Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy

doi:10.1016/j.ejca.2005.02.037

European Journal of Cancer

Volume 41, Issue 15, October 2005, Pages 2304-2311

https://doi.org/10.1016/j.ejca.2005.02.037 Get rights and content

Abstract

BRCA1 and BRCA2 germline mutations are associated with a strong risk of breast cancer, which may preclude breast-conserving treatment in carriers. This study examined whether mutation status influenced the rate of breast cancer recurrence following breast-conserving treatment. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer, who had been treated with breast-conserving surgery and radiotherapy. The 131 patients with familial history were matched to 261 patients without, according to age at diagnosis and year of treatment. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic testing in familial cases. Matched cohorts were compared according to rates of breast cancer recurrence as first event and contralateral breast cancer using log-rank tests. BRCA1/2 mutations were found in 20.6% patients with a family history. Nineteen patients had a BRCA1 mutation and 8 had a BRCA2 mutation. Breast cancers in mutation carriers were more often grade III (p < 10-4) and oestrogen receptor negative (p = 0.005) than tumours in both non-carriers and controls. Median follow-up for all 392 patients was 8.75 years. No significant differences in breast cancer recurrence as first event were seen between BRCA1/2 tumours and controls (p = 0.47), carriers and non-carriers with a family history (p = 0.96), or non-carriers and controls (p = 0.10). On multivariate analysis, age was the most important factor significantly predicting for breast cancer recurrence. The rate of contralateral breast cancer was significantly increased in all patients with a family history: BRCA1/2 carriers versus controls (p = 0.0003), non-carriers versus controls (p = 0.0034) and carriers versus non-carriers (p = 0.02). At a 9-year median follow-up, the rate of ipsilateral breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with a family history or sporadic cases. These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term.

Introduction

Breast conservative surgery and radiation therapy is a standard treatment for early stage breast cancer. Numerous randomised trials have proven the equivalence in survival between breast-conserving surgery with radiotherapy and mastectomy in early stage breast cancer 1, 2, 3, 4, 5, 6, 7, 8.

BRCA1 and BRCA2 mutations are found in approximately 5% of all breast cancers, and in up to 20–25% in the case of a family history of breast and/or ovarian cancer [9]. It has been shown previously that BRCA1 mutation carriers develop tumours with higher grade and proliferation index, and lower oestrogen receptor levels than those who do not have a mutation 10, 11. On the other hand, BRCA2 mutation carriers present tumours with pathological features similar to sporadic cases 10, 11, 12, 13, 14, 15, 16. It has also been shown that BRCA1 mutation carriers tend to have a worse outcome [13].

BRCA1 and BRCA2 proteins are involved in DNA repair in response to ionising radiation, through various mechanisms that are not yet fully understood, such as DNA double-strand break repair, apoptosis and cell cycle checkpoint control 17, 18. The safety of breast conservation with radiotherapy in BRCA mutation carriers is controversial, because of the potential of ionising radiation to induce new primaries in the treated breast.

The issue of breast cancer recurrence after breast-conserving treatment in BRCA1 and BRCA2 mutation carriers was addressed in a small number of studies, using different methodologies to compare breast cancer outcome in carriers and in patients with sporadic cancers, with several biases related to the retrospective nature of these studies 19, 20, 21, 22, 23, 24, 25. A matched cohorts study was conducted at the Institut Curie to assess the rate of recurrences and contralateral breast cancers in BRCA1/2 mutation carriers compared with sporadic control cases.

