Goetz, MP

Abstract Background: Estrogen receptor gene (ESR1) mutations present in breast cancer patients are associated with resistance to endocrine therapy and worse patient outcomes. Recent findings suggest ESR1 mutations are present in up to 40% of metastatic breast cancer (mBC) patients' tumors. The objective of this study was to evaluate the perceptions of precision medicine and biomarker testing specific to ESR1 mutations among medical oncologists. Methods: Ten 60-minute web-assisted, telephone interviews were conducted with medical oncologists. Each physician was prescreened prior to being interviewed to ensure board certification and practice experience between 2 and 35 years. Each participant spent greater than 30% of their time on direct patient care and managed the treatment of more than 30 different cancer patients per month, with a minimum of 15 breast cancer patients, including at least five who had metastatic breast cancer and at least one patient with an ESR1 mutation. Results: A 10-20% prevalence of ESR1 mutation was estimated by the oncologists. However, the practitioners did accept the possibility of a 40% prevalence. Physician knowledge of ESR1 mutations included the relationship between ESR1 mutations and efficacy of endocrine therapies and its association with poorer outcomes. None of the medical oncologists interviewed were highly satisfied with the existing armamentarium of treatments for patients with an ESR1 mutation. In general, the interview participants were highly comfortable ordering ESR1 companion diagnostics to test for an ESR1 mutation, pending viable treatment options are available. Nonetheless, most physicians will wait until the patient has progression of disease before ordering a biomarker test. Several areas of unmet need in the mBC arena were offered by the survey participants, including more efficacious hormonal options for later-line therapies, better durability of remission, improved drug tolerability profiles, and lower treatment costs. Conclusion: Most oncologists acknowledged that personalized treatment is beneficial because it allows for better efficacy than a “one size fits all” approach. The study results also suggest that there are few barriers and drawbacks to the use of personalized medicine in the mBC arena, as most physicians expect precision medicine to account for the majority of advances in breast cancer treatments in the foreseeable future. Support: Sermonix Pharmaceuticals Citation Format: Goldfarb SB, Goetz MP, Plourde PP, Attias E, Portman DJ. A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-11.

Abstract Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-05.

Abstract Breast cancer is a heterogeneous disease, and unsupervised clustering approaches using gene expression data have identified 3-6 distinct subtypes of triple negative breast cancer (TNBC). A genomically and clinically distinct subtype of TNBC is referred to as LAR (Luminal Androgen Receptor). Tumors with this subtype typically express high levels of the AR and exhibit alterations within genes involved in the PI3K pathway (e.g. PIK3CA mutations). Prospective studies are underway using drugs that target the AR alone or in combination with PI3K and CDK 4/6 inhibitors. Given the importance of accurately identifying this subtype, we sought to develop an online tool that uses submitted gene expression data to confidently characterize LAR samples by corroborating the classification with previously published clustering approaches. Methods: We have investigated TNBC RNA-Seq data from The Cancer Genome Atlas (TCGA) breast cancer study (N=123 samples) by cluster analysis. Analysis of the average silhouette width in both biased and unbiased K-means clustering approaches demonstrated LAR and basal as two distinct and significant clusters. A shrunken centroid model of 426 differentially expressed genes, named as CABAL (Clustering Among BAsal and Luminal androgen receptor), was constructed by comparing LAR and basal subtypes. Results: We applied the CABAL model to classify the four TNBC microarray datasets that were previously used in clustering experiments as well as an independent RNA-Seq data cohort. Non-negative matrix factorization (NMF) and fuzzy clustering were applied to the samples (N=1046). Clustering similarity among the methods was assessed with the adjusted rand index, and CABAL demonstrated significant similarity with both fuzzy and NMF clustering methods. Similarly, hierarchical clustering analysis performed on the pooled cohort of 1046 samples recapitulated the CABAL classification with an area under the receiver operating curve of 0.91. Conclusions: Confident and robust identification of samples with the LAR phenotype is paramount in the assessment of clinical associations and therapeutic efficacy. To facilitate LAR identification, we have provided a web-based prediction tool of the CABAL classification, integrated with the NMF and fuzzy clustering results to identify candidate LAR samples. The end user is provided with the pair-wise adjusted rand indexes, thus reinforcing in the clustering characterizations. Further, our online LAR depiction tool provides a set of graphical and tabular summaries, which will be illustrated, while providing additional molecular characterizations of the PAM50 and Metabric classifications. The availability of this tool could advance the genomic research and treatment of TNBC patients. Citation Format: Thompson KJ, Alaparthi T, Sinnwell JP, Carlson EE, Tang X, Bockol M, Vedell PT, Ingle JN, Suman V, Weinshilboum RM, Wang L, Boughey JC, Kalari KR, Goetz MP. Molecular subtyping of androgen receptor-positive patients using gene expression profiles [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-03-04.

