Are <Emphasis Type="Italic">BRCA1</Emphasis>- and <Emphasis Type="Italic">BRCA2</Emphasis>-related breast cancers associated with increased mortality?

There has been contradictory evidence as to whether BRCA1 associated breast cancers have a poorer prognosis than non-BRCA1 cancers. In this issue of Breast Cancer Research Robson and colleagues provide further evidence for poorer survival in BRCA1 carriers and show that it could be attributed to failure to treat small node-negative grade 3 breast cancers with chemotherapy. There still remains little evidence for a survival difference for BRCA2 related breast cancers. Although the high contralateral breast cancer risk is confirmed by this study there is no real evidence for an increase in ipsilateral recurrence or new primary breast cancers in mutation carriers up to the 10-year point.     

Is BRCA1/BRCA2-related breast carcinogenesis estrogen dependent?

Estrogen is a well known promoting factor of sporadic breast carcinoma. With regard to hereditary breast carcinoma, such as in BRCA1/BRCA2 syndromes, to date, the effects of estrogens on risk modification are not clear. Several studies have shown that prophylactic oophorectomy may decrease the risk of breast carcinoma in BRCA1/BRCA2 mutation carriers. Moreover, adjuvant tamoxifen therapy for primary breast carcinoma appears to diminish the risk of a second breast malignancy in BRCA1 mutation carriers. Conversely, exogenous estrogens, such as oral contraceptives, may increase the risk of breast carcinoma in familial breast cancer, as suggested by clinical studies. Paradoxically, the majority of BRCA1-related breast carcinomas are negative for ER. There is some biologic evidence of interactions between estrogens and BRCA proteins. BRCA1 expression could be induced by estradiol in experimental models, whereas recent studies indicate that BRCA1 modifies the regulatory effects of the estrogen receptor (ER) alpha (ERalpha). Prospective studies will be required to estimate the potential benefits of estrogen suppression therapies for the prevention and adjuvant treatment of BRCA1/BRCA2-related breast carcinomas.     

Are the hereditary forms of BRCA1 and BRCA2 breast cancer sensitive to estrogens?

There is emerging evidence from clinical and experimental data that familial breast cancers, including BRCA1 and BRCA2 related forms, could be in fact estrogen-sensitive. Interactions between BRCA1 gene expression and estrogens have been reported. On one hand, BRCA1 expression could be induced by estradiol in experimental models. On the other hand, recent studies indicate that BRCA 1 interacts with and regulates the activity of estrogen receptor ERalpha. Endogenous or exogenous estrogens, such as oral contraceptive, may also increase the risk of breast cancer in BRCA1 mutation carriers in clinical studies. Conversely, prophylactic oophorectomy and anti-estrogens may decrease the risk of familial breast cancer. Prospective studies are thus required to estimate the potential benefits of estrogen suppression therapies for prevention or adjuvant treatment of familial breast cancer. Oral contraception and hormonal replacement therapy after menopause should be used with caution in BRCA1 or BRCA2 mutation carriers.     

Are work-related stressors associated with diagnosis of more advanced stages of incident breast cancers?

Objective To assess the relation between work-related stressors and breast cancer incidence and prognostic characteristics (estrogen receptor status, grade, lymph node status, size, stage) at the time of diagnosis. Methods The 18,932 women included in the Danish Nurse Cohort reported work-related stressors in 1993 and again in 1999 and were followed until the end of 2003 in national registries. Prognostic characteristics were obtained from a clinical database and fewer than 0.1% were lost to follow up. Results During follow-up, 455 women were diagnosed with breast cancer. Neither women with high work pressure (HR = 1.17; 95% CI: 0.79, 1.73) nor women with self-reported low influence on work organization (0.98; 0.69, 1.39) or long working hours (0.93; 0.54, 1.58) were at higher risk of breast cancer than women with no such stressors. Women with high work tempo had a slightly higher risk of breast cancer (1.25; 1.02, 1.54) than women with a suitable work tempo, but there was no dose-response effect. There were no clear differences in the prognostic characteristics of breast tumors diagnosed in women with and without work-related stressors. Conclusions Work-related stressors do not affect breast cancer risk or the prognostic characteristics of incident breast cancers at the time of diagnosis. These results may be a comfort to working women and can hopefully prevent self-blaming among women who develop breast cancer.     

Are breast cancers driven by fusion genes?

For many years, it was assumed that gene fusions were a type of mutation confined largely to leukemias and sarcomas. However, fusion genes are now known to be important in several epithelial cancers and a number have been described in breast cancers. In the December 2011 issue of Nature Medicine, Robinson and colleagues reported many more gene fusions -including the first recurrent fusion, SEC16A-NOTCH1 - in breast cancers. Several genes, including members of the MAST (microtubule-associated serine threonine) kinase and Notch gene families, are fused more than once. This finding supports an emerging story that most breast cancers express a number of fusion genes.     

