BRCA-mutation associated breast cancer differs from sporadic breast cancer with regard to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available at the time of breast cancer diagnosis, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA mutation carriers with breast cancer. This article reviews surgical options for management of affected BRCA mutation carriers with emphasis on the risks of ipsilateral recurrence and contralateral breast cancer. The roles of breast conserving surgery, prophylactic mastectomy and oophorectomy are reviewed. In addition, sensitivity of BRCA mutation-associated breast cancer to endocrine therapy, platinum chemotherapy and poly (ADP-Ribose) polymerase inhibitors is reviewed.
BRCA1; BRCA2; Breast cancer; Treatment
Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1) account for about 40–45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary) breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s) is (are) most important for tumor suppression, nor is it clear why BRCA1-mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR), which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.
breast cancer susceptibility gene 1; DNA damage response; telomeres; ataxia-telangiectasia mutated; homology-directed repair; base excision repair; DNA damage signaling
Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients.
This article presents a comprehensive review of the literature on the role of BRCAness in ovarian cancer with respect to BRCA function, methods of BRCA epigenetic defect detection and molecular profiling, and the implications of BRCA dysfunction for ovarian cancer treatment.
Ovarian cancer is the leading cause of death among gynecological cancers. It exhibits great heterogeneity in tumor biology and treatment response. Germline mutations of DNA repair genes BRCA1/2 are the fundamental defects in hereditary ovarian cancer that expresses a distinct phenotype of high response rates to platinum agents, improved disease-free intervals and survival rates, and high-grade serous histology. The term “BRCAness” describes the phenotypic traits that some sporadic ovarian tumors share with tumors in BRCA1/2 germline mutation carriers and reflects similar causative molecular abnormalities. BRCA pathway studies and molecular profiling reveal BRCA-related defects in almost half of the cases of ovarian cancer. BRCA-like tumors are particularly sensitive to DNA-damaging agents (e.g., platinum agents) because of inadequate BRCA-mediated DNA repair mechanisms, such as nucleotide-excision repair and homologous recombination (HR). Additional inhibition of other DNA repair pathways leads to synthetic lethality in HR-deficient cells; this has been employed in the treatment of BRCA-like ovarian tumors with poly(ADP-ribose) polymerase inhibitors with promising results. This article presents a comprehensive review of the relevant literature on the role of BRCAness in ovarian cancer with respect to BRCA function, methods of BRCA epigenetic defect detection and molecular profiling, and the implications of BRCA dysfunction in the treatment of ovarian cancer.
BRCAness; BRCA1/2; Ovarian cancer; PARP inhibitors; Synthetic lethality
The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death following DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared to sporadic cases. While it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here we demonstrate that the p53-related gene p73, encoding a pro-apoptotic protein which is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region which includes the binding site for the p73 transcriptional repressor ZEB1, leading to abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 may represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.
Ovarian Carcinoma; BRCA1; Cisplatin; TP73; Methylation; Chemosensitivity
Breast cancer susceptibility genes BRCA1 and BRCA2 are tumour suppressor genes the alleles of which have to be inactivated before tumour development occurs. Hereditary breast cancers linked to germ-line mutations of BRCA1 and BRCA2 genes almost invariably show allelic imbalance (AI) at the respective loci. BRCA1 and BRCA2 are believed to take part in a common pathway in maintenance of genomic integrity in cells. We carried out AI and fluorescence in situ hybridization (FISH) analyses of BRCA2 in breast tumours from germ-line BRCA1 mutation carriers and vice versa. For comparison, 14 sporadic breast tumours were also studied. 8 of the 11 (73%) informative BRCA1 mutation tumours showed AI at the BRCA2 locus. 53% of these tumours showed a copy number loss of the BRCA2 gene by FISH. 5 of the 6 (83%) informative BRCA2 mutation tumours showed AI at the BRCA1 locus. Half of the tumours (4/8) showed a physical deletion of the BRCA1 gene by FISH. Combined allelic loss of both BRCA1 and BRCA2 gene was seen in 12 of the 17 (71%) informative hereditary tumours, whereas copy number losses of both BRCA genes was seen in only 4/14 (29%) sporadic control tumours studied by FISH. In conclusion, the high prevalence of AI at BRCA1 in BRCA2 mutation tumours and vice versa suggests that somatic events occurring at the other breast cancer susceptibility gene locus may be selected in the cancer development. The mechanism resulting in AI at these loci seems more complex than a physical deletion. http://www.bjcancer.com © 2001 Cancer Research Campaign
BRCA1; BRCA2; allelic imbalance; LOH; FISH
The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. The current study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n=283), BRCA2 mutations (n=204) or negative for both BRCA1 and BRCA2 mutations (n=894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.