Abstract Endocrine based therapy is the standard treatment for estrogen receptor positive (ER+) MBC. Agents targeting the ER pathway including aromatase inhibitors (AIs), fulvestrant and tamoxifen along with CDK 4/6 inhibitors are considered standard for first and 2nd line treatment. However, endocrine resistance develops in nearly all patients and the optimal systemic therapy after progression on a CDK 4/6 inhibitor is unknown. Lasofoxifene is a third generation SERM previously investigated for the treatment of osteoporosis and vulvo-vaginal atrophy (VVA). In a large phase 3 trial evaluating the efficacy of lasofoxifene for the postmenopausal treatment of osteoporosis, lasofoxifene significantly reduced the incidence of ER+ breast cancer. Further unpublished preclinical data have demonstrated significant in vitro and in vivo efficacy in non-clinical breast cancer models including models with and without ESR1 mutants. Moreover, lasofoxifene significantly reduced metastases in ESR1 mutated models. These non-clinical and clinical data provide a strong rationale to pursue a phase 2 clinical trial in women with ER+, ESR1 mutated MBC. This open-label, multi-center study will compare the efficacy and tolerability of lasofoxifene (5 mg orally daily) to fulvestrant (IM 500 mg D1,15,29 and then q30 D) in a 1:1 randomization. Inclusion criteria include postmenopausal women with ER+ advanced breast cancer; progression on a non-steroidal AI in combination with a CDK 4/6 inhibitor; and a known ESR1 mutation. Approximately 90 patients with measurable or evaluable disease (i.e. bone only) will be recruited to have at least 40 patients per treatment arm. The primary endpoint will be progression free survival (PFS) with secondary endpoints of objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and time to response (TTR). It is assumed that lasofoxifene will double the median PFS compared to fulvestrant in this ESR1 mutation patient population for a hazard ratio 0.5 and a power of 89% to reach a 1-sided p of <0.05. The study will commence in 4Q2018 and will complete recruitment in 1 year. It is anticipated that 25-30 centers in the US will be participating. Citation Format: Plourde PV, Schwartzberg LS, Greene GL, Portman DJ, Komm BS, Jenkins SN, Liu P-Y, Portman MD, Goetz MP. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-02.

Abstract Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) are standard first line (1L) and second line (2L) treatments of ER+ MBC. However, the optimal treatment strategy after progression on a CDK 4/6i is unknown. Given concern for rapid disease progression after discontinuation of CDK4/6is (Bashour, J Cancer 2017), further data on responses to subsequent lines of therapy post CDK4/6i are needed. We performed a single institution retrospective review of patients (pts) with ER+ MBC who received 1L or 2L CDK4/6i to examine the prescribing patterns and clinical responses to post-CDK4/6i treatment. Methods: We identified 136 ER+ MBC pts prescribed a CDK4/6i at Mayo Clinic Rochester (from 12/2014 to 2/2018) on 1L or 2L who received at least 30 days of therapy and ≥ two clinic visits during treatment. For the 1L and 2L cohorts we assessed the time to treatment failure during (TTF-1) and after CDK4/6i therapy (TTF-2). TTF was defined as time from start of therapy to discontinuation for any cause. Additionally, we assessed overall survival (OS) post CDK4/6i discontinuation (defined as the date of TTF-1 to death or last follow up). Results: The study cohort included 81 and 55 pts treated with 1L and 2L CDK4/6is, respectively. In the 1L cohort, palbociclib/letrozole (82.3%) and palbociclib/fulvestrant (13.6%) were most commonly prescribed. Treatment was discontinued in 39/81 pts due to: progression (84.6%), intolerability (7.7%), and other (7.7%). The median TTF-1 was 19.7 mo (95% CI 11.2 – 25.4 mo). Subsequent treatment and response data were available in 37/39 pts that progressed on 1L CDK4/6i. The most commonly prescribed regimens included single-agent hormonal therapy (29.7%), everolimus/exemestane (27.0%), and single agent chemotherapy (21.7%). The overall median TTF-2 were as follows: everolimus/exemestane 13.2 mo [95%CI 0.33 mo – not reached (NR)]; single agent hormonal therapy 3.1 mo (95%CI 1.4 – 5.4 mo); and single agent chemotherapy 4.1 mo (95%CI 1.4 - 5.4 mo). With a median post-CDK4/6i follow up of 11.2 mo, we observed 8 deaths and the median OS-post CDK4/6i was NR. In the 2L cohort, common regimens were palbociclib/letrozole (63.6%) and palbociclib/fulvestrant (27.3%). Treatment was discontinued in 30/55 pts due to: progression (73.3%), intolerability (13.3%), and other (13.3%). The median TTF-1 in the 2L