Paul Marcom

<jats:p> TPS1113 </jats:p><jats:p> Background: PARP inhibition (PARPi) with olaparib is approved in HER2-negative germline BRCA mutant (g BRCAm) metastatic breast cancer. Maintenance PARPi in relapsed platinum-sensitive ovarian cancer improves median PFS regardless of gBRCA mutation status. Preclinical work has shown that platinum response strongly correlates with olaparib response in breast cancer models; hence, maintenance therapy trials are underway in aTNBC. PARPi modulates immune responses and enhances immunogenicity in many preclinical models. We hypothesize that olaparib either alone or in combination with the PD-L1 inhibitor durvalumab will have clinical efficacy as maintenance therapy in aTNBC subjects who have responded to platinum-based chemotherapy. Methods: DORA is a randomized, international, multicenter, phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab as maintenance therapy in platinum-sensitive aTNBC. 60 subjects will be enrolled following a minimum of 3 cycles of treatment with platinum-based (cisplatin or carboplatin) chemotherapy as a single agent or combination therapy in the first or second-line setting. Subjects deriving clinical benefit (CR / PR / SD) from platinum-based therapy will be eligible and randomized in a 1:1 ratio. Patients in arm 1 will receive olaparib orally 300mg BID continuously and in arm 2 will receive olaparib orally 300mg BID continuously in combination with durvalumab 1500mg IV every 4 weeks. Assessment of tumor response will be done every 8 weeks. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, clinical benefit rate, safety. Correlative analyses: pre-treatment archival/fresh biopsy samples are mandated. Post-treatment tissue biopsy is requested. Serial ctDNA will be collected at baseline, staging, and progression to correlate with response and track emerging genomic alterations in a platinum sensitive cohort under the pressure of PARP inhibition. Whole exome DNA sequencing, IHC for PDL-1 and TILs will be performed on tissue samples. ClincalTrials.gov Identifier: NCT03167619. (Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR). Clinical trial information: NCT03167619. </jats:p>

<jats:title>Abstract</jats:title> <jats:p>Triple negative breast cancer (TNBC) represents a particularly aggressive and difficult to treat form of breast cancer. No specific genetic alterations have been described as characteristic of the disease, with the exception of association with BRCA1/2, EGFR, and KRAS mutations. In this study, we sought to define clinically actionable mutations in untreated metastatic tumors as well as compare the mutational status of metastatic samples with germ-line and primary tumors using whole exome sequencing.</jats:p> <jats:p>We prospectively enrolled 38 patients with newly diagnosed metastatic TNBC and collected matched specimens of germ-line DNA, primary tumor and metastatic tumor. Median DFI from time of initial primary diagnosis to recurrence was 18 months (IQR = 1-24 months) and 9 patients presented with de novo metastatic disease. 34/38 patients went on to receive first-line treatment with nab-paclitaxel, carboplatin, and bevacizumab and ORR/PFS/OS are available.</jats:p> <jats:p>Sites of TNBC metastatic tissue (n = 31) included: liver (10), chest wall (13), non-regional lymph nodes (4), and lung (4). 7 patients had inadequate metastatic tumor for sequencing. We performed whole-exome sequencing for all samples using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes (CCDS database), as well as ∼700 human miRNAs from miRBase (v13). In all, we generated over 10 GB of sequencing data using high throughput sequencing on the Illumina platform.</jats:p> <jats:p>We observed striking genetic heterogeneity among the metastatic and primary tumors. There was no single driver mutation that was common to the metastatic tumors indicating the diverse genetic pathways that contribute to metastasis. Early analysis suggests that mutations in APC and MTOR occur more frequently in metastatic tumors than in primary tumors. Nonsense mutations of ER were detected in both primary and metastatic tumors but not in germ-line DNA. EGFR and HER2 mutations were not found in any of the primary or metastatic TNBC samples.</jats:p> <jats:p>This data provides the most comprehensive genetic portrait of metastatic and primary TNBC to date, and represents a significant first step in identifying the genetic causes of the disease, drivers of recurrence, and potential therapeutic targets. Full results, including the primary versus metastatic tumor mutational analysis will be presented.</jats:p> <jats:p>This study was funded by a Susan G. Komen Grant SAC 100001.</jats:p> <jats:p>Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-03.</jats:p>

<jats:title>Abstract</jats:title> <jats:p>Background: Numerous gene-expression signatures have been developed for breast cancer. However, assessments of their validity continue to largely ignore the impact of intratumor heterogeneity and technical variation on clinical utility. Here, the collection of replicate specimen in Barry et al (2010) is used to evaluate a broad collection of gene-expression signatures of prognosis and tumor biology.</jats:p> <jats:p>Methods: Eighteen patients with multiple frozen cores (one patient with quadruplicate, twelve with triplicate, and five with doublet samples) were previously identified in the Duke Breast SPORE tissue repository. Cores were assessed for percent invasive cancer cellularity, and tumor size, grade, and ER/PR status. RNA was extracted and hybridized to AffymetrixH133Plus2.0 microarrays. Expression signatures of prognosis and tumor biology were developed or translated to the Affymetrix platform using routines by Prat et al. (2012) and Haibe-Keins et al. (2012). Association between signatures, and precision among replicates are evaluated using Pearson and intraclass correlation. Coefficients are reported with 95% confidence intervals.</jats:p> <jats:p>Results: Among prognostic signatures, an imputed 70-gene signature of MammaPrint had the highest level of precision (ICC = 0.96, 0.91–0.98); strong concordance is seen with Affymetrix-based PAM50 risk-of-relapse (ICC = 0.82, 0.65–0.92); 16 of 18 patients had constant subtype calls. Substantially lower concordance was seen in the GENIUS prognostic model (ICC = 0.62, 0.35–0.82). In ER+ patients (n = 13), two algorithms to impute the 21-gene model of OncotypeDX recurrence score were concordant (r = 0.98, ICC= 0.90 and 0.83) and distinct from the GENIUS ER+ score (average r = 0.74, ICC=0.78). Imputed models for the Rotterdam 76-gene model (+ER status), GGI (+grade), and ROR-T (+tumor size) showed lower levels of correlation (0.47&amp;lt;rho&amp;lt;0.64), suggesting independent prognostic information is conveyed by the unique combinations of clinical and genomic factors. High correlation is seen between models of ER status ranging from single-gene data (ICC = 0.90) to signatures from archived specimen (ICC = 0.96) and cell lines (ICC = 0.85), with almost complete agreement to IHC results. Two signatures of PI3K from specimen with mutation data were partially correlated and concordant (r = 0.52, ICC= 0.96 and 0.91), while two signatures from overexpression systems were uncorrelated, and one with poor precision (r = 0.12, ICC= 0.92 and 0.46). Signatures of PR, EGFR and p53 status will also be reported.</jats:p> <jats:p>Conclusions: The number of genomic signatures in breast cancer from archived specimen and cell-line experiments continues to grow, but there are limited resources for validating their prognostic/predictive value in patient populations. Reproducibility across biological replicates is a critical component in establishing clinical utility of a signature that is distinct from using technical replicates for the repeatability of analytes on the array platform. We demonstrate how archived specimen can confirm reproducibility in the ‘Test Validation Phase’ of biomarker development, as advocated by the Institute of Medicine, and inform trial designs to prospectively test clinical utility.</jats:p> <jats:p>Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-01.</jats:p>