Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations¹

Abstract

Background and purpose: The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy.

Materials and methods: A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size.

Results: Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21–77 years) and 42 years (range 23–83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan–Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years.

Conclusions: Despite their younger age at presentation, breast cancer patients harboring BRCA1 or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

Introduction

The inherited basis of certain breast cancers has been confirmed with the description of three dominant genes, namely BRCA1, BRCA2 and p53. All display a loss of heterozygosity consistent with the role of a tumor suppressor gene. In one study of young women with breast cancer (age less than 30 years), 13% were found to have BRCA1 mutations [9]. For Jewish women less than 40 years old diagnosed with breast cancer, 21% were found to have the specific BRCA1 mutation, 185delAG [9]. It is possible that less than 10% of all breast cancer cases are due to these genes; however, important aspects of breast carcinogenesis may be revealed in these syndromes [10]. With the potential advent of widespread genetic testing, further description of these clinical syndromes is needed.

Through genetic linkage analysis BRCA1 was localized to 17q21 [13]. The BRCA1 gene contains 22 exons distributed over more than 100 kb of genomic DNA and encodes for a protein of 1863 amino acids [20]. Recently, both BRCA1 and BRCA2 have been associated with the Rad51 protein, which is involved in the integrity of the genome 27, 29. Reduced expression has also been identified in transformation to a neoplastic state, which is consistent with its role as a tumor suppressor gene [34]. Many mutations have been described with the majority resulting in a truncated protein [30]. The precise frequency of the mutated gene is unknown; however, it has been estimated to be approximately one in 800 in the normal population [24]. BRCA1 and BRCA2 mutations are identified in approximately 12 and 3% of young women with breast cancer, respectively 9, 16.

BRCA2 has been identified on chromosome 13q12–13 and likely accounts for a large proportion of non-BRCA1 familial breast cancer 33, 37. BRCA2 has been implicated in male breast cancer and it displays the characteristic loss of heterozygosity (LOH) consistent with a tumor suppressor gene [35]. Additionally, LOH at 13q12–13 has been seen in a variety of different tumors from BRCA2 carriers suggesting a possible role in tumorigenesis [12].

Younger women with breast cancer have more aggressive lesions with an increased risk of relapse and death 14, 21. Tumor aggressiveness is manifest by an elevated S-phase fraction, abnormal p53 expression and higher histologic grade 1, 18, 19, 22. For BRCA1-related breast cancer, Eisinger et al. [8]noted that histopathologic grade appeared to segregate as a genetic trait, thus establishing a genotype–phenotype correlation.

On the other hand, familial breast cancer has been described to have a more favorable survival outcome than sporadic breast cancer 2, 25. In the study by Marcus et al. [18], BRCA1-related breast cancer patients had a higher proliferation rate, greater disease-free survival and similar overall survival compared with sporadic controls. Thus, an interesting dichotomy appears to exist for patients with BRCA1-related breast cancer where pathologic analysis yields a more aggressive grade while survival is improved or comparable to sporadic cases.

The objectives of this report are to analyze overall survival in patients with defined BRCA1 and BRCA2 mutations, review histologic findings and describe the response to radiation therapy.