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Background The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts. Objectives This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment. Methods We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson’s biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA). Results Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups. Conclusions CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

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.

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.

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 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.

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 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.

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]

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.

BACKGROUND Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. METHODS Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m2) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. RESULTS Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. CONCLUSIONS GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes. Cancer 2014;120:2684–2693. © 2014 American Cancer Society.

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.

These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m2 orally twice daily, days 1–14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45–0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44–0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71−1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand–foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. Clin Cancer Res; 19(10); 2745–54. ©2013 AACR.

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.

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

Background Recent studies suggest that older women derive similar benefits from adjuvant systemic chemotherapy (AST) as younger women. In older women, the ability to successfully complete chemotherapy may be complicated by other health conditions and performance status. We examined factors affecting the delivery of chemotherapy to older patients with breast cancer. Methods Women age ≥ 65 treated with adjuvant/neoadjuvant chemotherapy at Roswell Park Cancer Institute were identified from the RPCI database from 7/1997 to 4/2010. Endpoints were delay, hospitalization, dose reduction, relative dose intensity (RDI) Results 204 older women received AST. Median follow-up was 50.2 months. Seventy percent received anthracycline-based AST. In multivariate analysis, older age was a predictor for early termination of chemotherapy and RDI Conclusion Successful administration of planned chemotherapy to older women with breast cancer was associated with improved OS. However, delivery of chemotherapy was associated with increased toxicity and reduced tolerance. Models allowing physicians to better risk-stratify older patients with breast cancer are needed and under development.

US Oncology Research Trial 9735 reported that TC improved overall survival when compared to doxorubicin and cyclophosphamide in early-stage breast cancer. Despite 61% grades 3-4 neutropenia in the TC arm, only 5% of patients developed febrile neutropenia (FN) without primary prophylactic GCSF (ppGCSF). TC has risen in popularity, particularly in older patients or in those where an anthracycline is contraindicated. Other studies examining the toxicity of TC without ppGCSF reported a higher incidence of FN between 23 and 46%. We reviewed our institutional experience with ppGCSF and the TC regimen. Women treated with adjuvant TC and pegfilgrastim at Roswell Park Cancer Institute were identified from the pharmacy database between 8/2006 and 11/2010. Patient characteristics and comorbidities were abstracted. Endpoints included incidence of FN, hematologic toxicities, relative dose intensity (RDI), and other acute complications. Docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) were given every 21 day/cycle for a planned four cycles. All patients received pegfilgrastim 6 mg on day 3. One hundred and eleven women with median age of 56 years (27-79) were identified. Twenty-two percent of patients were ≥ 65 at diagnosis. Eight patients developed FN (7%). Ninety-five patients (86%) were able to complete four cycles. Completion rate was significantly lower in patients with age ≥ 65 (71% vs. 90%; P = 0.02). Incidence of hospitalization, delay, RDI85%, and dose reduction were not significantly different between the age groups. The overall incidence of FN was 7%. Older patients were significantly less likely to complete four cycles of TC as planned. ppGCSF should be strongly considered in breast cancer patients receiving adjuvant TC chemotherapy.

