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Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine.
- Source :
-
Cancer medicine [Cancer Med] 2015 Aug; Vol. 4 (8), pp. 1289-93. Date of Electronic Publication: 2015 Apr 13. - Publication Year :
- 2015
-
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.<br /> (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Subjects :
- Antimetabolites, Antineoplastic therapeutic use
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Breast Neoplasms diagnosis
Female
Genotype
Humans
Neoplasm Metastasis
Phenotype
Phosphoproteins
Proteome
Proteomics
Treatment Outcome
Breast Neoplasms drug therapy
Breast Neoplasms genetics
Capecitabine therapeutic use
Chromatin Assembly and Disassembly
DNA Repair
Genetic Variation
Receptors, Estrogen genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-7634
- Volume :
- 4
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25871911
- Full Text :
- https://doi.org/10.1002/cam4.464