0.27-2.21)	.63
BRCA2 carriers
RFS
BCT vs mastectomy plus RT	0.42 (0.22-0.80)	.009	0.71 (0.34-1.49)	.37
BCT vs mastectomy alone	0.96 (0.49-1.86)	.90	0.73 (0.36-1.48)	.38
DRFS
BCT vs mastectomy plus RT	0.39 (0.20-0.76)	.006	0.66 (0.31-1.44)	.30
BCT vs mastectomy alone	1.06 (0.51-2.19)	.88	0.83 (0.39-1.79)	.64
BCSS
BCT vs mastectomy plus RT	0.31 (0.11-0.83)	.02	0.46 (0.15-1.41)	.17
BCT vs mastectomy alone	0.96 (0.32-2.87)	.95	0.59 (0.18-1.93)	.39
OS
BCT vs mastectomy plus RT	0.37 (0.15-0.92)	.03	0.72 (0.26-1.96)	.52
BCT vs mastectomy alone	0.99 (0.38-2.56)	.98	0.62 (0.22-1.73)	.37
Noncarriers
RFS
BCT vs mastectomy plus RT	0.35 (0.30-0.40)	<.001	0.63 (0.54-0.74)	<.001
BCT vs mastectomy alone	0.87 (0.76-1.00)	.05	0.84 (0.73-0.97)	.02
DRFS
BCT vs mastectomy plus RT	0.27 (0.24-0.32)	<.001	0.49 (0.42-0.59)	<.001
BCT vs mastectomy alone	0.77 (0.66-0.90)	.001	0.75 (0.64-0.88)	<.001
BCSS
BCT vs mastectomy plus RT	0.22 (0.18-0.28)	<.001	0.45 (0.36-0.57)	<.001
BCT vs mastectomy alone	0.75 (0.61-0.93)	.009	0.71 (0.57-0.89)	.003
OS
BCT vs mastectomy plus RT	0.25 (0.21-0.31)	<.001	0.46 (0.37-0.58)	<.001
BCT vs mastectomy alone	0.70 (0.58-0.85)	<.001	0.71 (0.58-0.87)	<.001

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Abbreviations: BCSS, breast cancer–specific survival; BCT, breast-conserving therapy; DRFS, distant recurrence–free survival; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival; RT, radiotherapy.

^{^a}

Hazard ratio adjusted for clinicopathologic characteristics and treatment factors including age at first breast cancer diagnosis (≤45 vs >45 years), family history of breast and ovarian cancer (with vs without), year of diagnosis (2003-2009 vs 2010-2015), estrogen receptor status, progesterone receptor status, ERBB2 status, lymph node status (positive vs negative), tumor size (>3 vs ≤3 cm), grade (III vs I and II; unknown vs I and II), and adjuvant therapy (chemotherapy vs endocrine therapy or no therapy).

Among the 304 BRCA2 variant carriers, 106 (34.9%) underwent BCT, 67 (22.0%) underwent mastectomy with radiotherapy, and 131 (43.1%) underwent mastectomy alone; the clinicopathologic characteristics of the 3 groups are presented in eTable 2 in the Supplement. The Kaplan-Meier survival curves of RFS, DRFS, BCSS, and OS in the 3 treatment subgroups of BRCA2 variant carriers are presented in Figure 2. Multivariable analyses showed that BRCA2 variant carriers treated with BCT had similar survival compared with those treated with mastectomy with radiotherapy (BCSS: HR, 0.46 [95% CI, 0.15-1.41]; P = .17; OS: HR, 0.72 [95% CI, 0.26-1.96]; P = .52) or mastectomy alone (BCSS: HR, 0.59 [95% CI, 0.18-1.93]; P = .39; OS: HR, 0.62 [95% CI, 0.22-1.73]; P = .37) (Table 2). The details of RFS and DRFS are presented in Table 2.

Among the 7905 noncarriers, 2956 (37.4%) underwent BCT, 1414 (17.9%) underwent mastectomy with radiotherapy, and 3535 (44.7%) underwent mastectomy alone; the clinicopathologic characteristics of the 3 groups are presented in eTable 3 in the Supplement. The Kaplan-Meier survival curves of RFS, DRFS, BCSS, and OS in the 3 treatment subgroups of noncarriers are presented in Figure 3. Noncarriers receiving BCT had a significantly better survival than those receiving mastectomy with radiotherapy (BCSS: HR, 0.45 [95% CI, 0.36-0.57]; P < .001; OS: HR, 0.46 [95% CI, 0.37-0.58]; P < .001) or mastectomy alone (BCSS; HR, 0.71 [95% CI, 0.57-0.89]; P = .003; OS: HR, 0.71 [95% CI, 0.58-0.87]; P < .001) in multivariable analyses (Table 2). The details of RFS and DRFS are presented in Table 2.

