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The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006–2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan–Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Background: Breast cancer is the second most common cause of central nervous system (CNS) metastasis, leading to a significant decrease in survival rate. High risk groups for CNS involvement include younger age, human epidermal growth factor 2 (HER2) over-expression, estrogen receptor (ER) and progesterone receptor (PR) negativity, high histologic grade, and presence of systemic metastases. Young age at diagnosis of breast cancer is associated with more aggressive biological behavior and worse prognosis than in the elderly. However, data are limited regarding CNS involvement in this group of patients. Although it could be expected that younger patients would also have a poor prognosis after the diagnosis of CNS metastases, earlier studies have demonstrated conflicting results, some with favorable outcomes for this unique group. In this study we aimed to explore the differences in the patterns and outcome of CNS involvement according to age at diagnosis of breast cancer (≤45 years vs. >45 years). Methods: A retrospective database of consecutive breast cancer patients who were treated in our institute and were diagnosed with CNS metastases during 2006-2019 was generated. Data analyzed included age at diagnosis of breast cancer, age at diagnosis of CNS involvement, histopathological factors (histology, grade, hormone receptor and HER2 status), treatments given before and after CNS involvement, characteristics of CNS involvement (location, number of brain deposits, clinical manifestations), overall survival, time to CNS progression, and survival after diagnosis of CNS disease. Results: Study cohort was comprised of 174 patients: 65 patients were age≤45 and 109 patients were older than 45 at breast cancer diagnosis. The percentage of patients with triple-negative breast cancer was higher among the younger age group (24.6% vs. 14.7%). Median overall survival from breast cancer diagnosis was significantly longer for younger patients [117.1 months (95% CI 67.2-167) vs. 88 months (95% CI 65.6-110.4), p=0.017]. Median time from breast cancer diagnosis to development of CNS metastases was also significantly longer in the younger age group [58.1 months (95% CI 46.5-69.6) vs. 37.5 months (95% CI 22.9-52.2), p=0.021]. Median survival as measured from time of CNS involvement was 18.7 months (95% CI 10.8-26.6) in the younger group vs. 11.1 months (95% CI 7.8-14.5) in the older patients (p=0.341). Survival of patients with triple-negative breast cancer from time of CNS metastases diagnosis was significantly longer for the younger age group [22.5 months (95% CI 1.2-43.8) vs. 7.9 months (95% CI .77-15.1), p=0.033]. The number, location and clinical presentation of CNS metastases were not statistically different between the two groups. Systemic and CNS-directed treatment approaches were also similar. Conclusion: While the presentation of CNS metastasis was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival. Numerically, after diagnosis of CNS involvement younger patients had longer survival, but the difference was statistically significant only for patients with triple-negative disease. Citation Format: Matan Ben-Zion Berliner, Shlomit Yust-Katz, Inbar Lavie, Alexandra Amiel, Dalia Zoref, Daniel Hendler, Hadar Goldvaser, Michal Sarfaty, Ofer Rotem, Olga Ulitsky, Tali Siegal, Victoria Neiman, Rinat Yerushalmi. Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome [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 P3-08-41.

Background Combination of pertuzumab, trastuzumab and chemotherapy is standard of care for first-line treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. Most randomized studies used combination of taxanes and anti HER2 targeted treatment as 1st line treatment. The combination of vinorelbine, trastuzumab and pertuzumab has shown anti-tumor activity in a phase 2 trial. No trials have compared outcomes between vinorelbine to taxane in combination with pertuzumab and trastuzumab. Methods We retrospectively evaluated all patients with metastatic HER-2 positive breast cancer treated in two institutions between 3/2013 and 3/2018. Patients' clinical data were obtained from electronic medical records. We identified patients who were treated with vinorelbine (oral or intravenous) or a-taxane (docetaxel or paclitaxel) in combination with trastuzumab and pertuzumab as a first-line treatment. We compared progression free survival (PFS), overall survival (OS) and toxicity profiles between the two groups. Results The study included 120 patients (73 in the taxane and 47 in the vinorelbine group). There were several between-group differences: 65% of the taxane group patients were metastatic at diagnosis compared to 40% in the vinorelbine group (p=0.008), 18% of the taxane group received trastuzumab in the adjuvant setting vs. 45% in the vinorelbine group (p=0.003). More patients in the taxane group were asymptomatic (43.4% vs 23.4%, p=0.04). PFS was significantly longer in the taxane group compared to the vinorelbine group (35.4 months vs 13.9 months, p=0.0005). OS was also longer in the taxane group, but difference did not reach statistical significance (48.8 months vs 34.5 months, p=0.13). In the subgroup of patients with recurrent disease (excluding patients with de-novo metastatic disease), there was no difference for OS (32.6 vs 33.1 months for taxane and vinorelbine, respectively). Toxicity profiles differed between the groups, with more patients in the taxane group experiencing diarrhea, peripheral neuropathy and asthenia, and more patients in the vinorelbine group experiencing neutropenia. Discontinuation of chemotherapy due to toxicity was more common in the taxane group compared to the vinorelbime group. (38% vs. 17%, p=0.015). Conclusions In this retrospective analysis, first-line treatment with taxane combined with trastuzumab and pertuzumab for HER-2 positive metastatic breast cancer resulted in improved outcomes compared with the combination of vinorelbine, trastuzumab and pertuzumab. The vinorelbine arm revealed a favorable toxicity profile. Patients with recurrent disease (excluding de-novo metastatic disease) had similar outcomes with either chemotherapy. A randomized study is warranted. Citation Format: Daniel Jack Reinhorn, Irina Kuchuk, Judit Prus, Michal Sarfaty, Hadar Goldvaser, Ofer Rotem, Daniel Hendler, Dalia Zoref, Victoria Neiman, Tzipora Shohat, Olga Ulitsky, Shlomit Yust-Katz, Bella Nisenbaum, Maya Gottfried, Rinat Yerushalmi. Taxane versus vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with metastatic HER2-positive breast cancer - A retrospective two-center 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 P1-18-33.

