Abstract
We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients’ primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single-agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54–86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients’ cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients’ cancers had variants of unknown significance in these pathways. Mutations in PIK3CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients’ tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients’ cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER-positive, endocrine therapy-pretreated, HER2-negative metastases, are supported by preclinical data showing that sensitivity to 5-fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER-positive, HER2-negative breast cancers may predict for highly durable responses to capecitabine.
Highlights
There is considerable interest in oncology in prospectively identifying genomic alterations that may predict for response to a given therapy, and in selecting patients for standard or investigational therapies based on predefined genetic alterations
Cancer Medicine published by John Wiley & Sons Ltd
Four patients received capecitabine in combination with paclitaxel for a mean of 17 months; three of these patients continued with capecitabine monotherapy for a mean of 86 months after discontinuing paclitaxel for toxicity, and the fourth patient continued with combined capecitabine plus paclitaxel
Summary
There is considerable interest in oncology in prospectively identifying genomic alterations that may predict for response to a given therapy, and in selecting patients for standard or investigational therapies based on predefined genetic alterations. There is an emerging interest in identifying patients who have had an exceptional response a 2015 The Authors. ER-Positive MBC Patients with Exceptional Responses to Capecitabine to a therapy, and in evaluating these patients’ cancers for molecular alterations that may account for the observed marked benefit [1]. Such information could prove valuable in informing future treatment recommendations for phenotypically similar patients whose cancers harbor the same molecular alterations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