Are two-centimeter breast cancers large or small?

Background

Node-negative breast cancers from 2 cm to 5 cm in size are classified as stage ii, and smaller cancers, as stage i. We sought to determine if the prognosis of women with a breast cancer exactly 2 cm in size more closely resembles that of women with a stage i or a stage ii breast cancer.

Methods

Using a cohort of 4265 young women with breast cancer, we compared the 10-year breast cancer mortality rates for women who had a tumour 0.1–1.9 cm, exactly 2.0 cm, and 2.1–2.9 cm.

Results

In the first 3 years after diagnosis, the survival pattern of women with a 2.0-cm breast cancer was nearly identical to that of women with a larger cancer (2.1–3.0 cm). From year 3 to year 10, the relative survival of women with a 2.0-cm breast cancer was improved and nearly identical to that of women with a smaller cancer. The 10-year survival rate was 89.3% for women with tumours less than 20 mm, 86.1% for women with tumours equal to 20 mm, and 81.2% for women with 21-mm to 29-mm tumours.

Conclusions

For young women with small breast cancers, the relative mortality from breast cancer is dynamic with increasing tumour size and varies with time from diagnosis.     

Platinum chemotherapy for BRCA1-related breast cancer: do we need more evidence?

A recent prospective clinical trial provides further evidence that breast cancers arising in germline BRCA1 mutation carriers are highly sensitive to cisplatin chemotherapy. The potential significance of these data for the management of patients with BRCA1-related and BRCA2-related breast cancer is discussed.In a previous issue of Breast Cancer Research Tomasz Byrski and colleagues present the results of a prospective phase II study of cisplatin in BRCA1-related metastatic breast cancer - that is, breast cancer arising in women with a germline mutation in BRCA1 [1]. They report evidence of substantial efficacy with an overall response rate of 80%, including 45% with complete response, and a time to progression of 12 months. The majority of patients in the study had triple receptor-negative breast cancer, and this time to progression compares favorably with median progression-free survival for triple receptor-negative breast cancer in contemporary series [2]. This study follows on from a retrospective study by the same group that reported a pathological complete response rate of 83% with neoadjuvant cisplatin chemotherapy, compared with a rate of 15% with nonrandomized comparator neoadjuvant chemotherapy [3].The molecular basis for these high response rates is well understood. Both BRCA1 and BRCA2 are required for DNA double-strand break repair by homologous recombination (HR-based DNA repair) [4,5]. Mutations in BRCA1 and BRCA2 inactivate protein function, and in cancer the wild-type allele is almost invariably lost, leading to a defect in HR-based DNA repair in the cancer. Platinum chemotherapy generates interstrand cross-links that can only be adequately repaired by HR-based DNA repair, and consequently BRCA1-deficient and BRCA2-deficient cells are highly sensitive to platinum chemotherapy both in vitro and in vivo. With high response rates in a prospective clinical trial, and a strong biological rationale, it is time to ask whether we are moving towards a new chemotherapy standard for BRCA1-related, and potentially by inference BRCA2-related, breast cancer or whether we need more evidence.The main strength of the current study is that it has been carried out at all. BRCA1 mutations account for a small proportion of patients with advanced breast cancer, even in countries with founder mutations, and this presents a substantial barrier to running studies testing standard chemotherapy. Use of the chemotherapy regimen outside the trial, and the wide availability of novel therapy trials competing for the same patients, add to the challenges of recruiting such trials. Nevertheless, the study by Byrski and colleagues is an open-label single-arm study of only 20 patients, with no central radiological confirmation of response rates, and both this study design and this size make a meaningful interpretation of progression-free survival very difficult. The study was in addition not prospectively registered in a clinical trial registry, removing one of the safeguards against publication bias.The study is dominated by women with three specific mutations in BRCA1 that represent the three founder mutations found in the Polish population [1], with over one-half being the single mutation 5382insC. One of these mutations, C61G, is predicted not to sensitize to cisplatin on the basis of preclinical data [6] yet cancers with this mutation appear to be just as sensitive to cisplatin in the study [1], a discrepancy for which it is important to understand the basis. Prior studies reported by this group have also been drawn from the Polish founder mutations, and we have limited data on the response of cancers with other BRCA1 mutations, and very limited data for BRCA2 mutations.Although the data for BRCA1/2-related breast are therefore relatively limited, there are substantial data on the sensitivity of BRCA1-related and BRCA2-related ovarian cancers to platinum-based chemotherapy [7,8]. BRCA1/2-related serous ovarian cancers are highly sensitive to platinum chemotherapy, and remain sensitive to repeat challenges with platinum chemotherapy, which