This nonrandomized phase 2 clinical trial examines contralateral breast cancer risk reduction in women who choose radiation therapy or surveillance rather than mastectomy.

Supplementary Data from Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients

Overuse rates in oncology are high, but areas of possible improvement exist for reducing it and improving quality of care. This study explores perceptions and experiences of oncologists in Israel regarding overuse of health services within oncology. In-depth, semistructured interviews were conducted focusing on causes of overuse, facilitators for reduction, and suggestions for improvement. Interviews were audio recorded, transcribed, coded, and thematically analyzed. Physicians reported patient-level causes including “well-informed” and “demanding” patients; physician-level causes including desire to satisfy patients, lack of confidence, time, and skills; and system-level causes like ease of access, and lack of alignment and coordination. Physicians can reduce overuse through patient dialogue, building trust and solidifying patient–physician relationships, and further reduce overuse with better teamwork. Improvements can be made through educational initiatives, and bottom-up solutions. Policy makers and decision makers should develop appropriate interventions addressing health service overuse, including improving patient education and instilling confidence and knowledge in physicians.

Background: Bisphosphonate (BP) treatment to prevent bone loss in breast cancer patients is already well established. However, data on the association between oral BP exposure before cancer diagnosis and disease outcomes in patients with early breast cancer are still scarce. Limited information is available on alendronate, the most common oral agent for the treatment of post-menopausal osteoporosis, regarding the association with bone metastases. Aim: To examine the association between oral bisphosphonate exposure before cancer diagnosis and the risk of bone metastases in osteoporotic women diagnosed with early breast cancer. Subjects and methods: This historical cohort study was conducted at the oncology division at Tel Aviv Medical Center. The study population included post-menopausal women with early breast cancer, diagnosed between 2002 and 2012. Data on cancer characteristics, diagnosis of osteoporosis, prior bisphosphonate exposure and outcome were collected from medical files. Results: Among 297 osteoporotic women identified, 145 (49%) were treated with bisphosphonates (alendronate in 90% of the cases) before cancer diagnosis. BP-treated women were significantly older than the BP-naive ones (67.9 years vs 64.6 years, p = 0.01), but comparable in risk factors and disease characteristics. Over a mean follow up of 5.6 years, nine cases of bone metastases were identified, eight of them among BP-naive patient (cumulative incidence of 9.9%) and one among BP-treated patients (0.7%). In a multivariable Cox's proportional hazards survival model the use of BP prior to cancer diagnosis was associated with a hazard ratio of 0.04 (95%CI:0.004-0.403, p = 0.006) for bone metastasis. The HR remained similar after further adjustment for tumor stage and cancer therapy. Conclusions: History of alendronate use is associated with a lower likelihood of bone metastases in post-menopausal women with early breast cancer. Oral bisphosphonate treatment could be sufficient for reducing the risk of bone metastases.

In addition, the ESMO Guidelines Committee would like to extend thanks to the European Cancer Patient Coalition for their collaboration in arranging review of guidelines by patient representatives. The following patient organisations have provided input:

Background: Several observational studies have suggested a protective effect of oral bisphosphonates (BP) on the risk of breast cancer, but no such association has been seen in randomized control trials. The role of oral BP in breast cancer prevention remains unclear. Aim: To investigate the association between different levels of BP exposure and breast cancer incidence in a cohort of osteoporotic post-menopausal women. Subjects and methods: This historical prospective study was conducted using the computerized databases of Maccabi Healthcare Services (MHS) in Israel. Included in the study were osteopenic and osteoporotic women aged 55-75 years who started BP therapy between 1998 and 2012. The subjects were enrolled in MHS for at least 3 years before therapy initiation, and had a minimum follow-up of 5 years in MHS. Women with a previous cancer, and women treated with selective estrogen receptor modulators (SERMs) were excluded. BP exposure was expressed in quintiles of proportion of days covered (PDC) with BP during follow-up period and cancer incidence was ascertained by the Israel National Tumor Registry. Person-years of follow-up began on January 1st, 1998 and ended at the date of cancer diagnosis, death, or December 31st, 2012, whichever occurred first. Results: A total of 11,717 patients (mean age = 66.87 +/- 4.38) were eligible for the analysis. During a total of 130,252 person-years of follow-up, (mean 7.2 years) 173 incident cases of breast cancer were diagnosed. Compared to women with a PDC with BP of 20% or lower, the adjusted hazard ratio for breast cancer were HR = 0.81 (95%CI: 0.48-1.39), HR = 0.82 (95%CI: 0.50-1.33), HR = 0.72 (95%CI:0.45-1.15) and HR = 1.14 (95%CI:0.76-1.70) among women with 20-40%, 40-60%, 60%-80%, and 80% or higher, PDC, respectively. Conclusion: In this study, we did not find a significant association between oral BP therapy for osteoporosis and the risk of breast cancer in postmenopausal women. The discrepancy between our results and the reports of such an association in observational studies might originate from an indication bias.