Background: Recent studies suggest that older women derive the same benefits from adjuvant systemic chemotherapy (AST) as younger women. In older women, the ability to successfully complete chemotherapy may be complicated by other health conditions and performance status. This study examines the frequency of inability to complete planned AST and factors associated with difficulty administering AST in older women. Methods: We performed a retrospective analysis of breast cancer patients (age≥65) who received adjuvant/neoadjuvant chemotherapy at Roswell Park Cancer Institute from 9/1997 to 1/2010. Endpoints considered collectively as “difficulty “ in delivering AST were delay in treatment, hospitalization, dose reduction and discontinuation of AST. Factors defined a priori that could affect these outcomes were creatinine clearance (CCr), obesity (BMI ≥30), cardiac disease, hypertension, psychiatric disorders, diabetes, cerebrovascular disease, previous malignancy, COPD/asthma, Charlson comorbidity index, and use of anthracycline-based chemotherapy. The Pearson chi-squared test was used to identify the significant categorical factors associated with each of the five binary responses indicating difficulty administering AST. Logistic regression was used to obtain crude and adjusted odds ratios to further examine the relationships. Kaplan-Meier methods were used to estimate survival distributions, progression free and overall survival. The log-rank test was used for comparison between women experiencing difficulty with treatment and those with no difficulty with treatment. A 0.05 nominal significance level was used in all testing. Statistical analysis and plots were completed using SAS, version 9.2, statistical software (SAS Institute Inc., Cary, NC). Results: 193 women age 65 and over received AST (median age of 70 years - range 65-86). Median follow up was 40.9 months. 73% received anthracycline-based AST. Factors associated with difficulty, delay, dose reduction, hospitalization, or failure to complete planned AST are shown in the Table. Women who completed planned AST had better OS than those who did not complete AST (p=0.01). Women who completed therapy with difficulty had no difference in outcome compared to those without difficulty [DFS (p=0.07) and OS (p=0.18)]. Conclusions: Age, cardiac disease, diabetes, hypertension, CCr, obesity, CCI, and sum of comorbidity significantly impact the ability to deliver and complete AST in older women with BC. Completing planned chemotherapy is associated with improved survival. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-08.

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...

BACKGROUND Preclinical evidence supports the role of estrogen receptor signaling in prostate cancer. In this trial we investigated the tolerability and efficacy of fulvestrant, a pure estrogen receptor antagonist, in the treatment of castration resistant prostate cancer (CRPC). METHODS Patients with CRPC were enrolled after written informed consent. Fulvestrant was administered by intramuscular injection at a dose of 500 mg on day 0, then 250 mg on day 14, day 28 and monthly thereafter. History, physical examination, serum prostate specific antigen (PSA) levels and toxicity was evaluated monthly. Radiographic studies were repeated every 3 months to assess disease. Treatment was continued until disease progression, unacceptable toxicity, non-compliance or consent withdrawal. RESULTS Twenty patients were enrolled over a period of six months. All patients were Caucasians with median age of 69.5 years [range: 47–85 years]. Sixteen patients (80%) had radiological evidence of metastasis and four patients (20%) had rising PSA as the only evidence of progressive disease. Patients received a median of three treatment cycles of fulvestrant [range: 1–11]. Median time to progression was 4.3 months (95% confidence interval of 3–5.7 months) and median overall survival was 19.4 months (range: 9.9–19.4 months) after a median follow-up of 16 months. No patient showed ≥50% reduction in PSA or radiologic improvement. Few adverse events were noted, none of which were attributed directly to fulvestrant. CONCLUSION Fulvestrant was well tolerated but failed to produce clinical or PSA response in men with CRPC. Prostate 68: 1461–1466, 2008. © 2008 Wiley-Liss, Inc.

There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients.Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0-2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m(2) given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m(2)/day given days 2-15 and 23-36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients.The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m(2). Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m(2)/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3-4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent.IRN 80 mg/m(2) days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m(2)/day in divided dose days 2-15 and 23-36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted.

This is a retrospective study of the length of survival (LOS) in hospice of patients with cancer treated at a major cancer center compared to other treatment sites. Of 670 patients, the 185 (28%) treated at a major cancer center had unique characteristics, including higher median Palliative Performance Score (PPS) at the time of hospice enrollment (45 versus 40, p = 0.009), and longer median LOS in hospice (35 versus 21 days, p = 0.02: log rank test). Additional variables that predicted longer LOS were higher PPS, Medicare or Medicaid, self-referral, unmarried status, and non-executed advance directives. After adjusting survival for PPS with a Cox proportional hazard model, the hazard ratio for PPS remained statistically significant (95% confidence interval [CI]: 0.95-0.97] while that for the treatment site was not (95% CI: 0.73-1.04]. The performance status, and not the treatment site, was the dominant predictor of the LOS of patients with cancer in hospice.

