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On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer.

ABSTRACT: BACKGROUND:Neoadjuvant chemotherapy is increasingly given preoperatively to 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:This study included a total of 97 samples from a cohort of 50 women (aged 29-76, with 46% ER+ and 20% HER2+ tumours) with primary operable breast cancer who had been treated with neoadjuvant chemotherapy. Biopsies were taken at diagnosis, at 2?weeks on-treatment, mid-chemotherapy, and at resection. Fresh frozen samples were sequenced with Ion AmpliSeq Transcriptome yielding expression values for 12,635 genes. Differential expression analysis was performed across 16 patients with a complete pathological response (pCR) and 34 non-pCR patients, 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-SPY 1 Trial. RESULTS:Although changes upon treatment are largely similar between the two cohorts, very few genes were found to be consistently different between responders and non-responders, making the prediction of response difficult. AAGAB was identified as a novel potential on-treatment biomarker for pathological complete response, with an accuracy of 100% in the NEO training dataset and 78% accuracy in the I-SPY 1 testing dataset. AAGAB levels on-treatment were also significantly predictive of outcome (p?=?0.048, p?=?0.0036) in both cohorts. This single gene on-treatment biomarker had greater predictive accuracy than established prognostic tests, Mammaprint and PAM50 risk of recurrence score, although interestingly, both of these latter tests performed better in the on-treatment rather than the accepted pre-treatment setting. CONCLUSION:Changes in gene expression measured in sequential samples from breast cancer patients receiving neoadjuvant chemotherapy resulted in the identification of a potentially 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.

SUBMITTER: Bownes RJ

PROVIDER: S-EPMC6570893 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer.

Bownes Richard J RJ Turnbull Arran K AK Martinez-Perez Carlos C Cameron David A DA Sims Andrew H AH Oikonomidou Olga O

Breast cancer research : BCR 20190614 1

<h4>Background</h4>Neoadjuvant chemotherapy is increasingly given preoperatively to 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.<h4>Methods</h4>This study included a total of 97 samples from a cohort of 50 women (aged 29-76, with 46% ER+ and 20% HER2+ tumours) wi ...[more]

PMID: 31200764

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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:Objective: To develop and validate a prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NCT) of triple-negative breast cancer (TNBC). Methods: We systematically searched Gene Expression Omnibus, ArrayExpress, and PubMed for the gene expression profiles of operable TNBC accessible to NCT. Molecular heterogeneity was detected with hierarchical clustering method, and the biological profiles of differentially expressed genes were investigated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses, and Gene Set Enrichment Analysis (GSEA). Next, machine-learning algorithms including random-forest analysis and least absolute shrinkage and selection operator (LASSO) analysis were synchronously performed and, then, the intersected proportion of significant genes was undergone binary logistic regression to fulfill variables selection. The predictive response score (pRS) system was built as the product of the gene expression and coefficient obtained from the logistic analysis. Last, the cohorts were randomly divided in a 7:3 ratio into training cohort and validation cohort for the introduction of a robust model, and a nomogram was constructed with the independent predictors for pCR rate. Results: A total of 217 individuals from four cohort datasets (GSE32646, GSE25065, GSE25055, GSE21974) with complete clinicopathological information were included. Based on the microarray data, a six-gene panel (ATP4B, FBXO22, FCN2, RRP8, SMERK2, TET3) was identified. A robust nomogram, adopting pRS and clinical tumor size stage, was established and the performance was successively validated by calibration curves and receiver operating characteristic curves with the area under curve 0.704 and 0.756, respectively. Results of GSEA revealed that the biological processes including apoptosis, hypoxia, mTORC1 signaling and myogenesis, and oncogenic features of EGFR and RAF were in proactivity to attribute to an inferior response. Conclusions: This study provided a robust prediction model for pCR rate and revealed potential mechanisms of distinct response to NCT in TNBC, which were promising and warranted to further validate in the perspective.

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On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer.

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On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer.

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