Citations

Abstract Background: Preclinical and clinical data indicate a key role for the PI3-kinase (PI3K) pathway in the pathogenesis of resistance to endocrine therapies in hormone receptor-positive (HR) breast cancer (BC) and suggest that combining PI3K inhibitors with endocrine therapy may partially overcome this resistance. FERGI is the first randomized Phase II study testing pictilisib (GDC-0941), a PI3K inhibitor, in combination with fulvestrant to evaluate this hypothesis in MBC patients with and without PIK3CA-mutant tumors. Methods: 168 post-menopausal pts with ER-positive, HER2-negative MBC were randomized (1:1) to receive fulvestrant with either pictilisib 340 mg QD (n=89, "combination" arm) or matching placebo (n=79, "control" arm). To be eligible, pts had to have relapsed during or within 6 mos of completing adjuvant AI treatment or have progressed on an AI for MBC. Pts were stratified based on tumor PIK3CA mutation status, resistance to prior AI therapy and presence of measurable disease. The primary endpoint was PFS by investigator assessment in the intent-to-treat (ITT) group and in pts with centrally confirmed PIK3CA-mutant tumors. The primary analysis was based on a 6 mo median duration follow up. Results: Baseline disease and prior treatment characteristics were similar between study arms. Observed treatment-emergent AEs were consistent with those previously described for single agent pictilisib and fulvestrant (primary toxicities were rash and GI disorders). In the ITT population (84 events) the median PFS (mPFS) was 6.2 mo in the combination arm vs 3.8 months for the control arm (HR, 0.77; 95% CI, 0.50-1.19). For pts with PIK3CA-mutant tumors (37 events), mPFS was 6.2 mo in the combination arm vs 5.1 mo in the control arm (HR, 0.92; 95% CI, 0.48-1.76). For pts without a detectable PIK3CA mutant tumor (43 events), mPFS was 5.8 months in the combination arm vs 3.6 months in the control arm (HR, 0.64; 95% CI, 0.35-1.17). Exploratory post-hoc subgroup analysis suggested improvement in PFS in pts with ER+ and PR+ tumors (centrally confirmed) treated with pictilisib plus fulvestrant. In the ER+/PR+ subgroup (57 events) mPFS was 7.2 mo in the combination arm vs 3.7 mo in the control arm (HR, 0.46; 95% CI, 0.27 to 0.78). This improvement was independent of tumor PIK3CA mutation status. Multivariate analysis suggests that this treatment effect in pts with ER+/PR+ tumors is maintained after adjusting for possible baseline imbalances. A similar analysis on pts with luminal A tumors (per PAM50 analysis) was also consistent with the findings in pts ER+/PR+ disease. Conclusions: This is the first report of a blinded, randomized clinical study evaluating a PI3K inhibitor in pts with MBC. In the ITT population, the addition of pictilisib to fulvestrant was associated with a mPFS improvement of 3.8 mo to 6.2 mo. Exploratory subgroup analyses suggested in pts with ER+/PR+ tumors are more likely to derive benefit from the addition of pictilisib to fulvestrant irrespective of PIK3CA mutation status, though the subgroup analyses are limited by the sample size. Additional biomarker analyses will be reported. Citation Format: Ian Krop, Stephen Johnston, Ingrid A Mayer, Maura Dickler, Vinod Ganju, Andres Forero-Torres, Bohuslav Melichar, Serafin Morales, Richard de Boer, Steven Gendreau, Mika Derynck, Mark Lackner, Jill Spoerke, Ru-Fang Yeh, Gallia Levy, Vivian Ng, Carol O'Brien, Heidi Savage, Yuanyuan Xiao, Timothy Wilson, Soo Chin Lee, Katarina Petrakova, Susanne Vallentin, Denise Yardley, Matthew Ellis, Martine Piccart, Edith A Perez, Eric Winer, Peter Schmid. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results [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 S2-02.