Background In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. Objective To estimate the cost effectiveness of nivolumab for second-line treatment of advanced RCC from the US payer perspective. Design, setting, and participants A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. Outcome measurements and statistical analysis Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. Results and limitations The total mean cost per patient was $101 070 for nivolumab and $50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146 532/QALY versus everolimus and $226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to $121 788/QALY versus everolimus. The analysis is limited by data availability and our assumptions. Conclusions Our analysis established that with a willingness-to-pay threshold of $100 000 to $150 000 per QALY, nivolumab is estimated to be cost-effective versus everolimus, but not cost-effective versus placebo. Patient summary We assessed the cost effectiveness of nivolumab in previously treated metastatic kidney cancer. In the USA, it would cost $146 532 to gain one quality-adjusted life-year with nivolumab versus everolimus, or $226 197 versus placebo. Nivolumab is considered cost-effective versus everolimus, but not versus placebo.

The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

Background: Data regarding the impact of angiotensin receptor blockers (ARB) on breast cancer are inconsistent. We evaluate the association between ARB usage and breast cancer characteristics and outcomes. Methods: All patients who were treated in our institute for estrogen receptor positive, human epidermal growth factor receptor 2 negative early breast cancer between 4/2005 and 3/2012 and whose tumors were sent for Oncotype-DX analysis were included. Medical records were retrospectively reviewed for clinical-pathological parameters, related comorbidities, treatment and outcomes. Data regarding ARB usage was retrieved. Usage of several pre-specified medications for hypertension including angiotensin converting enzyme inhibitors (ACEI), mineralocorticoid receptor antagonists (MRA), and β-blockers (BB) was also evaluated. Each medication group was compared to the rest of the study population. Results:671 patients were included in the study cohort. Forty six (7%) were treated with ARB, 93 (14.2%) with ACEI, 14 (2.1%) with MRA, and 115 (17.5%) with BB. ARB usage was associated with different histological subtype distribution (P=0.009), higher incidence of macroscopic nodal involvement (P Conclusions: Patients treated with ARB presented with more advanced breast cancer disease and some distinct histological features. Further research is required to elucidate the effect of ARB treatment on breast cancer. Tumor burdenPopulation (no.)Tumor size, cm (SD)Macroscopic node posotive1Stage Mean, cm (SD)P, univariate analysis%P, univariate analysisI, %II, %P, univariate analysisAll (671)1.68 (0.8)-9-71.228.3-ARB (46)1.89 (0.81)0.05423.9 2 millimeter Histological characteristicsPopulation (no.)Ki67 (%)Estrogen recepator stain intensityHistology subtype Mean, (SD)P, univariate analysisMean, (SD)P, univariate analysisIDC (%)ILC (%)P, univariate analysisAll (671)15.91 (13.58)-2.47 (0.57)-80.912.2-ARB (46)12.27 (7.19)0.0052.57 (0.59)0.24665.226.10.009ACEI (93)17.1 (14.24)0.4032.44 (0.55)0.51575.5160.358MRA (14)21.4 (11.2)0.1972.63 (0.42)0.30385.87.10.841BB (115)15.93 (12.93)0.992.51 (0.58)0.49675.713.90.186IDC- invasive ductal carcinoma, ILC- invasive lobular carcinoma Citation Format: Goldvaser H, Rizel S, Hendler D, Neiman V, Shepshelovich D, Shochat T, Sulkes A, Brenner B, Yerushalmi R. The association between angiotensin receptor blockers usage and breast cancer characteristics [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-11.

Background: Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. The aim of this study was to evaluate the impact of smoking on the characteristics and outcome of estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative early breast cancer. Methods: This was a retrospective single center study. All patients diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, HER2 negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Patients were grouped and compared according to smoking history (present or past smokers vs. never smokers) and status (current vs. former and never smokers). Heavy smokers (pack years ≥30) were analyzed separately. Results: A total of 671 patients were included. 28.7% had a history of smoking, 17% were current smokers and 11.5% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (11% vs. 5.1%, p=0.023, 9% vs. 3.45%, p=0.013, respectively). Smoking had no other impact regarding histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcome. Conclusions: In patients with estrogen receptor positive, HER2 negative, early breast cancer, smoking had no clinically significant influence on tumor characteristics and outcome. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer. Breast cancer characteristics according to history of smoking, smoking status and pack yearsPopulation (no.)Mean tumor size, cm (SD)Macroscopic N + (%)Oncotype Dx RS, mean (SD)Histology, IDC (%)Angiolymphatic invasion (%)Perniural invasion (%)Ki67 (%), mean (SD)Hx smoking (178)1.66 (0.9)10.718.9 (9.4)817.75.915.8 (13.5)No Hx of smoking (443)1.7 (0.8)8.419.33 (10.8)805.43.816 (14.1)Active smokers (104)1.76 (1)9.619.7 (9)8211916.5 (14.6)Never/former smokers (513)1.68 (0.8)919.1 (10.5)805.13.515.8 (13.7)PY 0-29 (523)1.69 (0.8)9.419.2 (10.7)806416.2 (14.2)PY≥30 (67)1.67 (1)918.3 (8.8)859913.8 (12.1) Citation Format: Goldvaser H, Gal O, Rizel S, Hendler D, Neiman V, Shochat T, Sulkes A, Brenner B, Yerushalmi R. The association between smoking and breast cancer characteristics and outcome [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-25.

