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PURPOSE: To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). METHODS: Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I-III TNBC (n=171 including 124 NHW and 47 NHB) and HER2-positive (n=161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000–2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. RESULTS: There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54–2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36–3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. CONCLUSION: TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients’ race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography and clinical outcomes are warranted.

Background: The PROMIS trial (NCT01617954) previously evaluated how a definitive result from the MammaPrint 70-gene signature (70-GS) can impact treatment recommendations for patients with an intermediate range recurrence score (RS 18-30) from the 21-gene assay (21-GA, Oncotype DX). Since publication of this study, TAILORx results published in 2018 (and further explored in June 2019) suggested an interaction between the 21-GA, patient age (≤50 yrs), and clinical risk. Initially, chemotherapy (CT) was recommended for all women ≤50 with a RS>16. Based on the recent clinical-risk analysis, Ovarian Function Suppression (OFS) + endocrine therapy (ET) has been suggested as an alternative treatment for low clinical risk (clin-low) women ≤50yrs with an RS 16-25. This current analysis examines the updated treatment recommendations based on the interaction between patient age and clinical risk, and explores the impact that the 70-GS can have on adjuvant chemotherapy decisions for women ≤50 years of age. Methods: 70-GS risk of recurrence was determined for 21-GA intermediate patients by standard diagnostic testing (Agendia, Irvine, CA). Clinical risk was assessed using the MINDACT, modified Adjuvant Online! algorithm (Cardoso, NEJM 2016). The 70-GS High and Low Risk classification were subdivided by RS groups 18-20, 21-25, and 26-30 and by clinical risk stratification. Results: 181 patients in PROMIS were ≤50 yrs. Of those, 64% (116/181) were clin-low, and 35% (63/181) were high clinical risk (clin-high) (2 unknown). Among patients ≤50 yrs with RS 18-20, 60% (27/45) of clin-low and 56% (15/27) of clin-high were found to be 70-GS Low Risk. Among patients with RS 21-25, 55% (30/55) of clin-low and 30% clin-high (8/26) were Low Risk by the 70-GS. For patients ≤50 yrs with RS 26-30, 15% (4/27) were found to be 70-GS Low Risk. Of all patients with RS 26-30, 21% (32/156) were Low Risk by 70-GS. Conclusions: With the follow-up publication for TAILORx, incorporation of clinical risk in addition to age, RS group, and the assumed benefit of chemotherapy-induced menopause, has presented additional layers of complexity for physicians treating breast cancer. The current analysis demonstrates that 46% of women ≤ 50yrs with a RS 21-25 are 70-GS Low Risk, and based upon the prospective, randomized MINDACT* trial data, can safely avoid CT. Overall, the 70-GS can precisely identify 20-60% of women ≤ 50yrs with intermediate RS (18-30) as genomic Low Risk with excellent survival with ET alone (>95% 5-yr DMFI [MINDACT]), who may otherwise be candidates for treatment with CT or OFS. *(Microarray in Node Negative and 1-3 Lymph Node Positive Disease May Avoid Chemotherapy) AgeRS GroupClinical RiskNMP Low Risk% recommended ET alone based on 70 -GStreatment recommendation based on 21-GA≤ 50RS 18-20Clin-low452760%OFS+ET or ET aloneClin-high / (unknown)26 (1)1556%CT+ET or OFS+ETTotal724258% ≤ 50RS 21-25Clin-low553055%OFS+ETClin-high / (unknown)26 (1)830%CT+ET or OFS+ETTotal823846% ≤ 50RS 26-30Clin-low1616%All receive CT+ET regardless of clinical riskClin-high11327%Total27415% Citation Format: Michaela Tsai, Hatem Soliman, Shelly Lo, Rubina Qamar, Raye Budway, Ellis Levine, Pat Whitworth, Blanche Mavromatis, Robin Zon, Sarah Untch, Lisa Blumencranz, Joseph McKelley, William Audeh, PROMIS Investigators Group. Treatment recommendations in ER+ patients ≤ 50 years: Comparison of the 21-gene assay and 70-gene signature in the PROMIS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-11.

PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor outcomes among breast cancers. A subset of TNBCs demonstrates an aggressive course with marked chemoresistance, rapid distant metastatic spread, and poor survival. The clinicopathologic and sociodemographic features associated with rapid relapse among TNBCs remain poorly understood. Primary Objective: To evaluate the relationship between clinicopathologic and sociodemographic features with rapid relapse in TNBC (rrTNBC). Methods: This large multi-institutional study analyzed a cohort of breast cancer patients diagnosed with TNBC who received treatment at one of ten academic centers that previously participated in a National Comprehensive Cancer Network (NCCN) outcomes database between 1998 and 2012. We defined rrTNBC as a distant metastatic recurrence event or death from any cause ≤24 months after diagnosis. We included patients with ≥2 years follow-up or had suffered a survival event within that timeframe. We excluded patients with de novo metastatic disease and those who did not receive chemotherapy. We randomly divided the total dataset into 70% training and 30% validation cohorts, balanced by the number of rrTNBC events. Covariates included study site, age at diagnosis, body mass index (BMI), race/ethnicity, education, median annual household income (2000 census tract), insurance type (Managed Care, Medicare, Medicaid, and Other), Charlson comorbidity index, tumor stage and grade at diagnosis, and adjuvant radiation treatment. Logistic regression was performed among the training dataset univariately for associations with rapid relapse vs. not. Features with a p-value Results: Among 41,839 patients with invasive breast cancer treated in these ten centers, 5256 had TNBC (12.6%), among whom 3016 had adequate follow-up to be included in the analysis. Bivariable analyses in the training cohort (n=2112) identified tumor stage at diagnosis, insurance type, age at diagnosis, BMI, race, and income to be associated with rrTNBC events (p15x increased risk of rapid relapse (adjusted OR [95% CI]: 16.5 [10.3, 26.4]; p Conclusion: Advanced tumor stage at diagnosis was the most influential predictor of rapid relapse among patients who had TNBC, while type of insurance remains an independent predictor in training and validation cohorts. Given the known association of sociodemographic disparities with tumor stage, further study of underlying causes and potential interventions to reduce rapid relapse of TNBC is warranted. Citation Format: Sarah Asad, Carlos H. Barcenas, Richard J. Bleicher, Adam L. Cohen, Sara H. Javid, Ellis G. Levine, Nancy U. Lin, Beverly Moy, Joyce Niland, Antonio C. Wolff, Michael J. Hassett, Daniel G. Stover. Factors associated with rapid relapse in triple negative breast cancer: A multi-institution study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-02.

Background Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. Methods IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. Results The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. Conclusions The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. Trial registration “Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry” (NCT02670577) retrospectively registered on Jan 27, 2016.

Testicular cancer is relatively uncommon and accounts for 50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Progress made in early cancer diagnosis and therapy has translated into increased longevity for patients with breast cancer. As survival has increased, the potential cardiotoxicity of cancer chemotherapy regimens has become an important issue for survivorship. Doxorubicin-induced cardiotoxicity has been demonstrated at a cumulative dose of ≤ 300mg/m2, with histopathological changes seen in endomyocardial biopsy tissue from patients receiving as little as 240mg/m2 of doxorubicin. Individual risk stratification and early detection of chemotherapy-induced cardiotoxicity are crucial to prevent irreversible cardiac dysfunction. There is accumulating evidence for the utility of echocardiographic indices such as left ventricular global longitudinal strain (GLS) in the detection of early chemotherapy induced cardiac injury. We have previously highlighted a predictive role of genetic polymorphisms in the carbonyl reductase 3 gene CBR3 in anthracycline-related cardiomyopathy following childhood cancer. Consistent with our prior work, we hypothesized that breast cancer patients homozygous for the CBR3 V244M G allele would exhibit worsening GLS following DOX treatment when compared with patients homozygous for the A allele. We recruited 138 patients with breast cancer receiving treatment with DOX (total cumulative dose: 240mg/m2). 72 patients received an echocardiogram analyzing global longitudinal strain by speckle tracking at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Patients were genotyped for variants associated with anthracycline-related toxicity. In agreement with our previous findings and hypothesis, our interim analysis suggested that patients homozygous for the CBR3 V244M G allele (CBR V244) exhibited GL changes at 6 months after DOX therapy suggestive of cardiotoxicity in comparison to individuals homozygous for the A allele (CBR3 M244) (-1.2 ±3.5 vs 1±1.6; mean±SEM, p=0.8 by Mann-Whitney test). Although the differences between CBR3 genotype groups are not significant at p Citation Format: Lang JK, Quinones AL, Hageman Blair R, Early AP, Levine EG, Opyrchal M, Blanco JG, O'Connor T. Association of CBR3 polymorphisms with an early change in cardiac function as assessed by left ventricular global longitudinal strain in breast cancer patients treated with doxorubicin [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 P1-12-08.