Abstract Background. We recently identified an in-frame ESR1 translocation in a tumor and PDX pair from a patient with endocrine therapy resistant advanced disease. The fusion gene preserved the N-terminal 365aa of ESR1 containing the intact activation function 1 (AF1), DNA-binding domain (DBD) and hinge, followed by the C-terminal transactivation domain of YAP1. The ESR1-365>YAP1 fusion drove estrogen-independent and anti-estrogen-resistant tumor cell growth (Cell Reports 4:1116, 2013). We therefore sought to further investigate the role of ESR1 fusion genes in breast cancer. Methods. 711 cases from TCGA, 82 ER+ cases from neoadjuvant endocrine therapy trials and 25 ER+ systemic relapse samples were screened for fusion genes using RNAseq. Fusion genes involving ESR1 were subsequently assayed for estrogen response element (ERE)-mediated transcriptional activity and ability to drive estradiol independent breast cancer cell growth. Results. Multiple ESR1 fusions were identified in mostly luminal B cancers. ESR1 fusions resulted most frequently from rearrangements involving another gene on Chromosome (Chr) 6 but also fusions with genes on other chromosomes. The fusions involving partners on Chr6 that retained an intact N terminal AF1 and DNA binding domain (DBD) of ESR1 (≥1-253aa) included an Out-of-Frame (OF) fusion event with CCDC170 (a gene immediately centromeric to ESR1), POLH (in-frame or IF), AKAP12 (IF), PCMT1 (OF), SYNE1 (OF) and GPR126 (OF). Also identified were inter-chromosomal translocations involving Chr12p-NOP2 (IF) and ChrX-PCDH11X (IF) and Chr7q-AKR1D1 (OF). The ESR1 fusions with transcriptional potential (because of a retained DNA binding domain) included variable 5’ ESR1 exons that preserved 253aa, 365aa, 412aa or 458aa of ESR1 sequence: in all cases disrupting ligand binding though loss of C terminal sequence. The effect of the IF and OF 3’ sequences on the transcriptional activity of the relevant ESR1 fragment was highly variable. The most transcriptionally active fusion (more active than the relevant ESR1 fragment alone) was the ESR1-365>YAP1 as well as ESR1-365>PCDH11X and ESR1-253>CCDC170. This is remarkable since PCDH11X is not considered a transcription factor and the CCDC170 sequence was OF – in both cases suggesting the activity of the fusion was due to "neomorphic" properties. Two fusions, NOP2 and POLH were inactive in the ERE reporter assay, yet both stimulated estradiol independent growth. In these cases we suggest that the ESR1 locus can function as a "promoter trap" which allows the identification of genes with previously unknown functions in endocrine therapy resistance. Conclusions: In luminal-type breast cancer the ESR1 gene was fused to multiple 3’ partners with remarkably heterogeneous functions. The two most transcriptionally active, ESR1-365>YAP1 and ESR1-365>PCDH11X, were both identified in endocrine therapy refractory advanced disease – suggesting a role in fatal disease progression. Citation Format: Jieya Shao, Jin Zhang, Robert J Crowder, Rodrigo Goncalves, Chanpheng Phommaly, Breast AWG and Network, Charles M Perou, Christopher A Maher, E Aubrey Thompson, Matthew J Ellis. ESR1 gene fusions implicated in endocrine therapy resistance of ER+ 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 PD6-4.