Background. Our previous study of pulmonary function in 34 patients with early breast cancer without preexisting lung disease showed that anthracycline- and taxane-based adjuvant dose-dense chemotherapy (DDC) caused a significant 16.4% mean reduction in carbon monoxide diffusing capacity (DLCO). The present study reports the pulmonary and oncological outcomes of these patients on long-term follow-up. Patients and methods. The primary endpoint was DLCO measured by the pulmonary function test (PFT) performed at a median of 27 months after DDC (range, 8–97) in 25 patients without disease recurrence. DLCO values were recorded as a percentage of predicted values according to age, height, and hemoglobin level and analyzed relative to baseline pre-DDC DLCO values. The secondary endpoints were symptoms, additional therapies, and cancer outcomes during a median of 11 years’ follow-up (range, 4.4–11.4). Results. A longitudinal general linear model showed significant effects of time on DLCO and its trend (F(1, 87) = 14.68, p<0.001 and F(1, 87) = 10.26, p=0.002, respectively). Complementary descriptive analysis showed a significant recovery on the follow-up PFT (75.6% vs. 81.9%, p=0.002), but it was still significantly lower than the baseline DLCO (81.9% vs. 92.0%, p=0.003). Five patients (20%) still showed a >20% relative DLCO reduction from baseline. Patients with dyspnea or fatigue at later clinical follow-up had a significantly lower DLCO value on the follow-up PFT than nonsymptomatic patients (80.5% vs. 92.1%, p=0.02). DLCO recovery was inversely correlated with age (R = −0.39, p=0.05), but no significant correlation was found with the length of time until the follow-up PFT or additional therapies. There was no association of DDC-related DLCO reduction with cancer outcomes. Conclusions. The significant reduction in DLCO seen after DDC in patients with potentially curable breast cancer is evident years afterwards, especially in older patients. While most patients partly recover, some will have a lasting symptomatic DLCO impairment.

We report a previously undescribed fatal toxicity in a 54 years old female patient suffering from a locally advanced adenocarcinoma of the rectum. She received standard neoadjuvant chemoradiotherapy followed by an investigational preoperative chemoimmunotherapy regimen (mFOLFOX6 and nivolumab). On day 12 of the first cycle the patient became acutely ill with excruciating abdominal pain and a rapidly downhill course. At laparotomy severe retroperitoneal and mesenteric serositis was found with diffuse petechial lesions; no other gross pathology was evident; biopsies did not show vasculitis. The patient expired within 24 h from surgery. The possible interaction between radiotherapy to the pelvis and chemotherapy concomitantly with a checkpoint inhibitor resulting in unexpected toxicity is discussed. While serositis has been previously described as a possible side effect from checkpoint inhibitors, retroperitoneal and mesenteric serositis as an isolated finding has not been reported.

Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC.We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort.Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio3. Factors associated with OS were metformin use (hazard ratio, 0.21; P .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio 3.Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.

Purpose: To evaluate the association between angiotensin receptor blocker (ARB) usage and breast cancer characteristics and outcomes. Methods: All patients who were treated in our institute for estrogen receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer between April 2005 and March 2012 and whose tumors were sent for Oncotype-DX analysis were included. Medical records were retrospectively reviewed. Data regarding ARB usage were retrieved. Usage of several prespecified medications for hypertension was also evaluated. Each medication group was compared with the rest of the cohort. Results: A total of 671 patients were included. Forty-six (7%) patients were treated with ARB. ARB usage was associated with macroscopic nodal involvement (p < 0.001) and a more advanced stage at diagnosis (p < 0.001). These findings remained significant in the multivariate analysis. Patients treated with ARB also had a higher incidence of invasive lobular carcinoma subtype (p = 0.009), a worse 5-year breast cancer-specific survival (94.7 vs. 98.8%, p = 0.024) and a worse 5-year overall survival (94.6 vs. 98.8%, p = 0.015), but these differences were not demonstrated in the multivariate analysis. Conclusions: Patients treated with ARB presented with a more advanced breast cancer disease and some distinct histological features. Further research is required to elucidate the effect of ARB treatment on breast cancer.

609 Background: N+I demonstrated superior OS and ORR v S in intention-to-treat (ITT) and intermediate/poor-risk (IP) pts with aRCC in CheckMate 214. Here, we report OS, response outcomes per independent radiology review committee (IRRC), and safety with extended min follow-up of 42 mo. Methods: Pts with clear cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg Q3W×4 and then N 3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Endpoints were OS, ORR, and PFS per IRRC using RECIST v1.1 in IP (primary), ITT (secondary), and favorable pts (FAV; exploratory). Results: OS remained superior in ITT (HR 0.72) and IP (HR 0.66) pts with N+I v S (Table). ORR per IRRC was higher and more responses were ongoing with N+I v S (68% v 53% [ITT] and 68% v 52% [IP]). More pts achieved complete response (CR) with N+I and these were ongoing in 86% [ITT] and 84% [IP] of pts. The PFS probability with N+I stabilized after 24 mo at ~35% in ITT and IP pts, whereas probabilities declined over time with S. Among FAV pts, while ORR was 29% with N+I v 54% with S, more pts achieved CR (13% v 6%), and more responses were ongoing (69% v 54%) with N+I v S; 94% of CRs in FAV pts were ongoing with N+I. OS benefits were similar in both arms and PFS probabilities are stabilizing with N+I and declining with S in FAV pts. The incidence of any and grade 3–4 treatment-related AEs was consistent with previous reports and no new drug-related deaths occurred in either arm. Response outcomes per investigator will also be reported. Conclusions: Superior OS and ORR with N+I v S was maintained in ITT and IP pts. More pts treated with N+I experienced CR compared with S, responses and CRs were durable, and PFS probabilities stabilized with N+I after extended follow-up. No new safety signals emerged. Clinical trial information: NCT02231749 .[Table: see text]