Background:Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC.Methods:We included patients diagnosed with stage I–III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with aPResults:Among all patients with breast cancer treated at these centers, 3,016 fit the inclusion criteria. Training cohort (n=2,112) bivariable analyses identified disease stage, insurance type, age, body mass index, race, and income as being associated with rrTNBC (PP24 months), we found that insurance type and young age remained significant.Conclusions:Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Background Brain metastases develop in up to 50% patients with metastatic triple negative breast cancer (TNBC) and HER2+ BC and are an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2+ brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2/3 immunity. We have demonstrated that alphaDC1 loaded with glioma-specific peptides induce intratumoral production of chemokines (CXCL9, CXCL10, CXCL11, CCL5) which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells to brain tumors, inducing clinical responses and long-term disease stabilization in patients with aggressive recurrent primary brain tumors. Our preclinical data show that Chemokine modulating (CKM) regimen [rintatolimod, interferon (IFN)-α2b and COX-2 inhibitor] also selectively attracts effector CTLs and Th1 cells (but not suppressive regulatory T-cells or myeloid-derived suppressor cells) into tumors. Importantly, CKM preferentially promotes CTL migration into tumor rather than healthy tissues, providing rationale for its systemic use. We hypothesize that anti-HER2/3 type 1 polarized DC1s in combination with CKM and anti-PD1 will result in improved Th1/CTL response against HER2/3 epitopes, reduce brain recurrence and systemic progression. Methods This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes patients with triple negative and HER2+ BMBC ≥ 18 years, ECOG PS ≤ 1, normal marrow and organ function with asymptomatic untreated brain metastases who receive αDC1 q2 weeks x 3, with CKM [200 mg IV rintatolimod, IFN-α 20 million units/m2 IV, celecoxib 200 mg oral BID] on days 1-3 with second and third dose of αDC1, followed by pembrolizumab 200 mg IV. Thereafter, pembrolizumab is given every 3 weeks, along with αDC1 and CKM every 3 months as booster dose until disease progression, intolerable side effects or withdrawal from study, or up to 24 months. Baseline and 3-week post-CKM treatment peripheral (non-CNS) biopsies are required for six patients. Primary objective is CNS response rate (RR) using RANO-BM criteria. If no CNS response is observed after 12 patients, study will be terminated. If ≥ 1 response observed, then 9 more patients will be enrolled, for a total of 21 patients. If ≥ 3 CR observed, the proposed therapy will be considered promising for further study. Secondary objectives include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Analysis of change in intratumoral biomarkers is an exploratory objective. Results N/A Conclusions N/A Trial Registration NCT04348747 Ethics Approval The study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-19-04120.

Background Neoadjuvant chemotherapy (NAC) with taxanes is the standard of care in triple negative breast cancer (TNBC). Intratumoral prevalence of CD8+ cytotoxic T-lymphocytes (CTLs) is associated with an improvement in relapse-free survival (RFS) and overall survival (OS), while regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) are associated with poor survival. Higher ratio of CTL/Treg is associated with higher probability of obtaining pathological complete response (pCR), a surrogate marker for RFS. Intratumoral production of CCL5, CXCL9, CXCL10 and CXCL11 is critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction. Previous studies have shown that CXCL9 expression in the pre-treatment breast tissue is associated with a three-fold higher rate of achieving pCR. Our preclinical data show that Chemokine modulating (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b, and celecoxib (COX-2 inhibitor) increases CTL-attracting, and decreases MDSC-, Treg-favoring chemokines, increasing CTL/Treg ratio in tumor microenvironment, with preferential tumor tissue activation than adjacent healthy tissues. We hypothesize that the combination of CKM with paclitaxel will result in infiltration of TNBC with CTLs, and along with doxorubicin/cyclophosphamide (AC), result in higher pCR, translating into improved RFS and OS. Methods In this phase I study NCT04081389, eligibility includes age ≥18 years, confirmed resectable TNBC, radiographically measurable disease ≥1 cm, ECOG PS ≤ 2, adequate organ and marrow function. Patients with autoimmune disease, serious mood disorders, invasive carcinoma within 3 years, history of peptic ulcers or hypersensitivity to NSAIDs will be excluded. We plan to treat three patients with early stage TNBC with paclitaxel 80 mg/m2 IV weekly for 12 weeks, rintatolimod 200 mg IV, celecoxib 200 mg oral twice daily, and accelerated titration of IFN-α2b at doses 0, 5, or 10 million units (MU)/m2 [Dose Levels (DL) 1, 2 and 3 respectively] on days 1–3 (no intra-patient dose escalation) in weeks 1–3. Dose-limiting toxicity (DLT) is defined as grade 3 or higher toxicities within the first 3 weeks. Any DLT will mandate recruitment per the 3+3 model. If no DLT, three patients will be enrolled at DL 4 at 20 MU/m2 IFN- α2b. This will be followed by standard dose-dense AC, and then surgery. The primary endpoint is safety and tolerability of combination and to identify the appropriate DL of CKM and paclitaxel for extended efficacy study. The secondary endpoints include investigation of efficacy (pCR and breast MRI response), along with RFS and OS. Intratumoral biomarkers will be analyzed in an exploratory manner. Results N/A Conclusions N/A Trial Registration NCT04081389 Ethics Approval The study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-73718.

Background:Despite the approval of mTOR inhibitor everolimus and CDK4/6 inhibitors in the management of hormone-receptor-positive HER2 non-amplified metastatic breast cancer (HR+ HER2-MBC), the optimal sequence of therapy is unclear. There are no clinical data on efficacy of everolimus in HR+ HER2-MBC after cancer progresses on CDK4/6 inhibitors.Objective:The objective of this study is to find the efficacy of everolimus in HR+ HER2-MBC after they progress on a CDK4/6 inhibitor palbociclib.Methods:This is a retrospective, 2-institute review of HR+ HER2-MBC from Jan 2015 to March 2018 treated with everolimus after progression on palbociclib. Primary end point was median progression-free survival (PFS), secondary end points objective response rate (ORR), clinical benefit ratio (CBR), and overall survival (OS).Results:Out of 41 women with median age 61 years (33, 87) enrolled, 66% had received adjuvant systemic therapy, 61% had visceral disease, and 95% had prior nonsteroidal aromatase inhibitors. About 83% women had 3 or more chemotherapy or hormonal therapies prior to everolimus. Kaplan-Meier estimates showed a median PFS of 4.2 months (95% confidence interval [CI]: 3.2-6.2). The median OS was 18.7 months (95% CI 9.5 to not reached). Objective response rate and CBR were both 17.1%.Conclusion:Everolimus was associated with modest PFS and ORR in HR+ HER2-MBCs postprogression on palbociclib.