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.

Purpose: To develop and validate a model that can be used to predict the overall survival probability among metastatic hormone-refractory prostate cancer patients (HRPC). Patients and Methods: Data from six Cancer and Leukemia Group B protocols that enrolled 1,101 patients with metastatic hormone-refractory adenocarcinoma of the prostate during the study period from 1991 to 2001 were pooled. The proportional hazards model was used to develop a multivariable model on the basis of pretreatment factors and to construct a prognostic model. The area under the receiver operating characteristic curve (ROC) was calculated as a measure of predictive discrimination. Calibration of the model predictions was assessed by comparing the predicted probability with the actual survival probability. An independent data set was used to validate the fitted model. Results: The final model included the following factors: lactate dehydrogenase, prostate-specific antigen, alkaline phosphatase, Gleason sum, Eastern Cooperative Oncology Group performance status, hemoglobin, and the presence of visceral disease. The area under the ROC curve was 0.68. Patients were classified into one of four risk groups. We observed a good agreement between the observed and predicted survival probabilities for the four risk groups. The observed median survival durations were 7.5 (95% confidence interval [CI], 6.2 to 10.9), 13.4 (95% CI, 9.7 to 26.3), 18.9 (95% CI, 16.2 to 26.3), and 27.2 (95% CI, 21.9 to 42.8) months for the first, second, third, and fourth risk groups, respectively. The corresponding median predicted survival times were 8.8, 13.4, 17.4, and 22.80 for the four risk groups. Conclusion: This model could be used to predict individual survival probabilities and to stratify metastatic HRPC patients in randomized phase III trials.

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.

Purpose We evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH). Methods We retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated. Results One hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two-thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade ≥3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen. Conclusion TCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary to support the wider use of TCyH as an adjuvant regimen.

Doxorubicin-based chemotherapy in the adjuvant treatment of breast cancer has become standard. Use of doxorubicin is limited by cardiac dysfunction; however, the incidence is dramatically reduced by limiting the dose to less than 550 mg/m(2). Although the cumulative dose in breast cancer is typically 240 mg/m(2), multiple gated acquisition (MUGA) scans are still recommended for determining cardiac functional status in these patients. To examine the need for this practice, we reviewed 296 patients who underwent surgery for breast cancer at Roswell Park Cancer Institute between July 1997 and December 1998. Fifty-nine of 95 (62%) patients receiving doxorubicin-based regimens, and 3 of 39 (7%) receiving nondoxorubicin regimens had pretreatment MUGA scans. The MUGA scans showed normal results in 58 patients and low-normal in 4 (6.5%), with no wall motion abnormalities encountered. There were no cases where doxorubicin was not used because of an abnormal MUGA scan. There were no cardiac complications in the 59 women who received doxorubicin-based chemotherapy. MUGA will screen out few, if any, women under consideration for doxorubicin-based adjuvant therapy; the decision to avoid doxorubicin can be made based on age and preexisting comorbidity. Guidelines recommending routine use of MUGA before the administration of doxorubicin for adjuvant therapy for breast cancer should be reconsidered.

Inflammatory breast cancer (IBC) carries an ominous prognosis. Before 1988, women with IBC at our institution were treated with neoadjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without vincristine and prednisone (CMF/VP). After 1988, women with IBC were treated with cyclophosphamide, doxorubicin, and 5-fluorouracil (FAC). This study compares these two regimens with regard to response and survival.The records of all women presenting between January 1973 and December 1991 with a stage IIIB (T4d, any N, MO) breast cancer with proven dermal lymphatic invasion by tumor cells were reviewed retrospectively.The study comprised 38 women; 28 received CMF (22 CMF, 6 CMF/VP), and 10 received FAC. The overall response rate to induction chemotherapy in the CMF/VP group was 57% (40% PR, 17% CR), and 100% (60% PR, 40% CR) in the FAC group. The median overall survival for women receiving CMF/VP was 18 months compared with 30 months for women receiving FAC (p = 0.02). The median disease-free survivals for the CMF/VP and FAC groups were 6 and 24 months, respectively (p0.001). When comparing responders and nonresponders with CMF/VP induction therapy, the responders had a significantly longer overall median survival (24 versus 10 months) (p0.001) and disease-free median survival (8 versus 2 months) (p0.001). All of the five patients remaining alive received FAC with 80% (four of five) having a complete response. These four patients subsequently underwent mastectomy and radiation.This study suggests that a doxorubicin-containing chemotherapy regimen improves overall and disease-free median survivals when compared with the previously used CMF combination in the treatment of IBC. A favorable response to induction chemotherapy also appeared to be associated with an improved survival.