cohort was 8.3 mo (95%CI 4.6 – 12.7 mo). Subsequent treatment data were available in 24/30 pts and included single-agent hormonal therapy [n=7 (29.2%); median TTF-2 4.7 mo; 95%CI 1.9 – 14.0 mo], everolimus/exemestane [n=6 (25.0%); median TTF-2 3.2 mo, 95% CI 0.8-10.1 mo)] and single agent chemotherapy [n=6 (25.0%); median TTF-2 2.6 mo; 95%CI 1.7 mo – NR)]. With a median post-CDK4/6i follow up 18.7 mo in the 2L cohort, we observed 11 deaths, and the median OS-post CDK4/6i was 11.8 mo (95%CI 11.8 mo – NR). Conclusions: Single and combination-based endocrine strategies are commonly administered post-CDK4/6i without clinical evidence for rapid deterioration. The observation of a median treatment duration lasting >12 months in patients receiving everolimus/exemestane post-CDK4/6i supports ongoing studies evaluating drugs that target PI3K/mTOR pathway in combination and following progression on a CDK4/6i. Citation Format: Giridhar KV, Choong GM, Leon-Ferre RA, O'Sullivan CC, Ruddy KJ, Haddad TC, Hobday TJ, Peethambaram PP, Moynihan TJ, Loprinzi CL, Liu MC, Suman VJ, Goetz MP. Clinical management of metastatic breast cancer (MBC) after CDK 4/6 inhibitors: A retrospective single-institution study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-09.

Abstract Background: In the MONARCH 3 trial, abemaciclib plus an aromatase inhibitor (AI) significantly improved progression free survival and overall response rate with a generally tolerable safety profile compared to placebo plus AI. Here we report patient-reported outcomes (PRO) including health-related quality of life (Qol), functioning, and symptoms. Methods: MONARCH 3 was a double-blind, randomized phase III study of abemaciclib or placebo plus an AI in 493 post-menopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer with no prior systemic therapy in the advanced setting. Two European Organization for Research and Treatment of Cancer (EORTC) questionnaires were included: Quality of Life Questionnaire (QLQ)-Core 30 (C30) and the EORTC QLQ-Breast 23 (BR23) that were assessed at baseline, every 2 cycles through cycle 19, then every 3 cycles until treatment discontinuation, and at short-term follow up. Higher scores on functional and health status/QoL outcomes indicate higher/better levels of functioning or health; conversely higher scores on symptom outcomes indicate higher/worse levels of symptom burden. Between-arm comparisons of change from baseline were conducted using mixed model methods. Statistical significance was set at 0.05 and clinical meaningfulness was set at ≥10 points on a 0-100 scale1. Results: PRO completion rates were >91% through cycle 19; duration of treatment was longer for abemaciclib plus AI patients (median number of cycles 19 vs.15). Compared to the placebo arm, diarrhea PRO scores in the abemaciclib arm showed a clinically (18.68 points) and statistically significant (p<0.001) increase/worsening. By-cycle analysis showed group mean diarrhea scores returned to near-baseline levels post-therapy. Other symptom PROs showed statistically significant (<0.05) but not clinically meaningful differences; fatigue (4.96; p=0.004), systemic therapy side effects (4.48, p<0.001), appetite loss (4.03; p=0.034), and nausea/vomiting (2.77; p=0.013). These results were consistent with the investigator-reported treatment emergent adverse events (TEAEs). Several non-symptom results were also statistically significant but not clinically meaningful including global health/health status (-4.36; p=0.003), role function (-4.25; p=0.025), social function (-3.41, p=0.047), and body image (-5.11, p=0.009). No statistically significant between-treatment differences were observed for physical, emotional, and cognitive functioning or for symptoms of pain, dyspnea, insomnia, constipation, or financial difficulties. Conclusions: The addition of abemaciclib to an AI resulted in clinically and statistically significant changes in diarrhea without clinically meaningful differences in other symptom scores. Increased GI-related symptoms were consistent with the manageable, reversible AE profile; the highest symptom burden was reported during early visits. No clinically meaningful differences in global health status or functional scores were observed. ClinicalTrials.gov: NCT02246621 Reference: 1. Osoba D et al. J Clin Oncol 2002;20(14):3106-13. Citation Format: Goetz MP, Johnston S, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Price GL, Boye M, Li L, Forrester T, Gainford C, Gable J, Carter GC, Sood A, DiLeo A. Health-related quality of life in MONARCH 3: Abemaciclib plus an aromatase inhibitor as initial therapy in women with HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-16-01.