Section snippets

Patients

A cohort of women with small breast cancers treated at the Institut Curie with breast-conserving surgery and radiotherapy from 1981 to 2000, were analysed retrospectively. These patients were invited to attend the family cancer clinic of the institute between 1990 and 2001 if they presented a familial history of breast or ovarian cancer. Selection criteria and the procedure used for molecular testing, as well as the method of obtaining information such as family cancers, age at cancer diagnosis

Results

Nineteen patients had a BRCA1 mutation, and 8 had a BRCA2 mutation. This represents 20.6% of all patients with a family history (21.3% tumours). Patients’ characteristics are presented in Table 1. As shown in this table, the familial and sporadic cohorts were well-matched with regard to age at diagnosis. All cases were treated the same year as their controls, using the same treatment modalities. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic

Discussion

This retrospective case-control study showed that at a 9-year median follow-up, the rate of breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with family history, or sporadic cases, despite more aggressive features associated with BRCA1 mutations.

These results are in accordance with the findings of a multi-institute case-control study of Pierce and colleagues [24], where patients in the genetic cohort were matched by age and date of diagnosis with

Conflict of interest statement

None declared.

Acknowledgement

This paper was presented at the 4th European Breast Cancer Conference, 16th–20th March 2004, in Hamburg.

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BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations.
This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status.
Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively.
Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation.
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Germ-line mutation in BRCA (BReast CAncer gene) 1 or BRCA2 are found in 3–4% of all women with breast cancer. These patients have a significant increased risk of breast and ovarian cancer. They are often younger when diagnosed with the mutation, and the possible breast cancer they get is often aggressive with inferior outcome. There are risk reducing strategies, and the most powerful strategy is risk reducing surgery, both risk reducing bilateral mastectomy (RRM) and risk reducing bilateral salpino-oophorectomy (PBSO). This review is meant to address breast surgery in patients with germline BRCA mutation. The guidelines and techniques applied is under continuous change and it is important for the clinicians to be well informed to provide the patient with the information needed for them to make an informed decision on what risk strategy to choose.
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Mutation-positive patients who develop unilateral breast cancer require different treatments, such as prophylactic mastectomy of the contralateral breast, from those used for other breast cancer patients. If a mutation is found before surgery, it is necessary to consider a surgical procedure that includes reconstruction. For BRCA mutation-positive patients, a suitable treatment must be selected. In Japan, a test for BRCA mutation has been covered by health insurance since 2020, making it possible to preoperatively test patients who are suspected of being positive. We report a case of simultaneous bilateral breast cancer that was found to be BRCA mutation-positive preoperatively and underwent bilateral subcutaneous mastectomy and breast reconstruction.
A 57-year-old woman was admitted to our hospital after a breast cancer screening revealed a mass in the left breast. She had a family history of breast cancer, including her sister, aunt, and cousin. She was suspected of being malignant with a mass on both sides of her breast on imaging. She underwent needle biopsy and was diagnosed as having bilateral invasive ductal carcinoma, for which she was placed on preoperative chemotherapy. Due to the strong family history of bilateral breast cancer, the patient was recommended to undergo a BRCA gene-mutation test and she consented. The result was positive for BRCA1 mutation. Although it was judged that bilateral breast-conserving surgery was sufficiently possible, bilateral subcutaneous mastectomy and breast reconstruction were performed based on BRCA mutation-positive status.
Performing a preoperative BRCA test may change the surgical procedure.
BRCA tests are beneficial to patients, but the timing of the tests is important. Care must be taken not to force the patient.
Knowing whether the patient is BRCA mutation-positive is extremely important for selecting surgical procedures and treatment methods. BRCA testing should be recommended for patients who are strongly suspected of being positive, but the decision should be the patient’s. It is therefore necessary to provide accurate information and engage in a dialogue with the patient, but the medical staff should not pressure the patient to have the test.