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...

Mortality improvements in young women with breast cancer (BC) may be attributable to treatment advances; screening likely plays a less significant role as mammography is not recommended

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

The use of clinicopathologic features in decision-making in early stage estrogen receptor (ER)-positive breast cancer (BC) may lead to over or under treatment. We investigated the effect of the Oncotype Dx (ODX) on chemotherapy (CTX) utilization in two cancer centers. 276 cases of node-negative ER-positive BC had ODX between 2005 and 2009. Age at diagnosis, tumor size, grade, and progesterone receptor (PR) status were abstracted from records and provided to two medical oncologists blinded to the ODX score. A recommendation for or against CTX was made based on clinicopathologic characteristics. Median age was 55 years. Mean tumor size was 1.6 cm. The median 10-year Adjuvant! Online (AO) mortality risk was 8. The median Nottingham Prognostic Index (NPI) was 3.3. The median ODX recurrence score was 17. Without knowledge of the ODX, oncologists were more likely to recommend CTX to younger women (P0.0001), women with negative PR status (P0.0001), higher NPI (P0.012), and tumors1 cm (P = 0.033). On average, CTX recommended patients had larger tumors (2.0 vs. 1.2 cm) and higher AO 10-year mortality (11.4 vs. 4.4%). ODX resulted in a change in management for 38% of women. Of 188 total patients who did not receive CTX, 71 had a recommendation favoring CTX by an oncologist blinded to the ODX score. In our multi-institutional cohort, the ODX score had a significant impact on the receipt of adjuvant CTX and altered management for 38% of women.

Summary Background Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. Methods We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Findings Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8·94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0·76, 95% CI 0·64–0·91; p=0·002) but only marginally for the secondary endpoint of overall survival (HR 0·83, 0·68–1·01; p=0·057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0·84, 0·70–1·01; p=0·061) or overall survival (HR 0·90, 0·73–1·10; p=0·30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Interpretation Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. Funding National Cancer Institute (US National Institutes of Health).

This retrospective study examined 180 hospice patients referred from a comprehensive cancer center over 6 months in 2002 to (1) identify the variables associated with shorter length of survival (LOS) in hospice and (2) examine the LOS in hospice for those who previously participated in clinical trials and/or phase I studies. The median LOS in hospice for this cohort was 35 days. In multivariate analysis, low Palliative Performance Score (PPS) at hospice enrollment and male gender were associated with shorter LOS in hospice: males with low PPS had the shortest LOS while females with high PPS had the longest LOS. No correlation was found between the LOS in hospice and prior participation in clinical trials and/or phase I studies.

Background. To evaluate responses of residents to a hematology/oncology rotation.Methods. A self-administered mail survey among internal medicine residents in a university-based training program who were required to complete a hematology/oncology rotation at a comprehensive cancer center.Results. The majority of the residents rated the duration of the rotation as adequate and quality as excellent or good. It had a positive impact on certain knowledge areas, general opinion about hematology/oncology, preparation for board examination, and motivation to pursue this subspecialty, especially among residents who had performed additional electives.Conclusion. A hematology/oncology rotation received a generally positive evaluation from internal medicine residents.

Purpose: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients. Experimental Design: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m2 as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done. Results: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied. Conclusions: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.

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.