BACKGROUND: Holocaust survivors during World War II were exposed to various factors that are associated with cancer risk. The objective of this study was to determine whether Holocaust survivors had an increased risk for developing cancer. METHODS: The study population included 152,622 survivors. The main analysis was based on a comparison between individuals who were entitled to compensation for suffering persecution during the war and individuals who were denied such compensation. A complementary analysis compared survivors who were born in countries governed by Nazi Germany with survivors born in nonoccupied countries. A Cox proportional hazards model was used, with the time at risk of cancer development starting on either January 1, 1960, or the date of immigration to the date of cancer diagnosis or death or the date of last follow-up (December 31, 2006). RESULTS: Cancer was diagnosed in 22.2% of those who were granted compensation versus 16% of those who were denied compensation (P < .0001). Adjusting for birth cohort, sex, country of origin, and period of immigration, both analyses revealed significant increased risks of developing cancer in those who were exposed. For those who were granted versus denied compensation, the hazard ratios were 1.06 (P < .001) for all sites, 1.12 (P = .07) for colorectal cancer, and 1.37 (P = .008) for lung cancer. For those born in occupied countries versus nonoccupied countries, the hazard ratios were 1.08 (P < .001), 1.08 (P = .003), and 1.12 (P = .02), respectively. CONCLUSIONS: The current results, based on a large cohort of Holocaust survivors who were exposed to a variety of severe deprivations, add to the conflicting and sparse knowledge on this issue and support the notion that this group has a small but consistent increase in cancer development. (C) 2017 American Cancer Society.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P<0.001) in the dexrazoxane group, but no significant difference in the incidence of treatment delays or cancellations. The incidence of cardiac events was the same in both treatment groups with and without dexrazoxane. There was a nonsignificantly lower mortality rate in the dexrazoxane group (9.6%) compared with the nondexrazoxane group (15.0%) at data lock. Adding dexrazoxane to doxorubicin in adjuvant therapy patients leads to higher rates of bone marrow suppression in all blood components, as well as more febrile neutropenia events, and dose reductions. No differences in events defined as cardiac toxicities were detected. Dexrazoxane had no detrimental effect on survival, despite the higher hematological toxicity, the older median age, and the higher prevalence of HER2-positive disease in the dexrazoxane group.

6600 Background: Hospital Volume is associated with improved outcomes in cancer surgery, and some aspects of cancer care. The influence of hospital volume on outcomes in neutropenic patients is unknown. Known factors associated with increased mortality include age, race and co-morbidities. We hypothesized that large-volume hospitals would have reduced mortality rates for neutropenic patients compared with small-volume institutions. Methods: We utilized the NIS database of the Healthcare Cost and Utilization Project, focusing on year 2009. All inpatient episodes with a diagnosis of both neutropenia and cancer were included in the study. Hospital volume was defined as the number of neutropenic cancer episodes listed for each institution per year. Mortality was defined as death during admission. Patients were classified into four risk-of-mortality subclasses based upon the 3M APR DRG score. Results: 20,096 hospitalizations from 718 different institutions were analyzed. Median age was 59 years. The overall inpatient mortality was 5.7%. Mortality increased with patient age, for instance amongst those aged 30-39 years it was 3.1% compared to 9.2% for those aged 70-79 years. The average number of neutropenic inpatient episodes in each institution per year ranged from less than one to 548 (median 84). The population was split into four equal groups based upon hospital volume. Mortality was 7.1%, 6.4%, 4.8% and 4.6% for each group (from lowest to highest volume), likewise % discharged home was 77.6%, 82.1%, 88.9% and 91.0% (for both p<0.001). In a logistic regression model incorporating age, race and sex and stratified by 3M APR-DRG, hospital volume remained statistically associated with reduced mortality for 3M APR-DRG risk mortality subclasses 2 and 3 (comprising 78% of the population), but not subclasses 1 and 4. Conclusions: Neutropenic patients hospitalized in large-volume institutions have a substantially lower mortality and a higher likelihood of returning home compared to those hospitalized at low-volume institutions. The 3M APR-DRG risk-mortality score significantly modulates this effect. Our findings imply that the majority of neutropenic patients should be referred onto large volume cancer centers.