Purpose Outcome data on hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2) nonamplified (HER2−) metastatic breast cancer (MBC) treated with palbociclib after treatment with everolimus are lacking. The PALOMA-3 trial, showing benefit of palbociclib plus fulvestrant compared to fulvestrant alone in HR+HER2− MBC after progression while receiving endocrine therapy excluded women previously treated with everolimus. The objective of this study was to examine outcomes of HR+HER2− MBC with prior exposure to everolimus while receiving palbociclib-based therapy. Patients and Methods A retrospective, single-institute review was conducted of HR+HER2− MBC from January 2014 to November 2016 in patients treated with palbociclib after prior treatment with everolimus. Progression-free survival (PFS) was defined as the time from initiation of palbociclib to the date of progression as determined by the treating physician based on radiologic, biochemical, and/or clinical criteria. Response rates were determined on the basis of available radiologic data. Objective response rate (ORR) was defined as the rate of any complete or partial responses; clinical benefit rate (CBR) was the rate of complete response, partial response, or stable disease for at least 24 weeks. Results Twenty-three patients with a mean (range) age of 68 (42-81) years were identified. Kaplan-Meier estimate showed median PFS of 2.9 months (95% confidence interval, 2.1-4.2); ORR was 0 of 23 and CBR was 4 (17.4%) of 23. In the PALOMA-3 trial, median PFS, ORR, and CBR of palbociclib cohort were 9.5 months (95% confidence interval, 9.2-11.0), 19%, and 67%, respectively. Conclusion There is a limited clinical activity of palbociclib combinations after progression with everolimus combination therapy. Further studies are necessary to confirm these findings.

Background: IMPACt is a prospective, case-only study to measure the effect of MammaPrint (MP) and BluePrint (BP) on treatment decisions in breast cancer patients. Here, we report the results of the primary objective in women aged ≥18 years with histologically proven invasive stage I-II, hormone receptor (HR) positive, and HER2-negative breast cancer. Methods: The study included 369 women from 18 US institutions. The recommended treatment plan was captured before and after receiving results for MP and BP. Treatment was started after obtaining results. In addition to the effect of results on physician treatment decisions involving chemotherapy (CT) and physician confidence, the distribution of MP High Risk (HR) and Low Risk (LR) patients was also evaluated. Results: MP classified patients to 62% (n=228) LR and 38% (n=141) HR. Treatment decisions were changed for 25% (n=92) of women after receiving MP and BP results. Of the LR patients initially prescribed CT, 68% (45/66) had CT removed from their treatment recommendation. Of the HR patients who initially were not prescribed CT, 66% (42/64) had CT added. Overall, 89% (202/228) of LR patients did not receive CT, and likewise 84% (119/141) of HR patients did receive CT after receiving MP. Among those who did not change treatment (n=277), 68% of physicians reported having greater confidence in their prescribed therapy. Conclusions: The IMPACt trial shows MP generates a 25% overall treatment change in clinical practice. The highest impact is for women with LR results, where 68% are spared chemotherapy in favor of endocrine therapy alone. Additionally, 73% of physicians report having higher confidence in treatment decisions for their patient after MP. Table 1: Treatment changesTreatment Decision Pre- to Post-MPMP HRMP LRTotalCT to CT772198no CT tp CT42547CT to no CT04545no CT to no CT22157179Total141228369 Citation Format: Soliman H, Rehmus E, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, Srinivasiah J, Kassar M, Gabordi R, Yoder E, Qamar R, Audeh W, IMPACt Investigators Group I. IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-04.

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]