Comparison of Survival Among BRCA1 and BRCA2 Variant Carriers and Noncarriers With Early-Stage Disease

Patients with early-stage disease (ie, stages I and II) may be suitable for either BCT or mastectomy. Therefore, in this cohort, we compared the survival rates between patients with stage I and II disease (T3N0M0 excluded) who underwent BCT and those who underwent mastectomy with or without radiotherapy. Multivariable analyses still showed that BRCA1/2 variant carriers treated with BCT had a similar survival to those treated with mastectomy with radiotherapy (BCSS: HR for BRCA1, 1.31 [95% CI, 0.12-14.49]; P = .83; HR for BRCA2, 0.76 [95% CI, 0.13-4.50]; P = .77; OS: HR for BRCA1, 1.31 [95% CI, 0.13-13.33]; P = .82; HR for BRCA2, 0.98 [95% CI, 0.18-5.21]; P = .98) or mastectomy alone (BCSS: HR for BRCA1, 1.12 [95% CI, 0.30-4.22]; P = .87; HR for BRCA2, 0.90 [95% CI, 0.23-3.60]; P = .89; OS: HR for BRCA1, 1.29 [95% CI, 0.39-4.24]; P = .68; HR for BRCA2, 0.60 [95% CI, 0.16-2.20]; P = .44) (eTable 4 in the Supplement). Regarding noncarriers, we found that those who underwent BCT had significantly better survival than those who underwent mastectomy with radiotherapy (BCSS: HR, 0.56 [95% CI, 0.40-0.79]; P = .001; OS: HR, 0.58 [95% CI, 0.43-0.80]; P = .001) and those who underwent mastectomy alone (BCSS: HR, 0.69 [95% CI, 0.54-0.90]; P = .006; OS: HR, 0.68 [95% CI, 0.54-0.85]; P = .001) in multivariable analyses (eTable 4 in the Supplement).

IBTR and Contralateral Breast Cancer

The rates of IBTR were 2.1% for BRCA1 variant carriers (4 of 187), 4.6% for BRCA2 variant carriers (14 of 304), and 3.1% for noncarriers (249 of 7905) in the entire cohort (eTable 5 in the Supplement). The IBTR rates among BRCA1 variant carriers were 1.4% for BCT (1 of 73), 0.0% for mastectomy with radiotherapy (0 of 30), and 3.6% for mastectomy alone (3 of 84). The IBTR rates among BRCA2 variant carriers were 7.5% for BCT (8 of 106), 1.5% for mastectomy with radiotherapy (1 of 67), and 3.8% for mastectomy alone (5 of 131). The IBTR rates among noncarriers were 3.9% for BCT (115 of 2956), 2.7% for mastectomy with radiotherapy (38 of 1414), and 2.7% for mastectomy alone (96 of 3535) (eTable 5 in the Supplement). BRCA2 variant carriers who underwent BCT showed a nonsignificantly higher IBTR rate than BRCA1 variant carriers and noncarriers who underwent BCT (odds ratio, 2.02 [95% CI, 0.96-4.25]; P = .07; eTable 6 in the Supplement).

The rates of contralateral breast cancer among BRCA1 and BRCA2 variant carriers were significantly higher than that among noncarriers (BRCA1 vs noncarriers, 13.9% [26 of 187] vs 2.5% [198 of 7905]; P < .001; BRCA2 vs noncarriers, 13.5% [41 of 304] vs 2.5% [198 of 7905]; P < .001) (eTable 7 in the Supplement). The rates of contralateral breast cancer among BRCA1 variant carriers were 13.7% for those receiving BCT (10 of 73), 20.0% for those receiving mastectomy with radiotherapy (6 of 30), and 11.9% for those receiving mastectomy alone (10 of 84), whereas the rate of contralateral breast cancer was significantly higher among BRCA2 variant carriers treated with mastectomy alone than among those treated with BCT (19.8% [26 of 131] vs 6.6% [7 of 106]; P = .003) and was nonsignificantly higher than among those treated with mastectomy with radiotherapy (19.8% [26 of 131] vs 11.9% [8 of 67]; P = .16).