BACKGROUND: Immune-modulating drugs have recently been introduced to the second-line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared with chemotherapy in this setting based on the Keynote 045 study. The high cost of immunotherapy necessitates an assessment of its value by considering both efficacy and cost.OBJECTIVE: To estimate the cost-effectiveness of pembrolizumab for the second-line treatment of advanced bladder cancer from the perspective of payers in multiple countries.DESIGN, SETTING, AND PARTICIPANTS: We developed a Markov model to compare the cost and effectiveness of pembrolizumab with those of chemotherapy in the second-line treatment of advanced bladder cancer based on the Keynote 045 study. Drug costs were acquired for the United States (US), United Kingdom (UK), Canada, and Australia. All costs were converted from local currency to US dollars at the exchange rates in September 2017.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Health outcomes were measured in quality-adjusted life-years (QALYs).RESULTS AND LIMITATIONS: Pembrolizumab generated a gain of 0.36-0.37 QALYs compared with chemotherapy. Our analysis established the following incremental cost-effectiveness ratios (ICERs) for pembrolizumab versus chemotherapy in second-line advanced bladder cancer treatment: US $122 557/QALY; UK $91 995/QALY; Canada $90 099/QALY; and Australia $99 966/QALY. The willingness-to-pay (WTP) thresholds per QALY are considered to be around 100 000-150 000 US dollars for the US, 20 000-50 000 pounds for the UK (US$25 000-65 000), 20 000 -100 000 CAD for Canada (US$16 000-80 000), and 40 000-75 000 AUD for Australia (US$32 000-60 000).CONCLUSIONS: Cost-effectiveness and WTP thresholds vary between countries. Compared with the other countries examined, US drug prices were found to be the highest, leading to the highest ICER. With standard WTP thresholds, pembrolizumab may be considered cost-effective in the US but not in the other countries examined.PATIENT SUMMARY: This article assessed the cost-effectiveness of pembrolizumab for the treatment of patients with metastatic bladder cancer who had previously failed one treatment regimen. It would cost $122 557 in the United States, $91 995 in the United Kingdom, $90 099 in Canada, and $99 966 in Australia to gain one quality-adjusted life-year with pembrolizumab versus chemotherapy in these patients, which may be considered cost-effective only in the United States because of the differences in willingness-to-pay thresholds.

Background Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. Methods This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients’ history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. Results A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. Conclusions Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

Background The use of next generation sequencing (NGS) is in a constant rise, without clear evidence to its utility in guiding treatment choices in urologic malignancies. Here our aim was to retrospectively assess the utility of NGS in selecting advanced treatment lines and define the response rates (RR) to chemo and IO in a real-life cohort. Methods mUC patients receiving first-line chemo were included. Paraffin-embedded pathological samples were subjected to FoundationOne genomic analysis (Roche) and to PD-L1 IHC staining using the FDA-approved Ventana’s companion diagnostic test. Reports were anonymized and analysis was performed using Excel (Microsoft Office). Response was defined as either a clinically or radiologically-significant improvement. Results 60 pts were included in this analysis with a median age of 69, of which 87.7% were men and 70% were current or past-smokers. RR to first line chemo or IO was 66% (95% CI 50-82) and 33% (95% CI 12-64), respectively. RR to second-line IO was 14% ((95% CI 4-40). Median TMB was 10 Mut/Mb (range 1-62) with no difference between smokers and non-smokers. 31% pts had tumor PD-L1 staining of > 5% and 3.7% were MSI-high. 107 genes were altered across all pts. The median number of genomic alterations (mutations (muts), amplifications (amps), deletions (dels) and re-arrangements) was 7 (range 2-17). The most frequent were TERT promotor and TP53 mutations, occurring in in 39 (69.6%) and 30 (53.6%) pts, respectively. FGFR3 alterations were found in 9 (15%) pts (7 mut and 2 fusions), 12 pts (20%) had alterations in ERBB2/Her2 (6 amps, 3 muts, 3 equivocal amps), BRCA1 mutations were found in 6 (10%) pts, and TSC1 alterations were found in 6 (10%) pts (4 muts and 2 dels). Altogether, about 40% of patients had potentially actionable alterations; of these, to date, the treatment of 8 patients (13%) was consequently altered. The RR to IO was non-significantly higher in pts with TMB>10 (29% VS 20%, p = 0.1) across all pts in this cohort. Conclusions RR to first-line chemo is higher than to first-line IO, and the association between TMB and response to IO is still debatable. NGS can yield potentially ’actionable’ alterations in about 40% of UC pts, and can change the treatment paradigm in the third of them. Legal entity responsible for the study On behalf of the Israeli GU oncology group. Funding Has not received any funding. Disclosure D.L. Sarid: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1 % had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50 % in BRCA1 patients, and 18.4, 52.6, and 29 % in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45 months. Four BRCA patients (7 %) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naive patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group.

Purpose. To evaluate the associations between metformin, insulin, statins, and levothyroxine and breast cancer characteristics and outcome.Methods. Retrospective chart review of patients treated in our institute for early estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis. Patients were grouped according to medications usage during the time of breast cancer diagnosis. Each group was compared to the rest of the study population.Results. The study cohort included 671 patients. Sixty (9.1%) patients were treated with metformin, 9 (1.4%) with insulin, 208 (31.7%) with statins, and 62 (9.4%) with levothyroxine. Patients treated with metformin had more intense ER stain (p=0.032) and a lower ODX recurrence score (RS) (p=0.035). Diagnosis of diabetes mellitus was also associated with lower ODX RS (p=0.014). Insulin usage was associated with a higher rate of angiolymphatic invasion (p=0.041), but lower Ki67% (p=0.017). Levothyroxine usage was associated with different histological subtype distribution (p=0.02). Extended levothyroxine usage was associated with lower ODX RS (p=0.005). Statin usage had no impact on tumor characteristics. Outcome was comparable in the studied subgroups.Conclusions. Common medications for metabolic disorders might be associated with breast cancer characteristics.