Background: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 randomized phase II study reported an improvement in progression-free (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer. Protein lysine acetylation in peripheral blood mononuclear cells (PBMCs) was associated with prolonged PFS in the entinostat arm. Methods: E2112 is a multicenter randomized double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease had progressed on a non-steroidal AI in the adjuvant or metastatic setting (NCT02115282). Study participants were also required to have an ECOG performance status 0-1 with measurable or non-measurable (limited to 20% of the study population) disease. One prior chemotherapy for metastatic disease and prior treatment with fulvestrant and a CDK4/6 inhibitor was permitted but not required. Participants received exemestane 25mg po daily and entinostat (EE)/placebo (EP) 5mg po every week. Primary endpoints were PFS (central review) and OS. One-sided type 1 error 0.025 was split between two hypothesis tests: 0.001 for PFS test and 0.024 for OS. PFS tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS, 4.1 to 7.1 months); OS tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS, 22 to 29.3 months). Secondary endpoints included safety, objective response rate (ORR), and changes in protein lysine acetylation status in PBMCs (CD3+ T cells, CD14+ monocytes, CD19+ B cells, pan-leukocyte marker CD45+ cells, CD56+ NK cells) between C1D1 and C1D15 (integrated biomarker). Results: A total of 608 participants were randomized between March 2014 and October 2018 (305 EE, 303 EP), 98% enrolled in USA. Characteristics were well balanced between the arms. Median age was 63 years (range, 29-91), 99% female, 95% postmenopausal, 80% white and 15% black. A majority (84%) had disease resistant to AI in the metastatic setting at study entry, 78% had measurable disease and 60% visceral disease. Prior treatments included chemotherapy (60%), fulvestrant (30%), CDK4/6 inhibitor (35%), everolimus (3%). Median prior lines of chemotherapy was 1 (range, 0-4) and endocrine therapy was 2 (range, 1-7); in adjuvant/metastatic setting. Grade 3/4 adverse events in EE arm included neutrophil count decreased (20%), hypophosphatemia (14%), anemia (8%), white blood cell decreased (6%), fatigue (4%), diarrhea (4%), and platelet count decreased (3%). At final analysis, median PFS was 3.3 months (EE) versus 3.1 months (EP) (HR=0.87, 95% CI: 0.67, 1.13, p=0.30). Median OS was 23.4 months (EE) versus 21.7 months (EP) (HR=0.99, 95% CI: 0.82, 1.21, p=0.94). ORR was 4.6% (EE) and 4.3% (EP). The median fold change in lysine acetylation in PBMCs was approximately 1.5 in EE arm, and 1 in EP arm. Participants on EE had significantly higher increase in lysine acetylation by C1D15 than patients on EP (397 paired samples available for analysis, p Conclusion: The combination of exemestane and entinostat did not improve survival in AI resistant advanced HR-positive, HER2-negative breast cancer. Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Min-Jung Lee, Richard L Piekarz, Karen L Smith, Ursa Brown-Glaberman, Jennifer S Winn, Bryan A Faller, Adedayo A Onitilo, Mark E Burkard, George T Budd, Ellis G Levine, Melanie E Royce, Peter A Kaufman, Alexandra Thomas, Jane B Trepel, Antonio C Wolff, Joseph A Sparano. E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-02.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.

e16538 Background: Sipuleucel-T is known to have modest anti-tumor activity in pts with metastatic castration resistant prostate cancer (mCRPC). Synergy of radiotherapy and immunotherapy has been reported. We conducted a pilot study to assess the impact of radiation on immunogenicity of Sipuleucel-T. Methods: Pts with minimally symptomatic mCRPC and bone metastases were eligible. Pts received Sipuleucel-T every 2 wks x 3 infusions. 8 Gy RT to 1 bone lesion was given 2 days after the first infusion. Peripheral blood was collected at D0, 7d after each infusion, 3 and 6 m. Primary endpoint is the effect of RT on immunogenicity of Sipuleucel-T. Secondary endpoints were safety, PSA changes and survival. We will evaluate T cell proliferation and cytolytic response at baseline and post-treatment using thymidine incorporation assay, IFN-y ELISPOT and flow cytometry. Results: From 10/2013 to 7/2018, a total of 15 pts were enrolled. Median age was 69 years (59-77). 10 pts (67%) had GS > = 8 disease. 7 pts (47%) failed prior abiraterone or enzalutamide. 13 pts completed treatment per protocol (2 withdrew). During a median follow-up of 48 mos, the 3-year overall survival was 48% (95% CI, 21-71); median survival was 30.7 mos (95% CI, 14.6-NR). No PSA responses were observed. 11 pts had post-treatment imaging (non-mandatory). 10 had PD and 1 had SD. 10 pts (67%) had Grade 1-2 drug-related AEs (most common: dizziness and hematoma 20%). No DLT or grade 3-5 drug-related AEs were observed. Conclusions: Sipuleucel-T plus RT is well tolerated. Median overall survival in this limited subset of pts was encouraging, when compared with historical data (25.8 mos in IMPACT trial). The evaluation of immune response is ongoing. (Funded by DENDREON; ClinicalTrials.gov ID: NCT01833208) Clinical trial information: NCT01833208.