Abstract Background: The Preoperative Endocrine Prognostic Index (PEPI) is a method to predict outcome after neoadjuvant endocrine therapy that integrates Ki67, estrogen receptor (ER) analysis and pathological stage from the surgical specimen (Ellis, JNCI 100:1380, 2008). We sought to further develop the PEPI for use in clinical trials by: a) establishing an efficient SOP for Ki67 analysis, b) determining the effect of simplifying the score by removing the ER component (modified "mPEPI") and c) independent validation of mPEPI in the ACOSOG (Alliance) Z1031 neoadjuvant aromatase inhibitor trial (Ellis, M, JCO 29:234, 2011). Methods: Ki-67 assay development focused on reproducing a 2.7% Ki-67 cut point (CP) required for PEPI. Ventana Image analysis (IA) to replace labor-intensive visual point counting (VPC) was assessed to increase scoring efficiency. Discordant scores led to a triage approach where cases with complex histological features that could not be resolved by IA were flagged for VPC. The Ki-67 scoring approach was preliminarily validated on T1/2 N0 cases from the P024 and POL trials (SABCS 2013, abstract P3-05-190). Models with and without ER suggested ER was dispensable. A locked SOP for mPEPI was subsequently applied to the Z1031A trial. The primary endpoint was time from the date of surgery to local, regional, or distant recurrence in the mPEPI-0 group (T1/2 N0, Ki67 <2.7%) versus the mPEPI>0 group. Results. mPEPI by IA was evaluated on 202 of 377 (53%) patients enrolled into Z1031A (6% of IA results were triaged to VPC). All patients have been followed a minimum of 2 years (median: 5 years; max: 7 years). Only 10 patients in the mPEPI-0 group (22.7%) received adjuvant chemotherapy, versus 78 in the mPEPI>0 group (49.4%). Time to breast cancer recurrence was decreased among those with mPEPI>0 status relative to those with mPEPI-0 status (log rank p=0.012). Only one disease event among 44 (2%) cases with mPEPI-0 was observed versus 26 of 158 cases with mPEPI>0 (16.5%) Conclusions. mPEPI-0 status can identify patients at low risk of relapse after neoadjuvant endocrine therapy: therefore mPEPI-0 status has operational characteristics similar to pCR after chemotherapy for ER-negative disease. mPEPI is undergoing prospective validation in the Alliance ALTERNATE trial that will assess whether Fulvestrant increases the mPEPI-0 rate and also will prospectively determine whether patients with mPEPI-0 status can safely be managed without adjuvant chemotherapy treatment. Citation Format: Souzan Sanati, Vera J Suman, Rodrigo Goncalves, Katherine DeSchryver, Cynthia X Ma, Jeremy Hoog, Erika Crouch, Michael Barnes, Gary Unzeitig, A Marilyn Leitch, Kelly K Hunt, Matthew J Ellis. Validation of the preoperative endocrine prognostic index in the ACOSOG (Alliance) Z1031 neoadjuvant aromatase inhibitor trial [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 P4-11-13.

Abstract Neoadjuvant endocrine therapy (ET) in patients (pts) with locally advanced estrogen receptor positive (ER+) breast cancer (BC) improves breast conservation rate, and importantly offers an opportunity for individualized assessment of tumor responsiveness to ET to guide subsequent treatment. Previous neoadjuvant ET trials demonstrated that pathologic tumor size (pT), axillary lymph node status (N), and tumor Ki67 value at surgery predicted risk of relapse. Preoperative endocrine prognostic index (PEPI) was therefore developed to assign risk scores based on these factors. Modified PEPI 0, defined by pT1-2 N0 Ki67< 2.7%, was associated with extremely low risk of recurrence without adjuvant chemotherapy. In addition, high Ki67 post 2-4 weeks (wks) of neoadjuvant ET identified resistant tumors with poor outcome. ALTERNATE trial is a three-arm phase III neoadjuvant/adjuvant ET trial designed to achieve two primary objectives. The first is to prospectively validate that modified PEPI 0 predicts > 95% relapse-free survival (RFS). The second is to determine whether fulvestrant (F), or fulvestrant (F) plus anastrozole (A), is superior to A in inducing a higher rate of modified PEPI 0. Secondary objectives include assessing RFS for pts with endocrine resistant tumor, defined by Ki67 > 10% at 4 or 12 wk, disease progression, or modified PEPI non-0, and pathologic responses of resistant tumors to neoadjuvant chemotherapy. Correlative studies include degrees of Ki67 suppression and ER level post treatment. In addition, ongoing research sequencing studies of DNA and RNA will be performed to contrast sensitive vs resistant tumors. During the first phase of the trial, 1200 pts are randomized 1:1:1 to the F, A or F/A. This provides an 82% chance, 1-sided alpha 0.025 chi-square test to detect at least 10% difference in modified PEPI 0 rate comparing F or F/A with A. While waiting for result of analysis, the A arm will continue for the 2nd phase enrollment. Only the F-containing arm(s) superior over A will be continued to the 2nd phase. During the 2nd phase, an additional 540 pts in each arm is estimated to obtain 317 pts with PEPI score 0. This will have a 90% chance, with a one-sided alpha=0.025 nonparametric Brookmeyer-Crowley type one sample survival test, rejecting that 5 year RFS rate is 95%. The maximum sample size is 2820 pts. Eligible pts include postmenopausal women with newly diagnosed clinical stage II or III ER+ (Allred score 6-8) HER2- BC. Tumor biopsy is required at baseline, 4 wk, and surgery for central Ki67 analysis. Treatment decision is individualized based on 4 wk Ki67 and modified PEPI score. Pts with Ki67 > 10% at 4 wk are switched to chemotherapy. Pts with a modified PEPI score of 0 are recommended not to receive chemotherapy, but continue the assigned ET for 1.5 years followed by 3 years of A. This trial is currently accruing pts through CTSU. This research is supported in part by NCI BIQSFP, and grants from Breast Cancer Research Foundation, Genentech, and the Investigator-Sponsored Study Program of AstraZeneca. The Clinical Trials.gov Identifier: NCT01953588. Citation Format: Cynthia X Ma, Vera Suman, A Marilyn Leitch, Souzan Sanati, Katherine DeSchryver, Gary W Unzeitig, Paul Haluska, Mark Watson, Olwen Hahn, Jo Anne Zujewski, Kelly Hunt, Eric P Winer, Cliff A Hudis, Matthew J Ellis. Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III study [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 OT2-1-04.

