title: Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine.
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.
authors: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas.
authors: Maren K
authors: MK
authors: Levin
authors: Foundation Medicine Inc., Cambridge, Massachusetts.
authors: Kai
authors: K
authors: Wang
authors: Foundation Medicine Inc., Cambridge, Massachusetts.
authors: Roman
authors: R
authors: Yelensky
authors: Valley Medical Oncology Consultants, Pleasanton, California.
authors: Ying
authors: Y
authors: Cao
authors: Theranostics Health Inc., Rockville, Maryland.
authors: Corinne
authors: C
authors: Ramos
authors: Theranostics Health Inc., Rockville, Maryland.
authors: Nicholas
authors: N
authors: Hoke
authors: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas.
authors: John
authors: J
authors: Pippen
authors: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas.
authors: Joanne L
authors: JL
authors: Blum
authors: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas.
authors: Barry
authors: B
authors: Brooks
authors: Foundation Medicine Inc., Cambridge, Massachusetts.
authors: Gary
authors: G
authors: Palmer
authors: Foundation Medicine Inc., Cambridge, Massachusetts.
authors: Norma
authors: N
authors: Palma
authors: Foundation Medicine Inc., Cambridge, Massachusetts.
authors: Sohail
authors: S
authors: Balasubramanian
authors: Foundation Medicine Inc., Cambridge, Massachusetts.|Albany Medical College, Albany, New York.
authors: Jeffrey S
authors: JS
authors: Ross
authors: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas.
authors: Joyce
authors: J
authors: O'Shaughnessy
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D000069287:Capecitabine / Q000627:therapeutic use*; D042002:Chromatin Assembly and Disassembly; D004260:DNA Repair; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009362:Neoplasm Metastasis; D010641:Phenotype; D010750:Phosphoproteins; D020543:Proteome; D040901:Proteomics; D011960:Receptors, Estrogen / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D010750:Phosphoproteins; D020543:Proteome; D011960:Receptors, Estrogen; D000069287:Capecitabine
keywords: DNA damage response; capecitabine; chromatin remodeling genes; exceptional responders; metastatic breast cancer