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. Several previous studies also compared the survival rates of BRCA1/2 variant carriers who underwent BCT or mastectomy and found no difference in BCSS and OS between BCT and mastectomy.^27,28,29,30 However, the sample size of some studies was relatively small, particularly for BRCA2 variant carriers.^28,29,30 Therefore, these studies could not comprehensively analyze the survival of the BRCA2 subgroup, especially for multivariable analyses.^27,28,29,30 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 rate similar to mastectomy with or without radiotherapy among BRCA1/2 variant carriers in this subset of patients.

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) 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.

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.

Supplement.

eTable 1. 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

Click here for additional data file.^{(898.7KB, pdf)}

References

1.Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med. 1995;332(14):907-911. doi: 10.1056/NEJM199504063321402 [DOI] [PubMed] [Google Scholar]
2.van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst. 2000;92(14):1143-1150. doi: 10.1093/jnci/92.14.1143 [DOI] [PubMed] [Google Scholar]
3.Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227-1232. doi: 10.1056/NEJMoa020989 [DOI] [PubMed] [Google Scholar]
4.Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-1241. doi: 10.1056/NEJMoa022152 [DOI] [PubMed] [Google Scholar]
5.Litière S, Werutsky G, Fentiman IS, et al. Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial. Lancet Oncol. 2012;13(4):412-419. doi: 10.1016/S1470-2045(12)70042-6 [DOI] [PubMed] [Google Scholar]
6.Hwang ES, Lichtensztajn DY, Gomez SL, Fowble B, Clarke CA. Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. Cancer. 2013;119(7):1402-1411. doi: 10.1002/cncr.27795 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Agarwal S, Pappas L, Neumayer L, Kokeny K, Agarwal J. Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer. JAMA Surg. 2014;149(3):267-274. doi: 10.1001/jamasurg.2013.3049 [DOI] [PubMed] [Google Scholar]
8.Fisher S, Gao H, Yasui Y, Dabbs K, Winget M. Survival in stage I-III breast cancer patients by surgical treatment in a publicly funded health care system. Ann Oncol. 2015;26(6):1161-1169. doi: 10.1093/annonc/mdv107 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Hartmann-Johnsen OJ, Kåresen R, Schlichting E, Nygård JF. Survival is better after breast conserving therapy than mastectomy for early stage breast cancer: a registry-based follow-up study of Norwegian women primary operated between 1998 and 2008. Ann Surg Oncol. 2015;22(12):3836-3845. doi: 10.1245/s10434-015-4441-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Hofvind S, Holen Å, Aas T, Roman M, Sebuødegård S, Akslen LA. Women treated with breast conserving surgery do better than those with mastectomy independent of detection mode, prognostic and predictive tumor characteristics. Eur J Surg Oncol. 2015;41(10):1417-1422. doi: 10.1016/j.ejso.2015.07.002 [DOI] [PubMed] [Google Scholar]
11.Onitilo AA, Engel JM, Stankowski RV, Doi SA. Survival comparisons for breast conserving surgery and mastectomy revisited: community experience and the role of radiation therapy. Clin Med Res. 2015;13(2):65-73. doi: 10.3121/cmr.2014.1245 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.van Maaren MC, de Munck L, de Bock GH, et al. 10 Year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet Oncol. 2016;17(8):1158-1170. doi: 10.1016/S1470-2045(16)30067-5 [DOI] [PubMed] [Google Scholar]
13.Lagendijk M, van Maaren MC, Saadatmand S, et al. Breast conserving therapy and mastectomy revisited: breast cancer–specific survival and the influence of prognostic factors in 129,692 patients. Int J Cancer. 2018;142(1):165-175. doi: 10.1002/ijc.31034 [DOI] [PubMed] [Google Scholar]
14.Lazow SP, Riba L, Alapati A, James TA. Comparison of breast-conserving therapy vs mastectomy in women under age 40: national trends and potential survival implications. Breast J. 2019;25(4):578-584. doi: 10.1111/tbj.13293 [DOI] [PubMed] [Google Scholar]
15.Wrubel E, Natwick R, Wright GP. Breast-conserving therapy is associated with improved survival compared with mastectomy for early-stage breast cancer: a propensity score matched comparison using the National Cancer Database. Ann Surg Oncol. 2021;28(2):914-919. doi: 10.1245/s10434-020-08829-4 [DOI] [PubMed] [Google Scholar]