The purpose of this study was to assess pathological complete response and whether it serves a surrogate for survival among patients receiving neo-adjuvant doxorubicin–cyclophosphamide followed by paclitaxel for triple-negative breast cancer with respect to BRCA1 mutation status. From a neo-adjuvant systemic therapy database of 588 breast cancer cases, 80 triple-negative cases who had undergone BRCA genotyping were identified. Logistic regression model was fitted to examine the association between BRCA1 status and pathological complete response. Survival outcomes were evaluated using Kaplan–Meier method, differences between study groups calculated by log-rank test. Thirty-four BRCA1 carriers and 43 non-carriers were identified. The BRCA1 carriers had pathological complete response rate of 68 % compared with 37 % among non-carriers, p = 0.01. Yet this did not translate into superior survival for BRCA1 carriers compared with non-carriers. No difference in relapse-free survival were noted among those with or without pathological complete response in BRCA1 carriers regardless of pathological complete response status (Log-rank p = 0.25), whereas in the non-carrier cohort, relapse-free survival was superior for those achieving pathological complete response (Log-rank p < 0.0001). Response to neo-adjuvant systemic therapy differed in BRCA1-associated triple-negative breast cancer compared with triple-negative non-carriers, with a higher rate of pathological complete response. However, compared with non-carrier triple-negative breast cancer, pathological complete response was not a surrogate for superior relapse-free survival in BRCA1 patients. Future studies using specific chemotherapy regimens may provide further improvements in outcomes.

1023 Background: Pathological complete response (pCR) has been demonstrated to serve as a surrogate for outcome in patients receiving neo-adjuvant systemic therapy (NAT) for triple negative (TN) breast cancer (BC). To date no data has been published to establish if this is also true for BRCA1/BRCA2mutation carriers with TNBC. Methods: From a prospective NAT database of 588 BC cases, 80 TN cases who had undergone BRCA genotyping were identified. All received dose-dense chemotherapy with an anthracycline and a taxane. pCR was defined as absence of invasive disease in breast and lymph nodes. A logistic regression model was fitted to examine association between BRCA1/2 status and pCR. Survival outcomes were evaluated using Kaplan-Meier method, differences between study groups calculated by log-rank test. Results: 37 BRCA1/2 carriers and 43 non-carriers were identified. The BRCA1/2 carriers had superior pCR compare with non-carriers (61% vs. 39% , p=0.007). Despite the higher pCR, there was no difference in Relapse Free Survival (RFS) between the BRCA1/2 carriers and non-carriers. Amongst those that achieved pCR there was superior RFS for non-carriers compared with BRCA1/2 carriers (Log-rank p=0.043). Conversely, amongst those that did not achieve a pCR, the RFS was superior amongst BRCA1/2 carriers (Log-rank p=0.024). No difference in RFS were noted amongst BRCA1/2 carriers with or without pCR (Log-rank p=0.712), while in the non-carrier group RFS was superior for those achieving pCR compared with those not displaying a pCR (Log-rank p<0.0001). Preliminary translational data demonstrate ALDH1 over-expression in the BRCA1/2 carriers pre-treatment biopsies but not in the non-carriers. Conclusions: BRCA1/2 associated TN BC differs to non-BRCA TN in chemo-sensitivity as demonstrated by superior pCR, We demonstrate here for the first time that pCR in BRCA1/2 carriers, is not a surrogate for RFS as opposed to pCR in non-BRCA TN BC. The chemo-sensitivity in BRCA associated TNBC may increase the mutational spectrum in these tumors due to predisposition to DNA breaks, resulting in selection of more aggressive, metastases prone clones, in addition, BRCA1/2 tumors may be enriched for breast cancer stem cells.

