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

Abstract

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.

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

“…It is worth noting that BRCA1 plays a pivotal role in DNA repair and cell cycle regulation in response to DNA damage, potentially resulting from chemotherapy and radiotherapy. Indeed, several studies reported that BRCA1 mRNA expression had predictive impact on responses to chemotherapy, as well as to chemoradiotherapy in many types of cancer, such as breast cancer, lung cancer, and esophageal cancer [ 27 , 28 , 29 , 30 , 31 ], suggesting BRCA1 as an attractive candidate for predicting nCRT response in LARC. It has been reported that GPR110 ( ADGRF1 ) can induce cell cycle arrest and chemoresistance in breast cancer [ 32 ].…”

Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology

“…A potential role for BRCA1 as a biomarker for sensitivity to vinorelbine was identified in 2012 [ 53 ], and potentially confirmed through a pooled analysis [ 54 ]. On the basis of this observation a Phase II clinical trial (NCT02139904) was conducted with patients randomized 2:1 to receive either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal [ 55 ], and whilst the trial met its stated primary goal with respect to improved PFS, BRCA1 did not predict resistance to ASC + vinorelbine [ 55 ].…”

Promising Targeted Therapies Genes and Prognostic Biomarkers of Gastric Cancer

“…Выдвинута гипотеза, что повышенный уровень экспрессии BRCA1 положительно коррелирует с чувствительностью опухолевых клеток к таксанам: в исследованиях, проводившихся на клеточных линиях с идуцированной экспрессией BRCA1, обнаружилось, что чувствительность этих клеток к таксанам была резко повышена [63]. У пациентов с РЖ, имеющих повышенную экспрессию BRCA1, наблюдались большая частота объективного ответа и выживаемость без прогрессирования при назначении ингибиторов митоза [64].…”