16.Mavaddat N, Peock S, Frost D, et al. ; EMBRACE . Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812-822. doi: 10.1093/jnci/djt095 [DOI] [PubMed] [Google Scholar]
17.Robson M, Levin D, Federici M, et al. Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst. 1999;91(24):2112-2117. doi: 10.1093/jnci/91.24.2112 [DOI] [PubMed] [Google Scholar]
18.Haffty BG, Harrold E, Khan AJ, et al. Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet. 2002;359(9316):1471-1477. doi: 10.1016/S0140-6736(02)08434-9 [DOI] [PubMed] [Google Scholar]
19.Kirova YM, Stoppa-Lyonnet D, Savignoni A, Sigal-Zafrani B, Fabre N, Fourquet A; Institut Curie Breast Cancer Study Group . Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer. 2005;41(15):2304-2311. doi: 10.1016/j.ejca.2005.02.037 [DOI] [PubMed] [Google Scholar]
20.Robson M, Svahn T, McCormick B, et al. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer. 2005;103(1):44-51. doi: 10.1002/cncr.20728 [DOI] [PubMed] [Google Scholar]
21.Pierce LJ, Levin AM, Rebbeck TR, et al. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol. 2006;24(16):2437-2443. doi: 10.1200/JCO.2005.02.7888 [DOI] [PubMed] [Google Scholar]
22.Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, et al. Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer. 2007;43(5):867-876. doi: 10.1016/j.ejca.2006.12.009 [DOI] [PubMed] [Google Scholar]
23.Garcia-Etienne CA, Barile M, Gentilini OD, et al. Breast-conserving surgery in BRCA1/2 mutation carriers: are we approaching an answer? Ann Surg Oncol. 2009;16(12):3380-3387. doi: 10.1245/s10434-009-0638-7 [DOI] [PubMed] [Google Scholar]
24.Kirova YM, Savignoni A, Sigal-Zafrani B, et al. Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? long-term results and review of the literature. Breast Cancer Res Treat. 2010;120(1):119-126. doi: 10.1007/s10549-009-0685-6 [DOI] [PubMed] [Google Scholar]
25.Valachis A, Nearchou AD, Lind P. Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis. Breast Cancer Res Treat. 2014;144(3):443-455. doi: 10.1007/s10549-014-2890-1 [DOI] [PubMed] [Google Scholar]
26.Cao W, Xie Y, He Y, et al. Risk of ipsilateral breast tumor recurrence in primary invasive breast cancer following breast-conserving surgery with BRCA1 and BRCA2 mutation in China. Breast Cancer Res Treat. 2019;175(3):749-754. doi: 10.1007/s10549-019-05199-8 [DOI] [PubMed] [Google Scholar]
27.Pierce LJ, Phillips KA, Griffith KA, et al. Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat. 2010;121(2):389-398. doi: 10.1007/s10549-010-0894-z [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Nilsson MP, Hartman L, Kristoffersson U, et al. High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer. Breast Cancer Res Treat. 2014;147(3):571-578. doi: 10.1007/s10549-014-3115-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.van den Broek AJ, Schmidt MK, van ’t Veer LJ, et al. Prognostic impact of breast-conserving therapy versus mastectomy of BRCA1/2 mutation carriers compared with noncarriers in a consecutive series of young breast cancer patients. Ann Surg. 2019;270(2):364-372. doi: 10.1097/SLA.0000000000002804 [DOI] [PubMed] [Google Scholar]
30.Huang X, Cai XY, Liu JQ, et al. Breast-conserving therapy is safe both within BRCA1/2 mutation carriers and noncarriers with breast cancer in the Chinese population. Gland Surg. 2020;9(3):775-787. doi: 10.21037/gs-20-531 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Sun J, Meng H, Yao L, et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227 [DOI] [PubMed] [Google Scholar]
32.Zhang J, Sun J, Chen J, et al. Comprehensive analysis of BRCA1 and BRCA2 germline mutations in a large cohort of 5931 Chinese women with breast cancer. Breast Cancer Res Treat. 2016;158(3):455-462. doi: 10.1007/s10549-016-3902-0 [DOI] [PubMed] [Google Scholar]
33.Su L, Zhang J, Meng H, et al. Prevalence of BRCA1/2 large genomic rearrangements in Chinese women with sporadic triple-negative or familial breast cancer. Clin Genet. 2018;94(1):165-169. doi: 10.1111/cge.13256 [DOI] [PubMed] [Google Scholar]
34.Brekelmans CT, Seynaeve C, Menke-Pluymers M, et al. Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol. 2006;17(3):391-400. doi: 10.1093/annonc/mdj095 [DOI] [PubMed] [Google Scholar]

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Supplementary Materials