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Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts.

ABSTRACT: SUMMARY: About 10-25% of breast cancer patients achieve a pathologically confirmed complete response after neoadjuvant chemotherapy. Tissue samples of pretreatment core biopsies are a valuable resource for translational research aiming towards predictive biomarkers for selecting patients who are likely to benefit from neoadjuvant therapy. The German Breast Group (GBG) and the AGO-B Group (AGO = Working Group Gynecological Oncology) have extensive experience in conducting neoadjuvant clinical trials. Technologies as immunohistochemistry on tissue microarrays and standardized reverse transcription-polymerase chain reaction (RT-PCR) approaches on formalin-fixed paraffin-embedded samples allow high-throughput investigation of protein and mRNA biomarkers. With these approaches, we could demonstrate that molecular tumor subtypes and immunological infiltrates are valuable and independent predictors of therapy response. New biomarkers such as poly(ADPribose) polymerase (PARP) might be useful for the prediction of response to conventional and new targeted therapies. This review summarizes current research projects focusing on biomarker discovery in the neoadjuvant setting.

SUBMITTER: Denkert C

PROVIDER: S-EPMC3225210 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts.

Denkert Carsten C Sinn Bruno Valentin BV Issa Yasmin Y Maria Müller Berit B Maisch Andrea A Untch Michael M von Minckwitz Gunter G Loibl Sibylle S

Breast care (Basel, Switzerland) 20110829 4

SUMMARY: About 10-25% of breast cancer patients achieve a pathologically confirmed complete response after neoadjuvant chemotherapy. Tissue samples of pretreatment core biopsies are a valuable resource for translational research aiming towards predictive biomarkers for selecting patients who are likely to benefit from neoadjuvant therapy. The German Breast Group (GBG) and the AGO-B Group (AGO = Working Group Gynecological Oncology) have extensive experience in conducting neoadjuvant clinical tri ...[more]

PMID: 22135624

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Project description:Background: Neoadjuvant chemotherapy is increasingly being used to preoperatively shrink breast tumours prior to surgery. This approach also provides the opportunity to study the molecular changes associated with treatment and evaluate whether on-treatment sequential samples can improve response and outcome predictions over diagnostic or excision samples alone. Methods: A total of 95 samples from a cohort of 50 neoadjuvant chemotherapy-treated primary breast cancer patients (aged 29-76, 48% ER+, 20% HER2+) enrolled in the NEO trial taken before, at 2 weeks on-treatment, mid-therapy and at resection were sequenced with Ion Ampliseq transcriptome yielding expression values for 12,635 genes. Differential expression analysis was performed across 16 responders and 34 non-responders defined by pathological complete response and over treatment time to identify significantly differentially expressed genes, pathways and markers indicative of response status. Prediction accuracy was compared with estimations of established gene signatures, for this dataset and validated using data from the I-SPY1 trial. Results: AAGAB was identified as a novel on-treatment biomarker for pathological complete response, with an accuracy of 100% in the NEO training dataset and 78% accuracy in the I-SPY1 Trial. AAGAB levels on treatment were also significantly predictive of term survival (p = 0.048, p = 0.031) in the two cohorts. This single gene on-treatment biomarker, had greater predictive accuracy than established prognostic tests, Mammaprint and Pam50 risk of recurrence score, although interesting both of these tests performed better in the on-treatment rather than the accepted pre-treatment setting (accuracy improving consistently by 2-8%). Conclusion: Changes in gene expression measured in sequential samples from breast cancer patients receiving neoadjuvant chemotherapy resulted in the identification of a novel on-treatment biomarker and suggest that established prognostic tests may have greater prediction accuracy on- than before treatment. These results support the potential use and further evaluation of on- treatment testing in breast cancer to improve the accuracy of tumour response prediction.

Project description:Background: Early prediction of response to neoadjuvant chemotherapy (NAC) is critical in choosing appropriate chemotherapeutic regimen for patients with locally advanced breast cancer. Herein, we sought to identify potential biomarkers to predict the response to neoadjuvant chemotherapy for breast cancer patients.Methods: Three genomic profiles acquired by microarray analysis from subjects with or without residual tumors after NAC downloaded from the GEO database were used to screen the differentially expressed genes (DEGs). An array of public databases, including ONCOMINE, cBioportal, Breast Cancer Gene Expression Miner v4.0, and the Kaplan Meir-plotter, etc., were used to evaluate the potential functions, related signaling pathway, as well as prognostic values of FABP7 in breast cancer. Anti-cancer drug sensitivity assay, real-time PCR, flow cytometry and western-blotting assays were used to investigate the function of FABP7 in breast cancer cells and examine the relevant mechanism.Results: Two differentially expressed genes, including FABP7 and ESR1, were identified to be potential indicators of response to anthracycline and taxanes for breast cancer. FABP7 was associated with better chemotherapeutic response, while ESR1 was associated with poorer chemotherapeutic effectiveness. Generally, the expression of FABP7 was significantly lower in breast cancer than normal tissue samples. FABP7 mainly high expressed in ER-negative breast tumor and might regulate cell cycle to enhance chemosensitivity. Moreover, elevated FABP7 expression increased the percentage of cells at both S and G2/M phase in MDA-MB-231-ADR cells, and decreased the percentage of cells at G0/G1 phase, as compared to control group. Western-blotting results showed that elevated FABP7 expression could increase Skp2 expression, while decrease Cdh1 and p27kip1 expression in MDA-MB-231-ADR cells. In addition, FABP7 was correlated to longer recurrence-free survival (RFS) in BC patients with ER-negative subtype of BC treated with chemotherapy.Conclusion: FABP7 is a potential favorable biomarker and predicts better response to NAC in breast cancer patients. Future study on the predictive value and detail molecular mechanisms of FABP7 in contribution to chemosensitivity in breast cancer is warranted.

Dataset Information

Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts.

Publications

Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts.

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