Abstract Background: The LAR subtype is a genomically distinct subset of TNBC. Using a large cohort of non-metastatic TNBC patients (pts) with long term follow-up, we sought to further characterize the clinicopathologic features and outcomes of LAR vs non-LAR TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, 605 met criteria for TNBC (ER/PR<1% and HER2-negative) by central pathology. RNA extracted from 304 FFPE tumor specimens using the HighPure RNA extraction kit was subjected to TruSeq RNA Access library preparation and sequencing on a HiSeq2500. Adequate RNA was available for 283 pts. Tumors were classified as LAR or non-LAR using a shrunken centroid model, CABAL (Clustering Among BAsal and Luminal androgen receptor). In addition to previously described analyses [Leon-Ferre et al, Breast Cancer Res Treat 2017], immunohistochemical (IHC) androgen receptor (AR) staining was performed and the impact of various parameters on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: 58 (20%) tumors were classified as LAR and 225 (80%) as non-LAR. Compared to non-LAR, LAR pts were older (mean age 65 vs 54) and more often postmenopausal (79%vs53%), both p=0.01. Apocrine histology was more common among LAR tumors (21%vs0%), which were also lower grade (grade3: 69%vs95%) and had lower Ki-67 (Ki-67>15%: 64%vs82%), all p<0.01. Additionally, LAR tumors had lower median stromal tumor infiltrating lymphocytes (TILs, 20%vs25%) and were less frequently lymphocyte-predominant [≥50% stromal or intratumoral TILs (19%vs32%)], although neither reached statistical significance. AR IHC was available for 223 of 283 tumors. Median AR IHC score in LAR was 65% (range 0-100%) vs 0% (range 0-90%) in non-LAR. T/N stage, surgery type, and receipt of adjuvant chemotherapy (AdjCT) or radiotherapy were similar between LAR and non-LAR. LAR pts had shorter IDFS and OS compared to non-LAR (5.6 vs 11.8 yrs and 10.8 vs 20.8 yrs, respectively), although this did not reach statistical significance. Test of proportional hazard assumption was not significant for IDFS or OS (p = 0.30 and 0.09). IDFS estimates were numerically higher in LAR vs non-LAR (80.2%vs70.5%,p = 0.92) at 3yrs post-diagnosis; whereas the opposite was true (40.9%vs55.6%,p = 0.07) after 10yrs. OS estimates at 3 and 5yrs were similar between LAR and non-LAR, but at 10yrs OS was inferior in LAR (40.9%vs66.4%,p = 0.24). In a univariate analysis including both LAR and non-LAR, older age, higher N stage, lower TILs and absence of AdjCT were associated with poorer IDFS and OS. In a multivariate analysis, higher N stage and absence of AdjCT remained associated with both poorer IDFS and OS; while lower stromal TILs were associated with poorer IDFS (p=0.01), and with a trend towards poorer OS (p=0.07). Conclusions: LAR TNBCs occurred in older women, were lower grade, and had lower TIL density than nonLAR tumors. While significant differences in IDFS or OS were not demonstrated, LAR pts exhibited a numerically lower risk of a disease event at 3yrs, but higher risk by 10yrs compared to nonLAR pts. In the entire cohort, higher N stage, absence of AdjCT and lower TILs were independently associated with poorer outcomes. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Kalari KR, Boughey JC, Liu MC, Cafourek V, Negron V, Ingle JN, Thompson KJ, Tang X, Barman P, Carlson E, Visscher DW, Carter JC, Couch FJ, Goetz MP. Characteristics, outcomes and prognostic factors of luminal androgen receptor (LAR) triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-01.