58 Background: Androgen deprivation therapy (ADT)-induced immunosuppression has been described in animal models as contributing to castration-resistant prostate cancer (CRPC) development, but the clinical relevance of these observations has not been established. In this study, we compared the immune tumor microenvironment (iTME) of primary prostate cancer (PPC) versus metastatic CRPC (mCRPC). Methods: Genomic and clinically annotated data were obtained of PPC and mCRPC from the TCGA provisional and SU2C/PCF databases. Patients without RNA-seq data were excluded. 22 iTME cell subsets were estimated using CIBERSORT LM22 algorithm. Relative cell proportions and gene expression in log-transformed FPKM were compared using Wilcoxon tests. Results: 499 PPC and 118 mCRPC were studied. Compared to PPC, mCRPC had higher percentage of M2 macrophages (24.6% vs. 10.2%, p

561 Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A—500 mg intramuscular (i.m.) day −14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B—1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, β=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=−0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs. A proteasome inhibitor likely enhances the effectiveness of the breast cancer drug fulvestrant, according to a small, randomized trial. Kerin Adelson, formerly of Mount Sinai and currently of Yale University School of Medicine, led this New York Cancer Consortium, National Cancer Institute-funded randomized phase II trial testing fulvestrant (an estrogen receptor degrader) with or without the addition of bortezomib (a drug that blocks the cellular complexes that break down proteins) in 118 postmenopausal women with a form of hormone receptor-positive metastatic breast cancer that is often treated with fulvestrant. Although the median time before tumors started to grow was similar between the two treatment arms of the study, a significantly larger fraction of patients who received bortezomib were living without tumor growth at 12 months compared to those who received fulvestrant alone. The addition of bortezomib may help delay or reverse resistance to fulvestrant.

Objectives To evaluate the effect of suboptimal dosing on the outcomes of patients who received neoadjuvant chemotherapy (NAC) and robot-assisted radical cystectomy (RARC). Patients and Methods We retrospectively reviewed 336 consecutive patients with urothelial carcinoma of the bladder who were treated with NAC and RARC at three academic institutions. Outcomes were compared between 3 groups: patients who received optimal NAC; patients who received suboptimal NAC; and those who did not receive NAC. To adjust for potential baseline differences between the three groups, propensity-score-based matching was performed. The suboptimal dose group was defined as those who received fewer than three cycles of cisplatin-based chemotherapy, received decreased dosage, or one's not treated with cisplatin. Primary outcomes analyzed were recurrence-free survival (RFS) and overall survival (OS). Secondary outcomes were perioperative complications and readmissions after RARC. Results Within the cohort after propensity-score matching, 69 patients received optimal dose NAC, 41 received suboptimal NAC and 69 did not receive NAC. Complication rates and readmission rates between the 3 groups did not differ significantly. On multivariable analysis, suboptimal dosing and no NAC were independent predictors of worse RFS (HR: 2.5, 95%CI: 1.2-5.7, p=0.01 and HR 2.4, 95%CI 1.28-5.16, p=0.01) and worse OS (HR 4.5, 95%CI 1.6-15.0, p

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m 2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 A mu g) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations

e24229Background: Compared with breast invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) has been shown to be more strongly associated with risk factors that modulate hormone levels...

1064Background: BOLERO 2 trial showed improved progression free survival (PFS) with everolimus (EV) + exemestane combination over exemestane alone in hormone receptor positive, HER2 non-amplified m...

No predictors of a complete pathologic response (pT0) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma have been established. We performed a retrospective analysis of 50 patients to identify potential predictors. Our results showed that the presence of additional transitional cell variants on pathologic examination (mixed tumors) predicted against pT0, suggesting the avoidance of NAC and its morbidity in these patients with mixed tumors.Randomized trials have supported the use of cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma (MIBC) owing to the survival advantage, which has correlated with downstaging of the cancer to pT0. Only 30% to 40% of patients receiving NAC have attained a pT0 response at cystectomy; the remaining have either residual disease or progression. We aimed to identify the factors that could predict a pT0 response to NAC.Of 336 patients who had undergone robotic cystectomy at our institute from May 2007 to March 2014, we identified 50 patients who had undergone NAC for MIBC. We conducted a retrospective study, dividing these 50 patients into 2 groups, those with and without a pT0. Factors, including age, histologic features, hydronephrosis at initial presentation, and chemotherapy type, were examined by both univariate and multivariate logistic regression analysis.Of the 50 patients, 14 (28%) had pT0 at cystectomy, 20 (40%) had progressive disease, and 16 (32%) had residual disease. The median age was 67.5 years, the median glomerular filtration rate at presentation was 87.5 mL/min, the patients had undergone a median of 3 NAC cycles, and the median time from the end of chemotherapy to surgery was 4 weeks. The odds of a pT0 response for pure urothelial carcinoma (UC) were approximately 11 times greater relative to cancers with transitional cell variant histologic features or mixed tumors (odds ratio 0.09, 95% confidence interval 0.021-0.380; P = .0011), including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants.The presence of pure UC favored a pT0 response to NAC compared with those with variant histologic features or mixed tumors. These potential predictors warrant prospective validation to allow the ideal selection of patients for NAC.