likely explains the improved survival of BRCA1/2-related serous ovarian cancer compared with BRCA1/2 wild-type serous ovarian cancer [8].Should the accumulation of data, which includes this study by Byrski and colleagues, alter our approach to the treatment of BRCA1-related and BRCA2-related breast cancer? For patients with metastatic BRCA1-related breast cancer, although the data are limited, it seems clear that these patients should be offered the option of platinum-containing chemotherapy at some point during their treatment course. Whether platinum chemotherapy should be used as the first line in preference to other chemotherapy agents is unclear, and this is the subject of the BRCA trial ({"type":"clinical-trial","attrs":{"text":"NCT00321633","term_id":"NCT00321633"}}NCT00321633, {"type":"clinical-trial","attrs":{"text":"NCT00532727","term_id":"NCT00532727"}}NCT00532727) that randomizes first-line patients between carboplatin and docetaxel. For those with BRCA1 mutation-associated triple receptor-negative breast cancer and anthracycline-resistant and taxane-resistant disease, where there are few available active therapies, and the option of platinum-agent chemotherapy seems well founded.Whether the platinum agent should be cisplatin or whether carboplatin would have a similar response rate is unknown. Any difference in efficacy between the two drugs is likely to be small and may be outweighed by logistical and toxicity advantages for the patient. Whether patients with evidence of disease response and a long platinum-free interval (>6 months off chemotherapy) should be retreated with platinum-based chemotherapy on progression or whether they should be treated with alternative chemotherapy regimens remains unclear, and we await data to guide such decisions. Although there are few direct data on BRCA2-related breast cancer, the strength of the biological rational, the comparative data between BRCA1 and BRCA2 in ovarian cancer, and the evidence of poly(ADP ribose) polymerase (PARP) inhibitor efficacy in BRCA2-related breast cancer [9] all suggest that similar advice should apply to BRCA2-related breast cancer.What about the curative setting and patients receiving adjuvant or neoadjuvant chemotherapy? Here the data are less robust. Standard adjuvant anthracycline/taxane chemotherapy cures a substantial proportion of women with breast cancer, with evidence of better outcomes and therapy responses in the BRCA1/2 carrier population [10,11], so changes to this standard should only be made on the basis of strong evidence. At present the data to support platinum agents in this context are limited to retrospective analysis [3] or to prospective data for a very small number of patients [12]. Prospective studies are still required before routine practice changes in the curative setting. The one current exception to this is in the treatment of HER2-positive breast cancer in BRCA1/2 carriers. Relative equipoise has already been shown in the general breast cancer population for the TCH (docetaxel, carboplatin, trastuzumab) regimen compared with standard anthracycline-taxane-trastuzumab-based chemotherapy [13], and the TCH (docetaxel, carboplatin, trastuzumab) regimen presents an attractive option for BRCA1/2 carriers with HER2-positive breast cancer.PARP inhibitors target the same HR-based DNA repair defect as cisplatin chemotherapy, and there is evidence of efficacy for the PARP inhibitor olaparib in BRCA1-related and BRCA2-related breast cancer with substantial prior chemotherapy exposure [9]. PARP inhibitors target the DNA repair defect in a more specific fashion and are well tolerated without typical chemotherapy side effects [9]. The challenge in BRCA1/2-related advanced breast cancer is to develop and support a collaborative mechanism where patients can be identified and entered into randomized trials that test novel therapies such as PARP inhibitors, or mechanistically based chemotherapy, to robustly assess the efficacy relative to standard care, and therefore allow these patients to benefit from these BRCA1/2-focused treatments.     

A gene-environment interaction between occupation and BRCA1/BRCA2 mutations in male breast cancer?

The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.     

Inherited predisposition to breast cancer: after the BRCA1 and BRCA2 genes,what next?

Germline mutations of the breast cancer predisposing known genes, BRCA1 and BRCA2, with an autosomal dominant transmission explain only a part of the familial aggregation of breast cancer. Mainly involved in families with cases of ovarian cancer or male breast cancer, they account for a small proportion of families where only female breast cancer cases are observed. A third predisposing gene, called BRCA3, has been sought for a long time but without success. Recently, genetic epidemiology studies have shown evidence for non-mendelian inheritance. The familial residual risk non due to BRCA1 or BRCA2 genes could be explain by a polygenic model, corresponding to the multiplicative effects of several genes, more frequent in population but conferring moderate risks of cancer. The identification of these low penetrance genes is the challenge over the next years. We present here a focusing of recent knowledge on breast cancer predisposing genes, the perspectives of research and their implications in the practice of genetic counselling.