Abstract Introduction: The vast majority of cancer patients continue to receive treatments that are minimally informed by omics data. In the case of breast cancer, only ER and HER2 are routinely used for treatment selection. There is a particular need for personalized treatment in individuals with primary and secondary drug resistance or aggressive breast cancers. Emerging bioinformatics and statistical methods have made a fundamental impact on cancer research. However, challenges remains with regard to patient-centric data analysis and providing genomic data guidance to oncologists. There exists a large number of FDA approved anti-neoplastic drugs used to treat cancers other than breast and the development of innovative informatics methods and algorithms to repurpose those drugs should benefit breast cancer patients. Methods and Results: We have developed precision care systems (such as PANOPLY and CORPUS) to identify personalized therapies for an individual patient and to deliver genomic reports in a standard, searchable format so that a researcher or an oncologist can quickly navigate through molecular data and obtain prioritized drugs and targets.The PANOPLY (Precision cancer genomics report: single sample inventory) algorithm applies machine learning and topology-based network analysis methods to integrate multi-omics profiles and clinical data; individual-specific molecular alterations are identified and compared with a set of matched-controls having similar clinical data. Since there is a lack of a “gold standard” dataset to test such algorithms, we simulated 500 case-control sets and evaluated drug predictions across multiple simulation scenarios. We applied the PANOPLY algorithm to The Cancer Genome Atlas (TCGA) breast cancer cohort, which consists of multi-omics data and clinical data. In addition, PANOPLY was also applied to an in-house neoadjuvant breast cancer study (BEAUTY) that consists of multi-omics data, clinical data, and patient-derived xenografts (PDXs). In the TCGA breast cancer study we obtained survival data to determine the cases and matched-controls; and in the BEAUTY, we used pathologic complete response (pCR) as an outcome to determine responders and non-responders. Recurrent targetable alterations were not enriched in patients without pCR in the BEAUTY study. We have applied the PANOPLY to non-responder patients to identify individual specific alterations, dysregulated networks, drug targets, and drugs for each patient and stored them as case reports in CORPUS (Computational Oncology Reports and Precision therapeUticS), a web-based repository that allows clinicians to review genomic reports. Using comprehensive “omic” data derived from a triple negative breast cancer patient who had pre and post-neoadjuvant chemotherapy PDXs, PANOPLY prioritized the PARP inhibitors as the top class of drug. Using the PDX models available from this patient, we tested olaparib and confirmed the in vivo antitumor activity (more effective than vehicle with a p-value < 0.05 in the PDXs). Further studies to confirm PANOPLY findings are currently underway. Conclusions: In summary, the PANOPLY and CORPUS systems incorporate molecular data together with clinical data to provide genomic reports with proposed drug targets to advance or enable precision breast cancer care. Citation Format: Kalari KR, Sinnwell JP, Thompson KJ, Tang X, Carlson EE, Alaparthi T, Yu J, Vedell PT, Kalmbach MT, Bockol MA, Hossain A, Weinshilboum RM, Boughey JC, Wang L, Suman VJ, Goetz MP. Multiscale modeling of omics data for precision breast cancer treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-10.

