Breast cancer 1 (BRCA1) protein expression as a prognostic marker in sporadic epithelial ovarian carcinoma: an NCIC CTG OV.16 correlative study

Weberpals, Johanne I.; Tu, Dongsheng; Squire, Jeremy A.; Amin, Moein; Islam, Shahidul; Pelletier, Laurent; O'Brien, Anna; Hoskins, Paul; Eisenhauer, E. A.

doi:10.1093/annonc/mdq770

Cited by 41 publications

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“…19 If we combined those ovarian cancer with epigenetic inactivation of BRCA1 and BRCA2 (via methylation), 7 nearly 30% of ovarian serous carcinoma may have either defects or altered expression of BRCA1/2. However, based on several studies of BRCA1 protein expression analyses (by immunohistochemistry), the absence of or low BRCA1 expression was found in about 41-65% of ovarian cancer [20][21][22] (Table 5), indicating that there are additional as yet undefined mechanisms of BRCA1 inactivation involved in ovarian cancer development. Some of these data were further validated and correlated with BRCA1 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these data were further validated and correlated with BRCA1 mRNA expression. [20][21][22] Recent identification of MIR182 repression of BRCA1 expression 10 provides a new venue for the study of microRNA-mediated BRCA1 gene alteration. In the global profiling analyses of high-grade serous ovarian carcinoma, we 11 and others 23 found that MIR182 was significantly overexpressed in both early and late stages of this cancer.…”

Section: Discussionmentioning

confidence: 99%

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Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

et al. 2012

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BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P ¼ 0.0003) and HMGA2 (P ¼ 0.04) expression, and significantly lower BRCA1 (Po0.0001) and FOXO3 (Po0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r ¼ 0.31; Po0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (Po0.01), ascites (Po0.01) and high death rate (P ¼ 0.02). FOXO3 expression was associated with lower-stage disease (P ¼ 0.04) and solid growth pattern (P ¼ 0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes. Modern Pathology (2012) 25, 1644-1653; doi:10.1038/modpathol.2012.118; published online 13 July 2012Keywords: miR-182; ovarian cancer; BRCA1; HMGA2; MTSS1 High-grade serous ovarian carcinoma is an aggressive and deadly form of ovarian cancer, yet its pathogenesis is poorly understood. Despite significant efforts of clinical researchers, the survival rate of women with high-grade serous ovarian carcinoma has not changed in the past 50 years. 1 These tumors are often high-grade and aggressive at presentation, with a poor prognosis. Recent recognition of the existence of high-grade serous ovarian carcinoma precursor lesions, serous tubal intraepithelial carcinoma, 2,3 in the distal (fimbriated) ends of the fallopian tubes has renewed hope that we will be able to identify early tumorigenic events leading to high-grade serous ovarian carcinoma and reveal new opportunities for early detection and treatment that may decrease the mortality rate among women with this cancer.BRCA1 and BRCA2 mutations are a hallmark of high-grade serous ovarian carcinoma tumorigenesis. 4 Women with germline BRCA1/2 mutations have a 30-70% chance of developing high-grade serous ovarian carcinoma by age 70. 5 Germline BRCA mutations, 6 somatic mutations and epigenetic inactivation of BRCA1/2 (via methylation) can be found in nearly 30% of high-grade serous ovarian carcinoma cases. 7 BRCA1 has a broader role upstream of BRCA2, participating in various cellular

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

et al. 2012

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“…Formalin-fixed, paraffin-embedded patient tumor samples were collected and immunohistochemical (IHC) analysis and scoring were conducted as described in a previous study (17). Formalin-fixed, paraffin-embedded blocks representing areas of tumor were retrieved from the archives of the Department of Pathology and Laboratory Medicine.…”

Section: Methodsmentioning

confidence: 99%

BRCA1 protein levels and PIK3CA mutations as predictive biomarkers for response to neoadjuvant chemotherapy in locally advanced breast cancer: An exploratory analysis

