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Genome wide gene expression profiling of pre and post treatment breast cancer biopsy

ABSTRACT: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine (AZA) and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Patients and Methods: Patients received AZA 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3,10) of 28 day cycle. Continuation of epigenetic therapy was offered with addition of endocrine therapy at time of progression (optional continuation, OC phase). Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be >20% against null of 5% using Simon two-stage design. At least 1 response was required in 1st of 13 patients per cohort to continue accrual to 27 per cohort. Type I error 4%, power 90%. Results: There was one partial response among 27 women with hormone-resistant disease (ORR=4%, 95% CI=0-19%), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n=12). Mandatory tumor samples were obtained pre- and post-treatment (58% paired) with either up- or down-regulation of ER observed in approximately 50% of post-treatment biopsies in the hormone-resistant, but not TNBC cohort. Conclusion: Combination epigenetic therapy was well tolerated but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression but further study is needed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179674 | GEO | 2021/07/08

REPOSITORIES: GEO

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Project description:Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, with approximately 50% of patients having residual disease after neoadjuvant chemotherapy (NACT) and worse prognosis with higher residual cancer burden (RCB). Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. There is a need for PDX models encompassing the heterogeneity of TNBC both pre- and post- therapy and for identifying clinical and molecular features of patient’s tumors that are associated with success in establishing these models. Using fine-needle aspirates (FNAs), we established orthotopic PDX models of TNBC from the primary breast tumors of patients prior to and following neoadjuvant systemic therapy while enrolled in the ARTEMIS trial (NCT02276443). ARTEMIS is a prospective neoadjuvant clinical trial for women with primary TNBC who are treated with four cycles of Adriamycin combined with cyclophosphamide (AC) followed by taxane +/- different experimental therapies. Serial biopsies were obtained from patients prior to treatment (pre-therapy), from poorly responsive disease after four cycles of AC (mid-NACT), and in cases of AC-resistance, after a three-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 FNA biopsies from 217 women, generating a total of 62 successful PDX models (overall success-rate = 23%). This cohort includes five serial pre- and mid-NACT PDX pairs, as well as one serial pre-, mid-, post-NACT triplet. Success of PDX engraftment was generally higher from cancers that proved to be treatment-resistant: whether poor response to AC determined by ultrasound measurements mid-NACT (p=0.063), RCB II/III status after NACT (p=0.046), or metastatic relapse within two years of surgery (p=0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumor revealed no significant association with PDX engraftment rate (p=0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient’s diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient’s tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.

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Genome wide gene expression profiling of pre and post treatment breast cancer biopsy

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