Breast cancer; BRCA1; BRCA2; mutations; modifiers
Women with a germline BRCA1 or BRCA2 mutation or a hereditary predisposition for breast and ovarian cancer have substantial risk of breast or ovarian cancer relative to the general US population. Health care professionals can be instrumental in identifying women at increased risk through obtaining a comprehensive family history and becoming familiar with family history characteristics associated with hereditary predisposition for breast and ovarian cancer. BRCA carriers and women at very high risk benefit from multidisciplinary, individualized medical evaluation and risk management. We conducted a search of MEDLINE from 1989 through 2010 for the terms BRCA1, BRCA2, breast cancer, ovarian cancer, risk assessment, and genetic testing. We reviewed abstracts and relevant randomized and prospective studies that included very high-risk patient groups and BRCA mutation carriers. Herein, we review the role of genetic consultation and BRCA testing and the comprehensive, multisystem recommendations for risk management. A multidisciplinary approach offers the ability to educate those at very high risk about cancer prevention, reduce cancer risk, maximize early detection of breast and ovarian cancer, and improve survival.
BReast CAncer 1 (BRCA1) was initially identified as one of the genes conferring genetic predisposition to both breast and ovarian cancer. One of the interesting aspects of BRCA1 linked cancers is the observed specificity for oestrogen responsive tissues such as breast and ovary. Recent advances in our understanding of BRCA1 linked breast cancers have revealed a complex relationship between BRCA1 and oestrogen receptor alpha (ERα) signalling. Oestrogen stimulation increases expression of BRCA1 at the mRNA and protein level and conversely BRCA1 functions to both induce ERα mRNA expression and act as a negative regulator of ERα signalling. Here we review the relationship between BRCA1 and ERα and discuss the use of antioestrogen therapies in the treatment of BRCA1 mutation carriers.
Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer (BC). The resulting tumors typically lack homologous recombination repair, as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly(ADP)ribose polymerase (PARP) inhibitors (PARPi) have been demonstrated for BRCA-associated cancers. However, there is limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining survival of treated Brca-proficient and -deficient mouse embryonic stem cells (mESC). In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared to their isogenic BRCA-complemented lines. Whereas each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage, apoptosis and greater PARP activity in Brca/BRCA-deficient cells, and these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for BRCA patients.
BRCA1; BRCA2; Chemotherapy; PARP inhibitor; Platinum Drugs
Breast-conserving therapy (BCT) for sporadic breast cancer has been widely accepted by surgeons and patients alike. While BCT is associated with a higher risk of ipsilateral breast tumor recurrence (IBTR), it has not been shown to decrease overall survival (OS) in comparison with mastectomy. Many women with a BRCA1/2 mutation opt for mastectomy instead of breast-conserving measures at the time of a breast cancer diagnosis. In some cases, this is due to fear of aggressive disease, but to date, there have been no studies offering strong evidence that breast conservation should not be offered to these women. BRCA1/2-associated breast cancer has not been found to be more aggressive or resistant to treatment than comparable sporadic tumors, and no study has shown an actual survival advantage for mastectomy in appropriately treated affected mutation carriers. This paper reviews the available literature for breast conservation and surgical decision making in BRCA1/2 mutation carriers.
Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers.
One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival.
BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls.
Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis.
Primary systemic therapy (PST) downstages up to 40% of initial documented axillary lymph node (ALN) metastases in breast cancer. The current surgical treatment after PST consists of breast tumor resection and axillary lymph node dissection (ALND). This strategy, however, does not eliminate unnecessary ALND in patients with complete remission of axillary metastases. The aim of this study was to examine the accuracy of sentinel lymph node biopsy (SLNB) after PST among patients with documented ALN metastasis at presentation and to identify the rate of pathologic complete-remission (CR) with ALN after PST.
We analyzed 66 patients with ALN metastasis that was pathologically proven preoperatively who underwent SLNB and concomitant ALND after PST. Axillary ultrasound (AUS) was used to evaluate the clinical response of initially documented ALN metastasis after PST. Intraoperative lymphatic mapping was performed using blue dye with or without radioisotope.
After PST, 34.8% of patients had clinical CR of ALN on AUS and 28.8% patients had pathologic CR of ALN. The overall success rate of SLNB after PST was 87.9%, and the sentinel lymph node identification rate in patients with clinical CR was 95.7%. In patients with successful lymphatic mapping, 70.7% of patients had residual axillary metastases. The overall accuracy and false-negative rate were 87.9% and 17.1% in all patients: 95.5% and 10.0% in patients with clinical CR of ALN, and 83.3% and 19.4% in patients with residual axillary disease after PST.