Locoregional Treatments and Ipsilateral Breast Cancer Recurrence Rates in BRCA1/2 Mutation Carriers
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There is a paucity of data on the rates of ipsilateral breast tumor recurrence (IBTR) in BRCA1/2–associated breast cancer (BC). Scarcer yet are outcomes data in BRCA1/2 mutation carriers in the setting of newer mastectomy techniques, such as skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM).
Data were extracted from the medical records of BRCA1/2 carriers who were diagnosed with BC and treated at a single institution between 2006 and 2020. The data extracted included patient demographics, tumor characteristics, disease stage, surgical treatment, use of radiation therapy (RT), and disease outcome.
Overall, 255 BC patients with BRCA1/2 germline mutations were identified. Of these, 128 (50.2%) underwent a mastectomy (SSM or NSM in 82% of them), 76 (59.4%) without postmastectomy RT (non-PMRT) and 52 (40.6%) with PMRT, whereas 127 (49.8%) elected for breast-conserving treatment (BCT). The non-PMRT group had earlier disease stages (82.3% were Tis and T1N0) compared with the PMRT and BCT groups (3.6% and 48.1%, respectively; P < .05). The IBTR cumulative rate was 9 of 76 (11.8%) in the non-PMRT cohort compared with 0 of 52 in the PMRT group (P = .01) and 6 of 127 (4.7%) in the BCT group (P = .06). The cumulative incidences of IBTR at 5 and 10 years were 9.8% and 27.4%, respectively, in the non-PMRT group versus 2% and 11.3%, respectively, in the BCT group (P = .0183). No significant difference in overall survival was observed at the time of follow-up.
BRCA1/2 mutation carriers treated with mastectomy without PMRT had higher rates of IBTR than those who underwent mastectomy and PMRT or BCT, despite earlier stages of disease. The safety of SSM/NSM should be evaluated in a prospective trial.
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Similar to mastectomy, breast conserving surgery (BCS) is currently the reference standard of surgical treatment of sporadic breast cancer in patients. However, its oncologic safety for BRCA mutation carriers has remained controversial. Thus, we conducted a systematic review to critically evaluate the best evidence from reported studies. A comprehensive search was performed of the Medline, EMBASE, CINAHL, and Cochrane databases using a predefined strategy. The retrieved studies were independently screened and rated for relevance. Data were extracted for qualitative synthesis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol for systematic reviews. No randomized controlled trial has directly compared BCS and mastectomy for BRCA mutation carriers. Of the 18 studies included in our review, the pooled analysis of overall survival at 5, 10, and 15 years were comparable between BCS and mastectomy (88.7%, 89.0% and 83.6% with BCS and 83%, 86.0%, and 83.2% with mastectomy, respectively). However, the pooled ipsilateral breast cancer recurrence rates at 5, 10, and 15 years were higher in the BCS group (8.2%, 15.5%, and 23%, respectively) than in the mastectomy group (3.4%, 4.9%, and 6.4%, respectively). BCS was associated with a greater rate of ipsilateral breast cancer recurrence in BRCA mutation carriers. However, it was not associated with adverse short- and long-term survival outcomes. BCS should be offered as an option to BRCA mutation carriers with proper preoperative counseling.

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Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Conflict of interest statement

Acknowledgement

Ann Oncol

Cell

Lancet

Lancet

Genomics

The Breast

Eur J Cancer

Semin Radiat Oncol

Lancet

Eur J Cancer

Eur J Cancer

Lancet

Cell

Mol Cell

Twenty-year follow-up of a randomised trial comparing total mastectomy, lumpectomy and lumpectomy plus irradiation for the treatment of invasive breast cancer

N Engl J Med

Randomised clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer

J Natl Cancer Inst

Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: EORTC 10801 trial

J Natl Cancer Inst

Twenty-year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer

N Engl J Med

Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer

N Engl J Med

Danish randomised trial comparing breast conservation therapy with mastectomy: six years of life table analysis. Danish Breast Cancer Cooperative group

J Natl Cancer Inst Monograms

Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials

Lancet

Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer

Cancer Control

Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers

Cancer

Clinico-pathological characteristics of BRCA1 and BRCA2-related breast cancer

Semin Surg Oncol

Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases

Lancet

Familial invasive breast cancers: worse outcome related to BRCA1 mutations

J Clin Oncol

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations

J Natl Cancer Inst