1054 Background: Resistance mechanisms to CDK 4/6 inhibition are not well defined. Outcome data on hormone receptor positive (HR+) metastatic breast cancer patients (MBCP) treated with palbociclib (PA) after treatment with everolimus (EV) are lacking. The PALOMA 3 trial (P3) showing benefit of PA plus fulvestrant (FU) compared to FU in HR+ MBCP after progression on endocrine therapy excluded women previously treated with EV. The aim of our study was to investigate the outcomes of HR+ MBCP with prior EV treatment on PA based therapy. Methods: This is a retrospective, single institute review of HR+, HER 2 nonamplified MBCP from Jan 2014 - Nov 2016 treated with PA after treatment with EV. Women who received EV for < 1 month or PA < 14 days were excluded. Progression free survival (PFS) was defined as the time from the initiation of PA to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Response rates were determined based on available radiological data. Clinical benefit was defined as a complete response (CR), partial response (PR) or stable disease of at least 24 weeks. Results: 23 patients with mean age 67 years (42 to 81) were identified. 95% were postmenopausal, 81% had ECOG performance status 0 or 1, 83% had visceral metastases, 95% had > 2 lines of prior endocrine therapy (ET), 82% shown prior sensitivity to ET, 82% received prior chemotherapy, of which 84% were in metastatic setting. Kaplan Meier estimate showed median PFS of 2.9 months (95% CI 2.0-4.2); median PFS of P3 PA cohort was 9.5 months (95% CI 9.2-11.0). Fisher’s exact test comparing study cohort with P3 PA cohort showed statistically significant differences in objective response (CR or PR) rates of 0/23 (0%) vs. 66/347 (19%, p = 0.02) & clinical benefit ratio of 4/23 (17.4%) vs. 231/347 (66.5%, p = 0.00). Conclusions: Outcomes with PA in HR+ EV treated MBCP were worse when compared to the P3 PA cohort data. Treatment with EV may lead to resistance to CDK inhibition. Though limited by size, our data suggests that use of PA after EV is associated with low response & clinical benefit rates. Further studies are necessary to confirm the findings to determine sequencing of targeted therapies.

e13081 Background: Synchronous breast cancers are uncommon and account for around 2% of all breast cancer diagnosis. Lobular histology is considered a risk factor for synchronous breast cancers. We sought to study the trends in synchronous breast cancer of ductal histology and influence of age by interrogating the SEER database. Methods: The SEER Research data 1973-2013 was interrogated for synchronous infiltrating ductal carcinoma diagnosis (2 diagnosis within 6 months of each other). Overall survival (OS), the primary endpoint, was defined as the time (in months) from diagnosis to death from any cause. Univariate proportional hazards modeling results were used to assess the effect of age, race and stage on overall survival. All associations were considered statistically significant at an alpha error < 0.01. All analyses were performed using SAS version 9.4. Results: 1469 cases were identified. Data was categorized by age group: ≤ 65 years or > 65 years. 60% were 65 years or younger. 85% were Caucasians, 9.6% African Americans and 5.2% others. Younger women (≤ 65 years) had a statistically higher proportion of Stage III/IV breast cancer diagnosis as compared to older women (33.4% vs 25.2%; p = 0.002). The incidence rate of synchronous breast cancers has been rising since 1973, more pronounced in the older age group. Incidence rates overall have risen from 0.09/100,000 persons in 1973-1980 to 0.29/100,000 persons in 2001-2013 (p < 0.001). Incidence rates for synchronous breast cancer in women > 65 years has increased from 0.30/100,000 persons in 1973-1980 to 1.03/100,000 persons in 2001-2013. The adjusted OS among older women is significantly worse than that of younger women (HR 1.05; 95% CI 1.04-1.05; p < 0.001). Conclusions: Better imaging techniques and breast cancer screening guidelines have likely improved breast cancer detection rates thus leading to a rise in the incidence of synchronous breast cancers. It can be speculated that underlying medical problems and advanced age result in more morbidity and subsequent mortality in older women with standard treatment. The finding of more advanced disease among younger women deserves scrutiny as to cause.

e16513 Background: The prognosis of castration-resistant prostate cancer with skeletal metastasis (CRPCSM) is poor. The ALSYMPCA trial led to the approval of radium-223 (Ra223) in such patients. Factors that could predict hematologic toxicities associated with Ra223 remain poorly defined. We analyzed the utility of bone scan index (BSI) at baseline (BSI-B) as a predictive marker for such toxicities. Methods: This is a retrospective study of CRPCSM patients without visceral metastasis who received Ra223 at Roswell Park Cancer Institute from 2013 to 2015. BSI was defined utilizing the estimation of a numerical index (max, 70.8% for diffuse skeletal involvement) that expresses the fractional involvement of each bone by tumor. BSI-B values were classified into < first quartile ( < Q1), between first and third quartile (Q1-Q3), and > third quartile ( > Q3). The associations between BSI-B and different hematologic parameters [hemoglobin (Hgb), platelets (Plt), absolute neutrophil count (ANC)] over the Ra223 treatment duration were evaluated using linear mixed models. Results: A total of 79 patients were included in this analysis. The median Gleason score was 8 (range: 4-10) and the median age at first Ra223 was 71 years. Seventy percent of patients received 5 or more doses of Ra223. There was a significant association between BSI-B and Hgb (p = 0.005) and Plt (p = 0.011) levels at baseline and at all time points. The > Q3 BSI-B was associated with a greater drop in Plt from an elevated baseline with subsequent treatments of Ra223 [drop from a mean of 293.5±21.3 x109/L (n = 19) to 132.2±48.8 x109/L (n = 9) after sixth Ra223]; while such a decline was not observed for lower BSI-B (p < 0.001). The ANC decreased with each Ra223 in patients with > Q3 BSI-B but not in the ones with lower BSI-B (p = 0.003). Conclusions: Our work demonstrates that hematologic parameters at baseline and during Ra223 treatment are associated with higher BSI-B values, raising the possibility of BSI-B as a valuable tool for predicting the risk of cytopenias before initiating Ra223 in CRPCSM patients. Prospective validation is needed to confirm the utility of our findings.