We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10–3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22–90) years and for ovarian cancer (n = 15) 54 (38–69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.

PURPOSE This prospective, nonrandomized study evaluates 4 schedules of granulocyte colony-stimulating factor (G-CSF) for patients with breast cancer receiving adjuvant dose-dense chemotherapy regarding febrile neutropenia, treatment delays, and costs. PATIENTS AND METHODS Two hundred and thirty-one patients were enrolled to receive adjuvant dose-dense chemotherapy with 4 G-CSF schedules: filgrastim (300 mcg) days 3 to 10 [n = 84 (36.4%) group A]; days 3 to 7 [n = 26 (11.3%) group B]; days 5, 7, 9, and 11 [n = 64 (27.7%) group C], or pegfilgrastim (6 mg) on day 2 [n=57 (24.6%) group D]. RESULTS Thirteen patients were hospitalized due to 14 episodes of febrile neutropenia; 3 in group A, 3 in group B, 1 in group C, and 6 in group D. No statistically significant difference was observed among the 4 groups. Fewer febrile neutropenic events were observed in group C than in group D (P=0.041). No statistically significant differences were observed in treatment delays or other hematological toxicities. Average overall G-CSF cost per patient in groups A and D was $8500 versus $4400 in groups B and C. CONCLUSIONS We found a trend in favor of the shorter G-CSF schedule. A larger, prospective randomized trial should be carried out to evaluate shorter versus standard filgrastim and pegfilgrastim schedules with regard to clinical outcomes, hematological and nonhematological toxicities, and impact in costs.

e12537Background: We investigated pulmonary function in breast cancer patients receiving adjuvant dose dense chemotherapy (DDC). A total of 34 patients with no preexisting lung disease underwent re...

14 Background: 30% of pts with localized PC will have a biochemical relapse post local tx. The optimal tx of these pts remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit on survival remain undefined, and it is associated with significant cumulative toxicities.Thus, evaluation of new non-toxic compounds in this pt population is warranted. P-MCP is a competitive inhibitor of galectin-3, a carbohydrate-binding protein, which is known to be involved in cancer pathogenesis. Pre-clinical and clinical data suggest that P-MCP is active in PC. We aimed to evaluate the safety and PSA dynamics of tx with P-MCP in pts with BRPC. Methods: Pts with non-castrate non-metastatic BRPC were enrolled in a prospective phase 2 study of tx with oral P-MCP, at 4.8 grams X 3/day for 6 months (mos). Pts that did not progress clinically, biochemically (PSA), and radiologically, at 6 mos, were treated for subsequent 12 mos. Sample size provided 85% power to assess a decrease in PSA progression rate from 80% (natural history) to 40% (P-MCP tx) at 6 mos. Results: The study was initiated in June 2013. 35 pts were enrolled. Median age was 74 years. Treatment of the primary tumor consisted of surgery in 11% (n = 4), radiation in 69% (n = 24), and both in 20% (n = 7). No pt had tx related grade 3/4 toxicity. One patient withdrew his consent after 1 mos. Of the 34 pts analyzed, 18% (n = 6) had grade 1 toxicity. 62% (n = 21) had a stabilization/decrease of PSA, and negative scans, at 6 mos, and entered the second 12 mos tx phase. A stabilization or improvement (increase) of PSA doubling time was noted in 79% (n = 27) of pts. Disease progression at 6 mos was noted in 38% (n = 13: PSA only 29%, n = 10; PSA and scans 9%, n = 3). Conclusions: The present study suggests a potential benefit of P-MCP tx on progression of BRPC. P-MCP tx is safe. Clinical trial information: NCT01681823.

e12046 Background: The number of older adults diagnosed with breast cancer and the number of breast cancer survivors is on the rise. The majority of women with breast cancer are diagnosed with an early stage (non-metastatic) potentially curable disease. However, data regarding breast cancer characteristics, treatment, and survival for elderly women are sparse. Methods: We retrospectively reviewed all women with invasive, non-metastatic breast cancer treated in our tertiary medical cancer center from January 2004 to December 2007. Patients were divided into 2 groups: those aged 65-75 years and those aged >75 years. Data on tumor characteristics, treatment modalities, and outcome were retrieved from the patient computerized medical files and compared between the groups. Results: The study group comprised 390 patients. Of them, 252 were aged 65-75 years, and 138 were aged >75 years. Patients were followed for a median of 10.6 years.Tumor characteristics were similar in both groups, although older patients had larger tumors at diagnosis. Patients aged >75 years underwent more mastectomies, but were less likely to receive axillary surgery or adjuvant systemic therapy. When grouped according to subtype (luminal, Her-2+, triple-negative), an independent effect on recurrence rate and overall survival (OS) for both age and subtype was observed with the worst outcome in the women with triple-negative disease aged >75 years, and best outcome in the women with Her-2 positive aged 65-75 years (p=0.16 for recurrence, p 75 years. The disease-free survival rate after 8 years of follow-up was 88% for the younger women and 85% for those aged >75 years (p=0.27). Conclusions: The current study reveals the physicians' approach in treating breast cancer in the elderly age groups. It demonstrates the impact of both age and tumor subtype on recurrence rates and OS. Triple-negative disease had the worst outcome in both age groups. Physicians should be aware of the impact of the different breast subtypes on outcome in the older patients subgroup and consider treatment based on the individual patient comorbidities and life expectancy.

e16588 Background: 30% of pts with localized PC will have a biochemical relapse post local tx. The optimal tx of these pts remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long term benefit on survival remain undefined, and it is associated with significant cumulative toxicities.Thus evaluation of new non-toxic compounds in this pt population is warranted. P-MCP is a competitive inhibitor of galectin-3, a carbohydrate-binding protein, which is known to be involved in cancer pathogenesis. Preliminary pre-clinical and clinical data suggest that P-MCP is active in PC. We aimed to evaluate the safety and PSA dynamics of tx with P-MCP in pts with BRPC. Methods: Pts with non-castrate non metastatic BRPC were enrolled in a prospective phase 2 study of tx with oral P-MCP, at 4.8 grams X 3/day. Pts that did not progress clinically, biochemically (PSA), and radiologically, at 6 months (mos), were treated for subsequent 12 mos. Sample size provided 85% power to assess a decrease in PSA progression rate from 80% (natural history) to 40% (P-MCP tx) at 6 mos. We report here first results of a pre-planned interim analysis after ≤ 50% of planned enrolled pt completed 6 mos of tx. Results: The study was initiated in June 2013. We report here the 6 mos data of the first 35 pts enrolled. Median age was 74 years. Treatment of the primary tumor consisted of surgery in 11% (n = 4), radiation in 69% (n = 24), and both in 20% (n = 7). No pt had tx related grade 3/4 toxicity. One patient withdrew his consent after 1 mos. Of the 34 pts analysed, 18% (n = 6) had grade 1 toxicity. 62% (n = 21) had a stabilization/decrease of PSA, and negative scans, at 6 mo, and entered into the second 12 mos tx phase. A stabilization or improvement (increase) of PSA doubling time was noted in 79% (n = 27) of pts. Disease progression at 6 mos was noted in 38% (n = 13: PSA only 29%, n = 10; PSA and scans 9%, n = 3). A future final report will include full tx data (18 mos) and correlative analysis. Conclusions: The interim analysis of the present study suggests a potential benefit of P-MCP tx on progression of BRPC. P-MCP tx is safe. Final analysis is pending. Clinical trial information: NCT01681823.

e18338 Background: In recent years, new drugs have been introduced to the second line setting of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting based on the Checkmate 025 study. However, due to nivolumab's high cost there is a need to define its value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab for the second-line treatment of advanced RCC from the US payer perspective. Methods: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus or placebo in the second-line treatment of advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2016. Model robustness was addressed in univariable and probabilistic sensitivity analyses. We addressed the controversial issue of the extensive duration of immunotherapy treatment amongst long term survivors, which may or may not be approved by payers. Results: The total mean cost per-patient of nivolumab versus everolimus was $101,070 and $50,935, respectfully. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) over everolimus and 0.89 LYs (0.96 QALYs) over placebo. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146,532/QALY versus everolimus and $105,232/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to two years lowered the ICER to $121,788/QALY versus everolimus and $96,418/QALY versus placebo. Conclusions: Our analysis established an ICER of $146,532/QALY for nivolumab versus everolimus in second-line advanced RCC treatment.

Background Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC. Patients and Methods One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods. Results Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69). Conclusion A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

5057Background: Ra-223 is an alpha emitter that selectively targets BM. Ra-223 is an approved treatment option for CRPC patients (pts) based on a significant improvement in overall survival. The pivotal phase III ALSYMPCA trial did not mandate monitoring of antitumor activity by imaging. We aimed to describe the imaging response in pts treated with Ra-223. Methods: Retrospective evaluation of computed tomography (CT) and bone scintigraphy (BS) of consecutive CRPC pts treated with Ra-223. All patients had scans done at baseline. Patients were treated with Ra-223 in 8 centers across 3 countries. Therapy consisted of standard Ra-223 administration (50 kBq q4 weeks for up to 6 injections). Results: A total of 127 pts were included (median age 72), of which 68% (n = 86) were treated with Ra-223 post docetaxel chemotherapy. A total of 20% (n = 26) of patients received concomitant abiraterone or enzalutamide. 52% (n = 66) patients completed the planned 6 injections. Clinical benefit (improvement of skeletal pain...

e12000Background: Data regarding the impact of antihypertensive medications on breast cancer are inconsistent. We evaluated the association between antihypertensive medications on tumor characteris...

538 Background: Su is a standard treatment (tx) for mRCC. Octogenarian pts (aged ≥ 80) are often considered to be unfit for su tx, and recommendations for their tx is limited by the paucity of clinical trials data in this population. We aimed to study baseline characteristics and outcome of octogenarian vs young (aged ≤45) pts with mRCC treated with su. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with su in 8 centers across 2 different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and age, and outcome were performed using the entire pt cohort. Results: Between 2004-2013, 36 octogenarian (group 1; median age 83) and 37 young (group 2; median age 42) mRCC were treated with su. The groups were balanced regarding the following baseline clinicopathologic characteristics: gender, HENG risk, past nephrectomy, mRCC histology, ≥ 2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, and sunitinib induced hypertension (HTN). In group 1 vs 2, 53% vs 27% (p=0.006) had dose reduction/treatment interruption d/t side effects. Clinical benefit (partial response + stable disease) in group 1 vs 2 was 76% vs 84%, while 24% vs 16% had disease progression within the first 3 months of tx (p=0.09). Median PFS was 11 vs 8 months (p=0.1). Median OS was 22 vs 20 months (p=0.7). In multivariate analyses of the entire pt cohort (n=73), age was not significantly associated with PFS or OS. Conclusions: Su is active in octogenarian mRCC pts. Vs young pts, a significantly higher proportion of octogenarian pts had dose reduction/treatment interruption d/t side effects.

260 Background: Abi is a standard treatment (tx) in CN-pts with mCRPC. It is a potent and selective CYP 17 inhibitor. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17. Clinical data (Peer et al, Prostate 2014) suggests that in docetaxel (D) refractory mCRPC, the outcome of abi tx may be superior to keto. However, there are limited clinical data comparing both agents in CN-pts with mCRPC. We aimed to compare the clinical effectiveness of abi vs keto in CN-pts with mCRPC, who were treated after the year 2004 (approval of D for the tx of mCRPC). Methods: Records from 72 CN-pts with mCRPC treated with abi in 5 Israeli centers were reviewed retrospectively, and matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012) to pts treated with keto 200 - 400 mg 3x day (international database, n = 156, from 4 centers across the US and Israel). We compared the PSA response (decrease ≥ 50% from baseline), biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. Results: The groups were matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012), based on pretreatment NLR and PSA doubling time, and the prior response to a gonadotropin-releasing hormone agonist. The groups were balanced regarding age (72 abi vs 70 keto), time from primary tx to disease relapse, gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), and ECOG PS. In the groups of abi vs keto, PSA response was 75% vs 47% (OR 3.8, p = 0.04), median biochemical PFS 12 vs 6 months (HR 0.62, p = 0.03), median radiological PFS 16 vs 8 months (HR 0.54, p = 0.01), median OS not reached after a median follow-up time of 18 months vs 26 months, and tx interruption d/t adverse events 10% vs 22% (0R 0.65, p = 0.05). Conclusions: In CN-pts with mCRPC, the outcome of pts treated with abi may be superior to keto.

539 Background: Based on a single phase 3 study, the mTOR inhibitor tem was approved as 1st line therapy for prmRCC. However, in daily practice, prmRCC pts are often treated with the VEGFR and PDGFR inhibitor su. We aimed to compare the clinical effectiveness of su vs tem in prmRCC pts. Methods: We performed an international multicenter retrospective study of pts with prmRCC (HENG criteria), who were treated in 8 centers across 2 different countries. 31 pts were treated with 1st line tem. Each tem treated pt was individually matched with a 1st line su treated pt, by clinicopathologic factors. The effect of tx type (tem vs su) on clinical benefit, progression free survival (PFS) and overall survival (OS), was tested using a chi-square test and partial likelihood test from cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and tx type (tem vs su), and outcome were performed using the entire pt cohort (n=62). Results: The groups were matched by age (median 65), gender (male 68%), prior nephrectomy (58%), renal cell carcinoma histology (clear cell 81%), smoking status (active in 35%), use of angiotensin system inhibitors (42%), and pre-tx neutrophil to lymphocyte ratio >3 (58%). In tem vs su treated pts, clinical benefit (partial response + stable disease) was 61% (n=19) (partial response 6%, n=2) vs 71% (n=22) (partial response 29%, n=9) (p=0.62). Median PFS was 5 vs 8 mos (p=0.08), and median OS 9 vs 17 mos (p=0.03). In multivariate analyses of the entire pt cohort (n=62), su tx was independently associated with OS (HR 0.6, p=0.001). Conclusions: In prmRCC patient, the VEGFR inhibitor su may be associated with an improved outcome vs the mTOR inhibitor tem.

e15618 Background: Su is a standard tx for mRCC. Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent Met has antitumor activity. Met may negatively regulat...

564 Background: In about 10% of breast cancer (BC) cases, a genetic mutation in the BRCA1/2 genes can be found. BCs associated with BRCA2 mutations present with positive estrogen receptor (ER) stat...

372 Background: For patients with advanced TCC who have progressed on a platinum-based regimen, no widely accepted standard second line therapy currently exists. A 2-stage phase II study was conducted to assess the activity and toxicity profile of the microtubule inhibitor cabazitaxel (Jevtana; FDA-approved in hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen) in patients with metastatic TCC after failure of prior platinum-based chemotherapy. ClinicalTrials.gov NCT01600339. Methods: Patients with one prior platinum based systemic therapy for metastatic TCC received cabazitaxel at a dose of 25 mg\m2every 21 days with prophylactic GCSF support, until disease progression or unacceptable toxicity. The primary endpoint was objective tumor response rate (ORR). Secondary endpoints included safety, time to progression (TTP), and overall survival (OS). Results: Twenty-three patients were enrolled to the study, 19 of whom received treatment. Male\female ratio was 15\4 and the median age was 67 (range, 56-81) years. Partial response (PR) was observed in 1 patient (5.3%), 10 patients (52.6%) achieved stable disease (SD), including 8 (42.1%) that had prolonged SD (≥16 weeks).Furthermore, the disease control rate (PR or prolonged SD) was 47.4%. The median TTP and OS were 4.2 (95% CI, 2.0-6.0) months and 9.9 (95% CI 5.6-13.2) months, respectively. The median number of treatment cycles was 5 (range 1-10). One patient experienced Grade 5 toxicity. Neutropenic fever occurred in 10.6% of patients. Most common toxicities were anemia and diarrhea. Conclusions: Cabazitaxel had modest efficacy in the treatment of advanced TCC, and there was no evidence of a significant response. Toxicity profile was considerable. The role of Cabazitaxel in urothelial carcinoma may need further evaluation in rational combination strategies, but not as a single agent. Clinical trial information: NCT01600339.

440 Background: Sunitinib (Su) is a standard treatment (tx) for metastatic renal cell carcinoma (mRCC). Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent metformin (Met) has antitumor activity. Met may negatively regulate mTOR activity. Its effect on the outcome of targeted therapies in mRCC is poorly defined. We analyzed the effect of Met use on the outcome sunitinib tx in diabetic patients (pts) with mRCC. Methods: We performed a retrospective study of an unselected cohort of diabetic pts with mRCC, who were treated with Su in 7 centers across 2 countries. Pts were divided into 2 groups: (1) Met users and (2) Met naive. The effect of Met use on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from Cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and Met use, and outcome were performed using the entire pt cohort. Results: Between 2004-2014, 108 diabetic pts with mRCC were treated with sunitinib. There were 52 Met users (group 1) and 56 nonusers (group 2). The groups were balanced regarding the following clinicopathologic factors: age, gender, HENG risk, past nephrectomy, mRCC histology, ≥2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su-induced hypertension (HTN), and Su dose reduction/tx interruption. Clinical benefit (partial response + stable disease) in group 1 vs. group 2 was 96% vs. 84%, while 4% vs. 16% had disease progression within the first 3 months of tx (p=0.054). Median PFS was 15 vs. 11.5 months (p=0.1). Median OS was 32 vs. 21 months (p=0.001). In multivariate analyses of the entire pt cohort (n=108), factors associated with PFS were active smoking (HR=2.7, p3 (HR 1.8, p=0.012). Factors associated with OS were Met use (HR 0.2, p3 (HR 3.3, p

Purpose Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol. Methods Our study included all consecutive patients with stages I–II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel) from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. Results: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25–81 years). Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. In Conclusion Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.

e15550 Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pt...

508 Background: The VEGFR inhibitor sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). HTN, an on-target class effect of VEGF signaling-pathway inhibitors, has been shown to correlate with clinical outcome. Studies have shown the association between genetic polymorphisms in several genes, and the development of HTN in patients treated with targeted therapies. We aimed to study the association between readily available clinicopathologic factors and the development of sunitinib induced HTN in mRCC patients. Methods: Records from mRCC patients treated with sunitinib in 9 centers across 2 countries were retrospectively reviewed. Sunitinib induced HTN was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Analysis of the association between clinicopathologic factors and the development of HTN was performed using logistic regression. Results: Between 2004-2013, 302 patients with mRCC were treated with sunitinib. The incidence of sunitinib induced HTN was 50% (n=152). Clinicopathologic factors included in the analysis were age (median 63), gender (67% male), HENG risk (good 22%, intermediate 59%, poor 19%), smoking status (active 21%), BMI (obese=BMI ≥30, 28%; overweight=BMI 25-29.9, 37%; normal weight= BMI 1 metastatic site (82%), metastatic site (lung 72%, liver 25%, bones 40%), pre-treatment neutrophil to lymphocyte ratio (>3 in 45%), treatment line (first vs advanced), sunitinib dose reduction/treatment interruption (45%). Absence of liver metastases (OR 3.5, p=0.02), pre-treatment neutrophil to lymphocyte ratio ≤ 3 (OR 5.5, p=0.001), and BMI (overweight and normal weight vs obese, OR 2.2 and 2.3 respectively, p=0.01 both) were independently associated with the development of HTN. Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, readily available clinicopathologic factors may be used to identify patients who are prone to the development of HTN.

494 Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhäuser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib. Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naïve pts (n=27). Progression free survival and overall survival were determined by Cox regression. Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gender (male 74%), Heng risk (favorable 37%, intermediate 59%, poor 4%), sunitinib induced hypertension (67%), sunitinib dose reduction/treatment interruption (41%), smoking status (active 7%), use of angiotensin system inhibitors (41%), the presence of more than one metastases site (96%), and pre-tx neutrophil to lymphocyte ratio (> 3 in 22%). Furthermore, they were balanced regarding the presence of lung (68%), liver (31%), and bone (43%) metastases, and the use of bisphosphonates (32%). In prior HDIL2 versus tx naïve pts, objective response was partial response/stable disease 89% (n=24) versus 74% (n=20), and progressive disease at first imaging evaluation within the first 3 months (mos) 11% (n=3) versus 26% (n=7) (p=0.29, OR 2.4). Median progression free survival was 21 versus 12 mos (HR 2.3, p=0.005), and median overall survival 25 versus 20 mos (HR 2.2, p=0.013). Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, prior high dose IL-2 therapy may improve the outcome.

e16023 Background: Cabazitaxel (CAB) and Abiraterone-acetate (AA) have been approved after Docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following Docetaxel and AA in CRPC. Methods: Over 13 months until December 2011, 130 CRPC patients received AA after Docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). Results: Fourteen (58.3%) received CAB/prednisone at 20 mg/m 2 and 10 patients 25 mg/m2 , overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from Docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with Docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. Conclusions: Limited number of patients with CRPC received CAB following Docetaxel and AA. In this selected population CAB was active. Response to prior Docetaxel was associated with prolonged survival to CAB therapy.

202 Background: Four cycles of docetaxel/cyclophosohamide (DC) produced superior survival compared with doxorubicin/cyclophosphamide in the treatment of early breast cancer. The study reported 5% of febrile neutropenia (FN) events using prophylactic antibiotics with no growth factor (GF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events (up to 46%), prompting the addition of GCSF by most centers. We explored the use of GF support on days 8 and 12 to the original DC protocol. This report summarizes treatment related morbidity of the DC protocol with GF support given on days 8 and12. Methods: All consecutive patients with stages I-II breast cancer who were treated with the DC protocol in our institute from April 2007 to March 2012 were included. Patient characteristics and toxicity were reported. Results: 131 patients were identified. Median age- 60y (25-81), 65y and older- 25%; 5 patients did not complete the 4 planned cycles (12/524 cycles were missed). Fifteen patients (11.5%) experienced at least one event of FN (4 patients had 2 events), all requiring hospitalization. FN events occurred in 19 out of 512 cycles (3%). Median age of the patients who required hospitalization due to FN was 60y (42-73). Results were comparable in the older group (≥65): 15% developed FN with 6 NF events out of 130 cycles (4.6%), p>0.05. There were additional 14 hospitalizations events due to other causes (diarrhea n=2, chest pain=2, cellulitis n=2, COPD n=1, tonsillitis n=1, fever n=2, bone pain n=1, observation after treatment n=1 and hearing problem n=1, unknown n=1). Six patients had grade 2-3 diarrhea. 2/6 required hospitalization. There was no treatment related mortality. Conclusions: Primary prophylactic growth factor support on days 8 and 12 provides a safe and economic option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.