Joshua Jones

Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer

Purpose: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. Results: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764–73. ©2016 AACR.

Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma

Introduction: The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality. Methods: Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome. Results: The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7). Conclusions: This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.

Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma

Purpose The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. Methods Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome. Results In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P=0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer–specific survival (P<0.001 and 0.015, respectively), compared with low mPS. Conclusion This study validates CCP score and mPS as independent prognostic markers for lung cancer–specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.

Abstract P5-06-04: The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score

Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with that of BRCA1/2 mutation driven breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by dysfunction of genes other than BRCA1 or BRCA2. Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. Previously, we demonstrated that a subset of basal breast cancer (BBC) patient-derived xenograft (PDX) models responded robustly to single agent niraparib treatment. To understand the selectivity observed, the samples from a collection of 37 BBC PDX models have been subjected to homologous recombination deficiency (HRD) analysis. HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using three algorithms (LOH, TAI and LST scores), and the final HRD score is the sum of the LOH+TAI+LAST scores. Niraparib’s antitumor activity was investigated in patient derived BBC models with various HRD scores. The correlation between niraparib efficacy, HRD score and BRCA deficiency will be discussed. Citation Format: Yan Wang, Stefano Cairo, Olivier Deas, Anne-Renee Hartman, Joshua Jones, Alexander Gutin, Jerry Lanchbury, Zaina Sangale, Cara Solimeno, Jean-Gabriel Judde, Kirsten Timms, Keith Wilcoxen. The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-04.

Cost-Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early-Stage Non-Small Cell Lung Cancer

BACKGROUND A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC. MATERIALS AND METHODS Lifetime costs (2014 U.S. dollars) and effectiveness (quality-adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS Lifetime costs and effectiveness were

Abstract P3-06-11: Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer

137,403 and 5.45 QALYs with the prognostic test and

Abstract C53: Homologous recombination deficiency (HRD) of high grade serous ovarian tumors from the NOVA Phase III clinical study

127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was

Abstract P5-06-01: Homologous recombination deficiency (HRD) score predicts response to standard neoadjuvant chemotherapy in patients with triple negative or BRCA1/2 mutation-associated breast cancer

35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of

Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).

50,000/QALY. CONCLUSION The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost-effective compared with using the SoC based on globally accepted willingness-to-pay thresholds. IMPLICATIONS FOR PRACTICE Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests.

Use of homologous recombination deficiency (HRD) score to enrich for niraparib sensitive high grade ovarian tumors.

A significant proportion of triple negative breast cancers (TNBC) carry defects in DNA repair including Homologous Recombination (HR) defects and are sensitive to therapies that target these pathways. Several clinical trials have demonstrated improvement in pathologic response with the addition of platinum to standard of care neoadjuvant regimens but at a cost of increased toxicities. Recently three DNA based metrics (LOH, Abkevich et al. 2012 Br J Cancer; TAI, Birkbak et al. 2012 Cancer Discov; LST, Popava et al. 2012 Cancer Res) have been developed, shown to be highly associated with BRCA1/2 mutation status, and found to predict sensitivity to platinum based chemotherapy in TNBC. The HRD Score was defined as the sum of LOH, TAI, and LST measurements, and a threshold separating tumors with high and low HRD Scores was established. This study assesses the association of HRD Score with response to cisplatin neoadjuvant chemotherapy in patients with TNBC. A clinical test that identifies tumors with defects in HR may distinguish those patients more likely to benefit from the addition of platinum. Methods: Archival tumor samples were obtained from 74 patients with TNBC from 2 separate clinical trials conducted at DFHCC under IRB approved protocols. One trial enrolled 28 patients who received neoadjuvant cisplatin monotherapy (Silver et al., 2010 J Clin Oncol). The second trial enrolled 51 patients who received cisplatin and bevacizumab chemotherapy (Ryan, et al.,2009 J Clin Oncol). HRD Score and tumor BRCA1/2 mutation status were determined. BRCA1/2 deficiency was defined as the presence of BRCA1/2 mutation with loss of the second allele in the tumor. Response was categorized by the residual cancer burden (RCB) score with responders defined as RCB0 or 1, and non-responders as RBC2 or 3. A second measure of response, pathologic complete response (pCR), was defined as RCB0 and non-responders as RCB1,2 or 3. Logistic regression was used to evaluate HRD Score in combination with BRCA1/2 deficiency as a predictor of response to neoadjuvant therapy. All analysis was conducted according to a pre-specified Statistical Analysis Plan. Results: As of May 29, 2014 41 samples have been processed. Seven carried deleterious mutations in BRCA1/2 (17%). Thirty-three of the tumors produced SNP data of sufficient quality for HRD score calculation. HRD scores in the passing samples ranged from 7 – 74, with an average score of 45. The HRD scores observed in BRCA1/2 mutation carriers (n=6) ranged from 43 – 57 with an average HRD score of 55. We anticipate that all molecular data will be generated by July 1, 2014. Correlation with pCR and RCB0/1 will be assessed. Conclusions: The LOH, TAI, and LST metrics have been shown in previous studies to predict response to platinum-based neoadjuvant chemotherapy in patients with TNBC. This study will be a validation of LOH, TAI and LST in the form of a combined score, and will demonstrate that HRD Score can be used as a tool to identify patients with breast tumors with underlying HR deficiency who may benefit from platinum therapy. Citation Format: Andrea L Richardson, Daniel P Silver, Zoltan Szallasi, Nicolai J Birkbak, Zhigang C Wang, J Dirk Iglehart, Erica L Mayer, Eric P Winer, Nadine M Tung, Paula D Ryan, Steven J Isakoff, William T Barry, April Greene-Collozi, Alexander Gutin, Julia Reid, Chris Neff, Joshua Jones, Kirsten Timms, Anne-Renee Hartman, Judy E Garber. Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-11.