Abstract Background: Triple Negative Breast Cancer (TNBC) affects approximately 15-20% of BC patients, yet accounts for a disproportionately higher rate of BC morbidity and mortality, in part due to lack of targeted therapies. Using well-validated antibodies, Estrogen Receptor Beta (ERβ) protein has been shown to be expressed in approximately 25% of TNBCs and is associated with improved patient outcomes. Using multiple ERβ +/- TNBC cell lines and PDX models, we have demonstrated that ligand-mediated activation of ERβ by estradiol (E2) decreases cell proliferation, invasion, and migration in vitro, as well as primary tumor growth and metastatic spread in vivo. Methods: To determine the mechanisms by which ERβ elicits these anti-cancer effects, we elucidated the ERβ transcriptome and cistrome via Microarray and ChIPseq, respectively, in TNBC cells stably expressing ERβ in a doxycycline-inducible manner. We also performed gene expression and luciferase assays to assess the impact of ERβ on NFκB signaling, followed by ChIP-PCR and ChIPseq to assess how ERβ modifies chromatin architecture near NFκB target genes. Results: Pathway analysis of ERβ-regulated genes identified NFκB signaling as one of the most suppressed pathways in response to E2 treatment. Indeed, numerous NFκB target genes were among the most down-regulated genes following E2 treatment but only in the presence of ERβ expression. Chromatin Immunoprecipitation followed by sequencing (ChIPseq) revealed that ERβ primarily associated with estrogen response elements (EREs), but was also enriched around NFκB binding sites following E2 treatment. In fact, 12% of all ERβ binding sites were enriched for NFκB response elements and ERβ was shown to physically associate with NFκB protein. Using an NFκB reporter construct and qPCR, ERβ was shown to block TNFα-mediated induction of NFκB signaling and NFκB target gene expression. Globally, RNAseq identified 200 genes to be significantly regulated by TNFα in TNBC cells, of which 81 were significantly altered in the presence of E2+TNFα. ChIPseq demonstrated that ligand-mediated activation of ERβ significantly diminished an activating histone mark (H3K27Ac) at many of these NFκB target genes while enhancing a repressive mark (H3K27Me3). These modifications are also associated with recruitment of the histone methyltransferase, EZH2, to enhancer elements of these NFκB target genes. Drug-mediated blockade of HDAC and EZH2 activity reversed suppression of NFκB target gene expression by ERβ. Conclusions: Our data suggest that ERβ may elicit its anti-cancer effects in part via formation of a novel co-repressor complex consisting of ERβ, NFκB, and EZH2. These data are in keeping with prior observations of the importance of NFκB signaling as it relates to TNBC cell proliferation and invasion, and that decreased expression of NFκB target genes is associated with improved outcomes in TNBC patients. Currently, a Mayo Breast SPORE prospective study is underway to investigate the role of estradiol in ERβ expressing TNBC and to further evaluate the cross-talk between ERβ and NFκB signaling in TNBC. Citation Format: Aspros K, Nelson A, Ye Z, Sun Z, Chernukhin I, Carroll J, Ingle J, Goetz M, Hawse J. Estrogen receptor beta elicits anti-cancer effects in triple negative breast cancer through suppression of NFκB signaling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-03.

Abstract Background: Pre-clinical data and results from early phase clinical trials point to synergistic antitumor activity and potential efficacy of palbociclib when given in combination with anti-HER2 therapy (tx). The aim of PATINA is to determine the effect of adding palbociclib to anti-HER2 and ET maintenance after induction tx in the 1st line setting for HR+/HER2+ MBC. Trial Design: The PATINA trial (AFT-38/NCT02947685) is a pivotal, open-label, international, phase III study. Following 6-8 cycles of chemotherapy (taxane or vinorelbine) with anti-HER2 tx for MBC participants will be randomized 1:1 to standard anti-HER2 tx (trastuzumab +/- pertuzumab) in combination with ET with or without palbociclib until disease progression. ET options are either an aromatase inhibitor or fulvestrant. Premenopausal patients (pts) must receive ovarian suppression. The trial is open to men or women with histologically confirmed HR+/HER2+ MBC provided they are without evidence of disease progression by local assessment after induction tx. Total planned accrual is 496 pts. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 tx plus ET is superior to anti-HER2 tx plus ET alone in prolonging progression-free survival (PFS). Key secondary objectives are measures of tumor control, overall survival, safety and Quality of Life. The main translational science objective is to compare PFS estimates according to PIK3CA mutation status. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. All pts approached to participate in PATINA will be asked to share remaining biospecimens and clinical data with the Mastering Breast Cancer Initiative. This initiative was created in order to understand the natural history of MBC and how it envolves over time with the aim to develop new treatments for this patient population. Recruitment has started in 07/2017 and is planned for approximately 22 months in 140 sites in Australia, Germany, Italy, France, New Zealand, Spain, and the US. 69 pts have been recruited so far. The study is sponsored by Alliance Foundation Trials (AFT) and financially supported by Pfizer Citation Format: Metzger O, Mandrekar S, Loibl S, Mundhenke C, Seiler S, Valagussa P, Lim E, Tripathy D, Winer EP, Huang C, Carey L, Francis P, Miller K, Goetz MP, Prat A, Loi S, Krop I, Gianni L, Delalogue S, Vaz-Luis I, Dockter T, Lanzillotti J, Ciruelos E, DeMichele AM. PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-07.