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Biomedical subjects

Pierre O Chappuis

Publications and source records attributed to Pierre O Chappuis.

13 recordsLinked to original sources
PubMed2006

Survival after bilateral breast cancer: results from a population-based study.

BACKGROUND: Controversy exists on the impact of bilaterality of breast cancer on survival. We used population-based data to compare survival of women with unilateral versus bilateral breast cancer. PATIENTS AND METHODS: At the Geneva cancer registry, we identified all 7,912 women diagnosed with invasive breast cancer between 1970 and 2002. Breast cancers were categorized as unilateral, synchronous bilateral (contralateral tumour diagnosed within six months after the first tumour) and metachronous bilateral (contralateral tumour diagnosed over six months after the first tumour). With multivariate modelling we compared characteristics and survival between women with unilateral and bilateral disease. RESULTS: Patients with synchronous bilateral tumours (n = 155, 2.0%) had more often lobular histology and less frequently stage I disease than women with unilateral disease. Women with metachronous breast cancer (n = 219, 2.8%) received less often chemotherapy or hormone therapy for their first tumours. Ten-year disease-specific survival was similar (66%) after unilateral and metachronous bilateral breast cancer, but worse after synchronous bilateral cancer (51%). After adjustment, breast cancer mortality risks were not significantly increased for women with either synchronous or metachronous bilateral disease (Hazard ratios 1.1 (0.8-1.5) and 0.8 (0.5-1.4), respectively). CONCLUSION: This large population-based study indicates that bilaterality of breast cancer is not associated with impaired survival.

Adult↗
PubMed2006

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.

Adult↗
PubMed2006

Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients.

In 10-30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli (APC) gene can be identified (APC mutation-negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to (i) assess the MYH mutation carrier frequency among Swiss APC mutation-negative patients and (ii) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation-negative polyposis patients. Seventy-nine unrelated APC mutation-negative Swiss patients with either classical (n=18) or attenuated (n=61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance (n=45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly (p<0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation-negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: (i) presence of classical or attenuated polyposis coli, (ii) absence of a pathogenic APC mutation, and (iii) a family history compatible with an autosomal recessive mode of inheritance.

Adenomatous Polyposis Coli↗
PubMed2005

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 (p27(Kip1))-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.

Aged↗
PubMed2005

[Plea for the family history...in the area of molecular oncology].

Oncological family history allows to estimate an empirical risk to develop malignant tumors. Nowadays family history is crucial to determine the indication to perform screening of cancer predisposing genes. Five to 10% of all cancers are the result of highly penetrant genes. Most of the genes responsible for familial cancer syndromes have been characterized. It is now feasible, by a simple blood sample, to detect germ-line alterations of these genes and to identify the at risk individuals. Specific screening and preventive strategies are recommended in the management of these high risk individuals.

Genetic Predisposition to Disease↗
PubMed2004

The prognostic implication of the basal-like (cyclin E high/p27 low/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, p27(Kip1), 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, p27(Kip1), p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27(Kip1) 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.

Adult↗
PubMed2003

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

BACKGROUND: The 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. METHODS: Two 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. RESULTS: Genotyping 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). CONCLUSION: BRCA1 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.

Adult↗
PubMed2003

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

BACKGROUND: 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. METHODS: The relation between the greatest dimension of the resected breast tumor (size) and the presence of positive axillary lymph nodes (expressed as a percentage of all lymph nodes examined) was evaluated in 1555 women with invasive breast carcinoma who were ascertained at 10 centers in North America between 1975 and 1997. There were 276 BRCA1 mutation carriers, 136 BRCA2 carriers, and 1143 women without a known mutation (208 BRCA1/BRCA2 noncarriers and 935 untested women). Patients were stratified according to tumor size, and odds ratios were estimated for the presence of positive lymph nodes with increasing tumor size. RESULTS: A highly significant positive correlation between tumor size and the frequency of positive axillary lymph nodes was seen for BRCA1/BRCA2 noncarriers, for BRCA2 carriers, and for untested women (overall P < 0.0001 for each). In contrast, there was no clear correlation between tumor size and positive lymph node status in BRCA1 carriers (overall P = 0.20). CONCLUSIONS: The relation between tumor size and lymph node status in patients with breast carcinoma appears to be different in BRCA1 carriers compared with BRCA2 carriers and noncarriers. These findings have important implications for estimating the route of metastatic spread and for evaluating the effectiveness of early diagnosis in patients with BRCA1-related breast carcinoma.

Breast Neoplasms↗
PubMed2003

Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer.

A basal epithelial phenotype is found in not more than 15% of all invasive breast cancers. Microarray studies have shown that this phenotype is associated with breast cancers that express neither estrogen receptor (ER) nor erbB-2 (HER2/neu) (i.e., ER/erbB-2-negative tumors). The ER/erbB-2- negative phenotype is also found in breast cancers occurring in BRCA1 mutation carriers (i.e., BRCA1-related breast cancers). We tested the hypothesis that BRCA1-related breast cancers are more likely than non-BRCA1/ 2-related breast cancer to express a basal epithelial phenotype. Among 292 breast cancer specimens previously analyzed for ER, erbB-2, p53, and germline mutations in BRCA1 and BRCA2, we identified 76 that did not overexpress ER or erbB-2. Of the 72 specimens with sufficient material for testing, 40 expressed stratified epithelial cytokeratin 5 and/or 6 (5/6). In univariate analysis, the expression of cytokeratin 5/6 was statistically significantly associated with BRCA1-related breast cancers (odds ratio = 9.0, 95% confidence interval = 1.9 to 43; P =.002, two-sided Fisher's exact test). Thus, germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype.

Breast Neoplasms↗
PubMed2003

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

BACKGROUND: 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. METHODS: A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review. RESULTS: In total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCA1 mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCA1 mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02). CONCLUSIONS: Germline BRCA1 mutations and p53 overexpression carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001).

Adult↗
PubMed2002

Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers.

We evaluated the presence of glomeruloid microvascular proliferations (GMPs) in 723 patients with melanomas, breast, endometrial, or prostate cancer. Presence of GMPs was associated with markers of aggressive tumor behavior and significantly reduced survival or increased clinical recurrences in all four of the cancer types in univariate analysis. GMPs were related to increased microvessel density in prostate cancer only. In the case of melanomas, breast, and prostate cancers (but not endometrial cancers), GMPs were a significant prognostic factor in the final multivariate models (P all <or= 0.02), and was a better predictor of outcome than was microvessel density. In conclusion, GMPs might indicate a more aggressive vascular phenotype associated with poor prognosis and could be a novel prognostic marker in human cancer.

Breast Neoplasms↗
PubMed2002

Risk assessment & genetic testing.

Ovarian cancer is the fifth most common cause of cancer death in women in Western countries and family history is one of the strongest known risk factors. Approximately 5 to 13% of all ovarian cancer cases are caused by the inheritance of cancer predisposing genes with an autosomal pattern of transmission. The inherited fraction of ovarian cancer may differ between populations. Based on analysis of familial ovarian cancer pedigrees and other epidemiological studies, three hereditary ovarian cancer syndromes have been defined. The identification of the genes responsible for most hereditary ovarian cancers has open a new area of early detection methods and preventive procedures specifically dedicated to women identified as carrying ovarian cancer predisposing genes. Predictive oncology is best performed by a dedicated unit with professionals aware of all the issues surrounding genetic testing.

Adaptor Proteins, Signal Transducing↗