e12096Background: Pathologic complete response (pCR- ypT0/isN0) could predict long-term outcomes in breast cancer. This study seeks to ascertain pCR reproducibility with neoadjuvant dual Her2 block...

5065Background: Considerable evidence indicates that exposure of tumor cells to high concentrations of 1,25(OH)2 vitamin D3 [1,25D3] in vitro can suppress in vivo tumor growth. Several studies have...

Purpose: Fulvestrant (F) is a selective estrogen receptor downregulator (SERD) with activity in aromatase-inhibitor (AI) resistant estrogen receptor (ER)-positive metastatic breast cancer (MBC). In preclinical studies, the proteasome inhibitor bortezomib (B) enhances the antineoplastic effects of F, in part by promoting accumulation of large ER-aggregates that lead to cell death (Ishii et al. Clin Cancer Res 2011 17:2292). The objective of this study was to determine if the combination of F+B was more efficacious than F alone in MBC after AI progression. Patients and Methods: Postmenopausal women with ER-positive MBC who had progressive disease after prior AI therapy were eligible. They were randomized to F alone (500 mg IM days -15, 1, 15 in cycle 1, and day 1 of each subsequent cycle) or in combination with B (1.6 mg/m2 IV on days 1, 8, 15). The primary endpoint was progression free survival (PFS), measured from cycle 1, day 1 of starting F. A sample size of 118 was pre-specified in order to provide sufficient power to detect an improvement in median PFS from 5.4 to 9.0 months, and compare PFS rates after 6 and 12 months (1-sided alpha=0.10, beta=0.10). Patients with progression on F could cross over to the F+B combination. Results: Of 118 patients enrolled, 59 received F alone (arm A), 57 received F+B (arm B), and 2 assigned to arm B never initiated protocol therapy. There were no significant differences in patient characteristics between arms with regard to median age (57 vs. 59 years), ECOG performance status (0 and 1, 64% and 36%, respectively), prior chemotherapy for metastasis (25%), or liver metastases (37%), although patients in arm A had longer median interval between diagnosis and metastasis (49 vs. 28 months) and were more likely to present with metastasis (32% vs. 26%). Patients in arm B had more adverse events (all grades), including nausea (63% vs. 29%), diarrhea (47% vs. 8%), sensory neuropathy (46% vs. 29%), and limb edema (37% vs. 19%), although grade 3-4 events were uncommon, and only 11% discontinued B due to toxicity. At 12 months, the PFS proportion in Arm A and Arm B was 13.6% vs. 28.1%, respectively (P=0.03, 1-sided chi-square test) (95% CI for difference [14.5%] = -0.06%, 29.1%). Although median PFS was similar in the two arms (2.69 vs. 2.73 months, respectively), the hazard ratio for Arm B vs. Arm A (referent) was 0.73 (95% CI = 0.49, 1.09, P=0.06, 1-sided log rank test). Both results were significant at the pre-specified 1-sided 0.10 alpha level. Of 27 patients on arm A who crossed over to F+B at progression, 4 (15%) were progression-free for at least 24 weeks and had periods of disease control that were longer than when treated with F alone. Conclusion: Adding bortezomib to fulvestrant in AI-resistant ER-positive MBC enhances its effectiveness by delaying acquired fulvestrant resistance. These results support additional evaluation of proteasome inhibitors in combination with SERDs. Acknowledgement: Supported by contract N01-CM-62204 to the New York Cancer Consortium (P.I. J. Sparano) and grant P30 CA013330 (P.I. D. Goldman) from the National Institutes of Health, and by a grant from Millennium, Inc. Citation Format: Kerin B Adelson, Bhuvaneswari Ramaswamy, Joseph A Sparano, Paul J Christos, John J Wright, George Raptis, Miguel C Villalona, Cynthia X Ma, Dawn Hershman, Joseph Baar, Paula Klein, Tessa Cigler, G Thomas Budd, Yelena Novik, Antoinette R Tan, Susan Tannenbaum, Anupama Goel, Ellis Levine, Charles L Shapiro, Eleni Andreopoulou, Michael Naughton, Kevin Kalinsky, Samuel Waxman, Doris Germain. Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York cancer consortium 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 S6-03.