Objectives(1) To describe the application of a detailed cost‐accounting method (time‐driven activity‐cased costing) to operating room personnel costs, avoiding the proxy use of hospital and provider charges. (2) To model potential cost efficiencies using different staffing models with the case study of outpatient adenotonsillectomy.Study DesignProspective cost analysis case study.SettingTertiary pediatric hospital.Subject and MethodsAll otolaryngology providers and otolaryngology operating room staff at our institution.ResultsTime‐driven activity‐based costing demonstrated precise per‐case and per‐minute calculation of personnel costs. We identified several areas of unused personnel capacity in a basic staffing model. Per‐case personnel costs decreased by 23.2% by allowing a surgeon to run 2 operating rooms, despite doubling all other staff. Further cost reductions up to a total of 26.4% were predicted with additional staffing rearrangements.ConclusionTime‐driven activity‐based costing allows detailed understanding of not only personnel costs but also how personnel time is used. This in turn allows testing of alternative staffing models to decrease unused personnel capacity and increase efficiency.

Abstract Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

Abstract Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was > 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if < 10% (AI sensitive) the patient completed 16 to 18 weeks of neoadjuvant AI treatment. Co-primary endpoints were: 1) to confirm that the pathological complete response (pCR) rate to standard NCCN chemotherapy in the AI resistant population is in the range of 20% (similar to ER− disease). This required the observation of least 4/35 pCRs; 2) whether patients were willing to accept a recommendation of no chemotherapy when the preoperative endocrine prognostic index score was zero (PEPI-0) (pStage 1 or 2A, Ki67<2.7% and ER+) since, according to the PEPI model, these patients have such a low relapse risk that chemotherapy is unlikely to be of value (Ellis, M JNCI 100:1380–8, 2008). Feasible was defined as <10% PEPI-0 cases receiving adjuvant chemotherapy. Secondary endpoints included a determination of the distribution of intrinsic subtypes in the AI sensitive and resistant groups (using a research use only assay). Results: 51 patients (21%) had 2 to 4 week Ki67>10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 <10%, of these 176 had PEPI score information. 65 had a PEPI-0 (37%), of which 61 (94%) reported a treatment plan that did not include adjuvant chemotherapy. The AI resistant group had a significantly higher frequency of baseline high-risk intrinsic subtypes (LumB: 26, HER2-E: 2 versus LumA: 7) at baseline than the AI sensitive group (LumB: 40, HER2-E: 0 versus LumA: 66) Fishers exact test p = 7.16E−6. Additional molecular data will be presented at the meeting. Conclusion. A Ki67 value >10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.