Our findings suggest that SLNB may be feasible in patients with initial documented ALN metastasis who have clinical CR for metastatic ALN after PST. Further investigation in a prospective setting should be performed to confirm our results.
Breast neoplasms; Primary systemic therapy; Sentinel lymph node biopsy
About 5% of all breast cancer cases are attributable to germline mutations in BRCA1 or BRCA2 genes. BRCA mutations in suspected carriers, however, may be missed, which hampers genetic counselling.
Materials and methods
Different clinicopathological features were compared between 22 breast cancers from carriers of proved BRCA1 mutations and 604 cancers from sporadic controls. In addition, 5 BRCA2‐related breast cancers and 66 breast cancers of untested patients at intermediate risk and 19 breast cancers of untested patients at high risk of hereditary disease on the basis of family history were evaluated.
A “probably sporadic” class (age ⩾54 years and epidermal growth factor receptor (EGFR) negative; 68% of cases) with a 0% chance of BRCA1‐related breast cancer containing 79% of the sporadic cases was yielded by using a decision tree with age, Ki67 and EGFR. A 75% chance of BRCA1‐related breast cancer was shown by the “probably BRCA1‐related” class (age <54 years and Ki67 ⩾25%; 8% of cases) with 82% of the BRCA1‐related cases but only 1.4% of the sporadic cases. Most cases at intermediate or high risk of hereditary disease on the basis of family history could be classified with high probability as either probably BRCA1 related or probably sporadic.
Breast carcinomas can be classified with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR. This can be clinically useful in mutation analysis in families with a borderline risk of hereditary disease.
Most breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.
Clinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.
BRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).
BRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.
BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports carried out in non-cancerous mouse BRCA1- or BRCA2-deficient embryonic stem (ES) cells, and hamster BRCA2-deficient cells have demonstrated that the targeted inhibition of poly(ADP-ribose) polymerase (PARP-1) kills BRCA mutant cells with high specificity. Although these studies bring hope for BRCA mutation carriers, the effectiveness of PARP-1 inhibitors for breast cancer remains elusive. Here we present the first in vivo demonstration of PARP-1 activity in BRCA1-deficient mammary tumors and describe the effects of PARP-1 inhibitors (AG14361, NU1025, and 3-aminobenzamide) on BRCA1-deficient ES cells, mouse and human breast cancer cells. AG14361 was highly selective for BRCA1-/- ES cells; however, NU1025 and 3-aminobenzamide were relatively non-selective. In allografts of naïve ES BRCA1-/- cells there was either partial or complete remission of tumors. However, in allografts of mouse, BRCA1-/- mammary tumors, there was no tumor regression or remission although a partial inhibition of tumor growth was observed in both the BRCA1-/- and BRCA1+/+ allografts. In human tumor cells, PARP-1 inhibitors showed no difference in vitro in limiting the growth of mammary tumors irrespective of their BRCA1 status. These results suggest that PARP-1 inhibitors may non-specifically inhibit the growth of mammary tumors.
PARP inhibitors; BRCA1; breast cancer; therapeutic treatment; tamoxifen
Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies.
Primary prevention of breast cancer through prophylactic mastectomy can reduce the risk of malignancy in high-risk individuals. No type of mastectomy completely removes all breast tissue, but a subcutaneous mastectomy leaves more tissue in situ than does a simple mastectomy.
We report a case of invasive breast cancer in a BRCA2-positive woman 33 years after bilateral subcutaneous mastectomy. To our knowledge, only one case of primary breast cancer after prophylactic mastectomy in a BRCA1-positive patient has been reported in the literature and none in BRCA2-positive individuals.
Careful documentation and long follow-up is essential to fully assess the benefits and risks of preventive surgical procedures in BRCA1 and BRCA2 mutation carriers.
In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.
British Journal of Cancer (2002) 86, 76–83. DOI: 10.1038/sj/bjc/6600008 www.bjcancer.com
© 2002 The Cancer Research Campaign
segregation analysis; BRCA3; Polygenes; high-risk families; population studies
The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers.
Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers.
Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞).
We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.
The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman’s reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers.
We conducted a matched case–control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer.
After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001).
In a woman with a BRCA1 or BRCA2 mutation who is diagnosed with breast cancer, the risk of cancer in the contralateral breast depends on the first diagnosis. That observation supports the hypothesis that there are important genetic or non-genetic modifiers of cancer risk in BRCA carriers. Discovering risk modifiers might lead to greater personalization of risk assessment and management recommendations for BRCA-positive patients.