et al. 2012

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Abstract. BRCA1 overexpression and phosphoinositide 3-kinase (PIK3CA) pathway activation are involved in the resistance to DNA damaging agents. Thus, we hypothesized that BRCA1 protein expression and activating PIK3CA mutations are potential tumor biomarkers for the chemotherapeutic response to doxorubicin/cyclophosphamide plus docetaxel in locally advanced breast cancer. Informed consent was obtained and clinical, pathological and response data were collected. BRCA1 protein expression levels were assessed by immunohistochemistry of the archived tissue by two independent pathologists. The PIK3CA mutation status was assessed by nested PCR amplification and DNA sequencing. BRCA1 protein levels and the PIK3CA mutation status were correlated with pathological complete response and a partial response or better using the Chi-square test, Fisher's exact test and logistic regression. Of the 136 eligible participants, 59 samples could be analyzed. There was a trend of relatively low levels of BRCA1 protein achieving a pathological complete response (pCR), although this was not statistically significant [odds ratio (OR)=1.74; p=0.437]. Twenty-eight percent of patients had PIK3CA mutations, but no statistically significant association with pCR (OR= 0.977; p= 0.971) was noted. Neither BRCA1 protein levels (OR=1.18; p=0.818) nor PIK3CA mutations (OR=1.03; p=0.971) appeared to be associated with the likelihood of achieving a partial response or better from neoadjuvant chemotherapy. PIK3CA wild-type mutation status showed a trend towards an increased likelihood of not presenting with inflammatory disease (OR=5.34; p=0.101). In this exploratory study, neither BRCA1 protein expression levels nor the presence of PIK3CA mutations were significantly associated with chemotherapy response in locally advanced breast cancer. However, the relatively small sample size limits the overall interpretation.

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“…Figure 1 summarizes the flow chart. Among these studies, the object response rate (ORR) was provided in 9 studies (5,7,(14)(15)(16)(17)(18)(19)(20), the remaining 4 studies provided only OS or PFS (21)(22)(23)(24). Characteristics of all involved studies are summarized in Table S1.…”

Section: Eligible Studiesmentioning

confidence: 99%

“…Of the 13 included studies, 4 were for non-small-cell lung cancer, 3 were for breast cancer, and 2 were for ovarian cancer; the remaining four were for malignant pleural mesothelioma, esophageal squamous cell carcinoma, small cell lung cancer and gastric cancer. Of the 13 studies, 7 were from an EastAsian population (14,(16)(17)(18)(19)(20)24), the other 6 studies were from a European population (5,7,15,(21)(22)(23). Characteristics of included studies are summarized in Table S1.…”

Section: Characteristics Of Eligible Studiesmentioning

confidence: 99%

Predictive value of BRCA1 expression on the efficacy of chemotherapy based on anti-microtubule agents: a pooled analysis across different malignancies and agents

Zhang

Zhang³

et al. 2016

Ann. Transl. Med.

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Background: Breast cancer susceptibility gene 1 (BRCA1) expression has been suggested as a predictor in antineoplastic treatment with anti-microtubule agents. However, the existing evidence is conflicting. Consulting the literature, we sought to examine the true impact of BRCA1 expression on the efficacy of anti-microtubule agents.Methods: Medline by PubMed and Embase databases were searched for eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Additional subgroup analyses stratified for detection methods, regimen, and patient origin were also performed.Results: A total of 13 relevant studies involving a total of 1,490 cases were enrolled. Involved agents included paclitaxel, docetaxel and vinorelbine; Malignancies included non-small cell lung cancer, gastric cancer, esophageal carcinoma, ovarian carcinoma, malignant pleural mesothelioma, breast cancer, and small cell lung cancer. Through meta-analyses, we observed a potentially greater ORR in the population with high BRCA1 expression vs. low BRCA1 expression (OR 1.63, 95% CI: 0.92 to 2.88, P=0.09) but the heterogeneity is severe (P=0.01; I 2 =61%). Similar results were observed in PFS (high vs. low expression, HR 0.93, 95% CI: 0.75 to 1.15, P=0.49; heterogeneity, P<0.01, I 2 =75%). After stratification by testing methods, a significantly higher ORR in the population with high BRCA1 expression was shown in the subgroup using mRNA as a quantitative method (OR 2.90, 95% CI: 1.92 to 4.39, P<0.01; I 2 =0) whereas the difference in the subgroup using immunohistochemistry (IHC) was not significant (OR 0.60, 95% CI: 0.33 to 1.10, P=0.10; I 2 =0). Stratification by regimen (platinum-based vs. non platinum-based) and patient origin (Asian vs. Caucasian) did not reduce the heterogeneity. Conclusions:Although the predictive value of BRCA1 expression on the anti-microtubule chemotherapy remained uncertain based on overall results, our exploratory analyses suggested that detection using mRNA might be a preferred technique, however, further validation is required to substantiate our findings.

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Breast cancer 1 (BRCA1) protein expression as a prognostic marker in sporadic epithelial ovarian carcinoma: an NCIC CTG OV.16 correlative study

Abstract: This study suggests that BRCA1 protein is a prognostic marker in sporadic OC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity.

Cited by 41 publications

References 31 publications

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

BRCA1 protein levels and PIK3CA mutations as predictive biomarkers for response to neoadjuvant chemotherapy in locally advanced breast cancer: An exploratory analysis

Predictive value of BRCA1 expression on the efficacy of chemotherapy based on anti-microtubule agents: a pooled analysis across different malignancies and agents

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