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An update on biomarkers of potential benefit with bevacizumab for breast cancer treatment: Do we make progress?

ABSTRACT: As the first monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (BEV) is a definitely controversial antiangiogenic therapy in breast cancer. The initial excitement over improvements in progression-free survival (PFS) with BEV was tempered by an absence of overall survival (OS) benefit and serious adverse effects. Missing targeted population urged us to identify the predictive biomarkers for BEV efficacy. In this review we focus on the research in breast cancer and provide recent investigations on clinical, radiological, molecular and gene profiling markers of BEV efficacy, including the new results from randomized phase III clinical trials evaluating the efficacy of BEV in combination with comprehensive biomarker analyses. Current evidences indicate some predictive values for genetic variants, molecular imaging, VEGF pathway factors or associated factors in peripheral blood and gene profiling. The current challenge is to validate those potential biomarkers and implement them into clinical practice.

SUBMITTER: Liang X

PROVIDER: S-EPMC6736652 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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An update on biomarkers of potential benefit with bevacizumab for breast cancer treatment: Do we make progress?

Liang Xu X Li Huiping H Coussy Florence F Callens Celine C Lerebours Florence F

Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 20190801 4

As the first monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (BEV) is a definitely controversial antiangiogenic therapy in breast cancer. The initial excitement over improvements in progression-free survival (PFS) with BEV was tempered by an absence of overall survival (OS) benefit and serious adverse effects. Missing targeted population urged us to identify the predictive biomarkers for BEV efficacy. In this review we focus on the research in breast cancer and ...[more]

PMID: 31564802

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Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes

Project description:In 2009 a prospective, randomized Phase II trial (NCT00842998) was initiated to evaluate the activity of HER2-targeting agents without chemotherapy (CT) in HER2-positive metastatic breast cancer (MBC) patients. The primary tumors of the patients enrolled in this study offered a unique opportunity to identify biomarkers that could predict durable clinical benefit from CT-free anti-HER2 therapy. Patients with HER2-positive MBC were randomized to trastuzumab or lapatinib as first-line therapy. CT was added to anti-HER2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated by HERmark® and VeraTag® assay, respectively. Predictors of persistence on protocol (PP) were studied by Cox univariate and multivariate analysis. Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8-38.8+), with 4 patients (21.1%) persisting on single agent trastuzumab or lapatinib for longer than 12 mo (14.9-38.8 + mo). Seventeen patients were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile correlated with reduced PP. Moreover, increasing H2T/p95 ratio was found to be significantly associated with longer PP (HR 0.56 per 2-fold increase in H2T/p95, P = 0.0015). Our data suggest that patients belonging to the "HER2-enriched" subtype and/or having high H2T/p95 protein expression ratio are exquisitely sensitive to anti-HER2 agents. MBC patients with these tumors could be candidates for studies aimed at establishing chemotherapy-free regimens.

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An update on biomarkers of potential benefit with bevacizumab for breast cancer treatment: Do we make progress?

Publications

An update on biomarkers of potential benefit with bevacizumab for breast cancer treatment: Do we make progress?

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