BRCA1; BRCA2; contralateral breast cancer
Positive selection for inherited mutations in breast and ovarian cancer predisposing genes, BRCA1 and BRCA2, may contribute to the high frequency of BRCA mutations among the Ashkenazi Jewish population. Impact of BRCA mutations on fertility has not been generally explored in epidemiologic studies. There are reports of distorted sex ratios in BRCA carrier families but these findings have been attributed to bias. We investigated the effect of BRCA mutations on female fertility and offspring sex ratio in a study of 260 Ashkenazi Jewish women with ovarian cancer and 331 controls, unselected for age or family history of the disease. Pregnancy success was similar for 96 mutation carrier (0.84) and 164 noncarrier cases (0.87) and controls (0.83). After adjusting for covariates, there were no significant differences between BRCA carrier and noncarrier cases and controls with regards to fertility, despite lower pregnancy rates among all cases compared to controls (P = 0.0049). Male/female sex ratios were significantly lower among offspring of carriers (0.71) than offspring of noncarriers (0.95) or those of the controls (0.99). Comparisons among the three groups yielded statistically significant distortion against males among the offspring of known and obligate BRCA carriers compared to noncarriers (OR = 0.74, 95% CI:0.55–0.99) and controls (OR = 0.71, 95% CI:0.54–0.94). In conclusion, we did not find evidence for an effect of BRCA mutations on female fertility. We found a significant excess of females among the offspring of female carriers of BRCA1 and BRCA2 mutations. Potential contribution of observed sex ratio distortions to positive selection for BRCA mutations may warrant further investigation.
Germline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility. Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments.
We performed ovarian stimulation in 126 women with breast cancer by using letrozole and gonadotropins for the purpose of fertility preservation by embryo or oocyte cryopreservation. As surrogates of ovarian reserve, the oocyte yield and the incidence of low response were compared with ovarian stimulation according to BRCA mutation status.
Of the 82 women who met the inclusion criteria, 47 women (57%) had undergone BRCA testing, and 14 had a mutation in BRCA genes, of which two were of clinically undetermined significance. In BRCA mutation–positive patients, low ovarian response rate was significantly higher compared with BRCA mutation–negative patients (33.3 v 3.3%; P = .014) and with BRCA-untested women (2.9%; P = .012). All BRCA mutation–positive low responders had BRCA1 mutations, but low response was not encountered in women who were only BRCA2 mutation positive. Compared with controls, BRCA1 mutation– but not BRCA2 mutation–positive women produced lower numbers of eggs (7.4 [95% CI, 3.1 to 17.7] v 12.4 [95% CI, 10.8 to 14.2]; P = .025) and had as many as 38.3 times the odds ratio of low response (95% CI, 4.1 to 353.4; P = .001).
BRCA1 mutations are associated with occult primary ovarian insufficiency. This finding may, at least in part, explain the link between infertility and breast/ovarian cancer risks.
Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers.
The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy. All study participants were screened for BRCA1 and BRCA2 mutations using denaturing high-performance liquid chromatography (DHPLC) to detect genetic variants in the coding and flanking regions of the genes. Conditional logistic regression was used to compare the risk of CBC associated with chemotherapy and tamoxifen in BRCA1/BRCA2 mutation carriers and non-carriers.
Chemotherapy was associated with lower CBC risk both in non-carriers (RR = 0.6 [95% CI: 0.5-0.7]) and carriers (RR = 0.5 [95% CI: 0.2-1.0]; p-value = 0.04). Tamoxifen was associated with a reduced CBC risk in non-carriers (RR = 0.7 [95% CI: 0.6-1.0]; p-value = 0.03). We observed a similar but non-significant reduction associated with tamoxifen in mutation carriers (RR = 0.7 [95% CI: 0.3-1.8]). The tests of heterogeneity comparing carriers to non-carriers did not provide evidence for a difference in the associations with chemotherapy (p-value = 0.51) nor with tamoxifen (p-value = 0.15).
Overall, we did not observe a difference in the relative risk reduction associated with adjuvant treatment between BRCA1/BRCA2 mutation carriers and non-carriers. However, given the higher absolute CBC risk in mutation carriers, the potentially greater impact of adjuvant therapy in reducing CBC risk among mutation carriers should be considered when developing treatment plans for these patients.
adjuvant therapy; BRCA1; BRCA2; breast cancer; chemotherapy; contralateral; counter-matching; tamoxifen
Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1–positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n= 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERα; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploin-sufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers.