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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.

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.

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], pINTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

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.

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.

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.

Background Prompted by complaints of dyspnea in breast cancer patients receiving adjuvant dose-dense chemotherapy (DDC), we sought to evaluate the possible association of DDC with pulmonary dysfunction. Patients and methods A total of 34 consecutive patients receiving adjuvant DDC were enrolled. The chemotherapy regimen consisted of i.v. doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 14 days ×4 with growth factor support followed by weekly i.v. paclitaxel 80 mg/m2 ×12. The following parameters were prospectively measured before and after the AC protocol (P1, P2) and at completion of paclitaxel treatment (P3): presence of dyspnea, blood pressure, pulse rate, hemoglobin, erythrocyte sedimentation rate, C-reactive protein level, cardiac ejection fraction, and pulmonary function. Repeated measures analysis was used to evaluate differences among the time points, and paired t-test was used to evaluate differences between consecutive time points. Results Although only five patients (15%) complained of dyspnea, there was a significant decrease in mean carbon monoxide diffusing capacity (DLCO), in all patients from P1 (22.09 ml/min/mmHg) to P3 (15 ml/min/mmHg) and in 29 of 32 patients (90.6%) from P1 to P2 (15.96 ml/min/mmHg) (P Conclusions DDC is associated with a statistical significant reduction in DLCO. Awareness of this potential toxicity may be important in women with preexisting lung disease.

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.