Pierre O. Chappuis

The Prognostic Implication of the Basal-Like (Cyclin Ehigh/p27low/p53+/Glomeruloid-Microvascular-Proliferation+) Phenotype of BRCA1-Related Breast Cancer

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.

BackgroundThe prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.MethodsTwo retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.ResultsGenotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).ConclusionBRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.

Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis

PURPOSE Surgery of the primary tumor usually is not advised for patients with metastatic breast cancer at diagnosis because the disease is considered incurable. In this population-based study, we evaluate the impact of local surgery on survival of patients with metastatic breast cancer at diagnosis. METHODS We included all 300 metastatic breast cancer patients recorded at the Geneva Cancer Registry between 1977 and 1996. We compared mortality risks from breast cancer between patients who had surgery of the primary breast tumor to those who had not and adjusted these risks for other prognostic factors. RESULTS Women who had complete excision of the primary breast tumor with negative surgical margins had a 40% reduced risk of death as a result of breast cancer (multiadjusted hazard ratio [HR], 0.6; 95% CI, 0.4 to 1.0) compared with women who did not have surgery (P = .049). This mortality reduction was not significantly different among patients with different sites of metastasis, but in the stratified analysis the effect was particularly evident for women with bone metastasis only (HR, 0.2; 95% CI, 0.1 to 0.4; P = .001). Survival of women who had surgery with positive surgical margins was not different from that of women who did not have surgery. CONCLUSION Complete surgical excision of the primary tumor improves survival of patients with metastatic breast cancer at diagnosis, particularly among women with only bone metastases.

Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer.

Purpose:BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261 breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor– and KIP1 (p27Kip1)–negative tumors, with expression of cytokeratin 5/6, cyclin E, TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node–negative and –positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

A significant response to neoadjuvant chemotherapy in BRCA1 / 2 related breast cancer

Neoadjuvant (preoperative) chemotherapy was initially developed as a first line treatment for locally advanced breast cancer. More recently, it has been used to treat earlier stage operable disease, with the hope that not only could the treatment be used as an in vivo assessment of tumour response, but also that it might more readily eradicate occult distant micrometastases. Many studies have shown a small but significant increase in breast conservation when neoadjuvant chemotherapy was used but, overall, most randomised studies have not shown any survival advantage following this treatment.1,2 Despite this, it has been noted that women receiving neoadjuvant chemotherapy who experience either a clinical complete response (cCR) (≤40% of all those treated) or, more clearly, a pathological complete response (pCR) (≤10%) have a better long term outcome than women who achieve less than a complete response.1,2 Germline mutations in the BRCA1 and BRCA2 genes are the major genetic predisposition to breast cancer. Some of the functions of BRCA1 and BRCA2 proteins could be directly involved in response to cytotoxic agents, such as the role of BRCA1/2 in DNA repair3 or apoptosis.4,5 Distinct pathological features6 and gene expression profiles7 suggest that there are differences in hereditary breast cancer compared to sporadic cases, which might lead to differences in treatment response. In vitro data suggest that cells without functional BRCA1 or BRCA2 protein are particularly sensitive to several chemotherapeutic drugs4 or ionising radiation.8 Mouse and human cell lines deficient in BRCA1 or BRCA2 display an increased sensitivity to agents causing double strand DNA breaks.9,10 This hypersensitivity has been shown for mitoxantrone, amsacrine, etoposide, doxorubicin, and cisplatin with a subsequent increased level of apoptosis.9,11–13 Differences in drug sensitivity might be explained by interaction of BRCA1/2 proteins …

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

Approximately 2% to 5% of all breast cancers are hereditary, meaning that the cancer predisposition is carried as a monogenic trait. Several highly penetrant breast cancer predisposing genes have been identified. These discoveries will permit a refined description of breast cancer occurring as part of the different genetic syndromes. We reviewed the medical literature on the clinico-pathological features of breast cancer associated with the major breast cancer susceptibility genes BRCA1 and BRCA2. BRCA1-associated breast cancers are more frequently ductal invasive, high-grade carcinomas with an important lymphocytic infiltration. They are aneuploid, estrogen and progesterone receptors negative, and p53 positive. BRCA2-related breast cancers tend to be higher-grade tumors than are non-hereditary cases, although this association is less strong then for BRCA1 cases. These tumors exhibit substantially less tubule formation, but mitotic count and cellular pleomorphism do not differ significantly from those of sporadic cases. The overall pattern of the identified pathological characteristics suggests a carcinogenic pathway in BRCA1- and BRCA2-related breast cancers different from that found in sporadic cases. The probability of finding a BRCA1/2 germ-line mutation is partly determined by these characteristics. In addition, these features will likely influence the behavior of BRCA1/2-related breast cancer.

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)

Germline BRCA1/2 Mutations and p27Kip1 Protein Levels Independently Predict Outcome After Breast Cancer

PURPOSE Decreased levels of the cyclin-dependent kinase inhibitor p27(Kip1) in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27(Kip1) protein levels, and outcome has not been studied. PATIENTS AND METHODS Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27(Kip1) expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P =.009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P =.003). Similar results were seen for women whose tumors expressed low levels of p27(Kip1), compared with those with high levels (5-year DDFS, 68% v 93%; P<.0001). In a multivariate analysis, both BRCA1/2 mutation and low p27(Kip1) expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P =.05; and RR, 3.9; 95% CI, 1.4 to 11.1; P =.01, respectively). CONCLUSION In this study, we showed that BRCA1/2 mutations were associated with low levels of p27(Kip1) in breast cancer. Both BRCA1/2 and p27(Kip1) status were identified as independent prognostic factors.

Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data.

Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCA1 interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow‐up.

Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1‐related breast carcinoma

A positive correlation between breast tumor size and the number of axillary lymph nodes containing tumor is well established. It has been reported that patients with BRCA1‐related breast carcinoma are more likely than patients with nonhereditary breast carcinoma to have negative lymph node status. Therefore, the authors questioned whether the known positive correlation between tumor size and lymph node status also was present in women with BRCA1‐related breast carcinomas.