Senthil Damodaran

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

Purpose We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. Patients and Methods High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Results Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). Conclusions SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Abstract OT2-01-22: NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients (pts) with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy (NACT)

BACKGROUND: Approximately 50% of TNBC pts treated with standard taxane/anthracycline-based NACT will have chemo-insensitive disease (CID) manifested as extensive residual disease (RCB-II or III) at the time of surgery. 40-80% of these pts will develop recurrence within 3 years of initial diagnosis. Recent advances in molecular profiling have identified subsets of TNBC with distinct, targetable molecular features. We developed a clinical trial to identify and characterize CID (ARTEMIS: ARandomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). In the ARTEMIS trial, treatment naive pts with localized TNBC undergo a pretreatment biopsy and then immediately start their initial phase of anthracycline-based chemotherapy so that the results of the molecular characterization are used in combination with response assessment (clinical exam/diagnostic imaging) to identify CID and inform the second phase of NACT, thus using a 9second hit9 strategy in the middle of NACT to overcome drug resistance. The mesenchymal subtypes of TNBC have a high incidence of PI3K pathway activation. Preclinical models demonstrated response to PI3K inhibitors in this subtype. Metaplastic breast cancers make up ∼30% of tumors characterized as 9claudin-low/mesenchymal9 by gene signature and are also associated with a high rate of PI3K activating molecular aberrations. A combination regimen of liposomal doxorubicin, bevacizumab and the mTOR inhibitors temsirolimus or everolimus (DAT or DAE) demonstrated response (including durable complete responses) in metastatic metaplastic breast cancer. PRIMARY OBJECTIVE: Determine the rate of pathologic complete response (pCR/RCB-0) or minimal residual disease (RCB-I) after 4 cycles of DAE for treatment of mesenchymal TNBC deemed to be CID through the ARTEMIS trial TRIAL DESIGN AND STATISTICAL METHODS: Only pts deemed to have mesenchymal CID on the ARTEMIS trial can enter this non-randomized phase II study. Realizing that pts without response to their initial cycles of chemotherapy have very low chance (5%) of achieving pCR with additional cycles of chemotherapy, it would be clinically meaningful to see pCR in this pt population improved to 20%. Counting pCR (RCB-0) or RCB-I as response, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more pts will be added for a total of 37 pts. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage and a total of 37 pts are enrolled, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA:Inclusion: localized TNBC enrolled onto ARTEMIS trial, adequate organ, bone marrow and cardiac parameters Exclusion: metastatic disease, pregnant or lactating pts, medical illness that increases chance of moderate to severe toxicity CORRELATIVE SCIENCE: Correlate vimentin expression by IHC, mesenchymal signatures and PI3K pathway aberrations with response. Citation Format: Moulder S, Hess K, Rauch M, Astrada B, Litton J, Mittendorf E, Ueno N, Tripathy D, Lim B, Piwnica-Worms H, Thompson A, Symmans WF. NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients (pts) with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-22.