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Objective: To evaluate the safety and efficacy of tamoxifen co-administration during conventional controlled ovarian hyperstimulation (COH) protocols for a fertility-preservation IVF cycle in breast cancer patients.Design: Two groups: retrospective descriptive cohort study and prospective study.Setting: Breast cancer oncology and fertility-preservation centers in a tertiary hospital.Patient(s): Two groups of breast cancer patients: premenopausal patients treated with adjuvant tamoxifen; and patients undergoing in vitro fertilization (IVF) for fertility preservation.Intervention(s): Fertility-preservation cycles, tamoxifen co-administration during conventional IVF.Main Outcome Measure(s): Endocrine records, and IVF results.Result(s): Estradiol (E-2) levels were chronically high (mean 2663 pmol/L, maximum: 10,000 pmol/L) in 38 of 46 breast cancer patients treated with adjuvant tamoxifen. Co-administration of tamoxifen (48 cycles) during conventional IVF or without tamoxifen (26 cycles), using either the long gonadotropin-releasing hormone-agonist or-antagonist protocols, resulted, respectively, in a mean of 12.65 and 10.2 oocytes retrieved, and 8.5 and 6.4 embryos cryopreserved. Average peak E-2 levels were 6,924 pmol/L and 5,093 pmol/L, respectively, but long-term recurrence risk (up to 10 years) was not increased.Conclusion(s): In breast cancer patients, co-administration of tamoxifen during conventional COH for fertility preservation does not interfere with IVF results. The high serum E-2 levels during COH should be considered safe, as it simulates the high prevalence of persistently high serum E-2 levels in premenopausal breast cancer patients safely treated with adjuvant tamoxifen. (C) 2014 by American Society for Reproductive Medicine.

ABSTRACT Introduction Magnetic Resonance guided Focused Ultrasound (MRgFUS) is a non-invasive, non-ionizing treatment for thermal ablation of tumors. The technology uses high intensity focused ultrasound ablation combined with continuous MR imaging to denervate pain. Precise targeting of the lesion and real time monitoring of tissue temperature rise are cornerstones of the technique. We present here results of multiple multi-center studies evaluating the safety and effectiveness of MRgFUS for painful bone metastases. Methods 93 patients with painful bone metastases underwent MRgFUS in 14 medical centers worldwide. Treated lesions had to be remote from nervous structures or joints. Effectiveness of pain palliation was evaluated with a standardized 11-point pain rating scale (0-no pain/10-worst pain) and by monitoring changes in pain-relieving medication. A reduction of 2 points or more was considered a significant response. Safety events were recorded and evaluated by severity. Results of 31 patients treated in initial safety studies were previously reported by Liberman et al (Ann Surg Oncol. 2009 Jan; 16(1):140-6). Results 107 procedures were performed, targeting 96 lesions in 93 patients. 3 patients were treated twice targeting a different lesion; another 11 patients underwent a second treatment due to large lesions. Patients were followed-up for a period of 3 months. Pain response was relatively rapid: within 3 days, on average, the clinical endpoint was met and maintained. Pain scores averaged 6.9 pre-treatment, decreased to 4.5 within 3 days post-treatment, to 3.3 at one month post-treatment, and further decreased to 2.6 at three month follow-up. There were no serious adverse events related to the treatment. 2 patients had mild skin erythema following the treatment and 5 patients (5%) had pain progression. Our updated results are similar to early reports. Conclusions The presented results clearly show that MRgFUS can provide a quick, effective and safe palliative therapy for patients suffering from painful bone metastases. Current results are consistent with initial reported results. Randomized trials are being conducted in patients as a first line treatment of painful bone metastases vs. radiation therapy and in patients who failed radiation therapy vs. sham. Disclosure L. Shay Levi: I work in InSightec as the global bone applications specialist. InSightec is the company sponsered these clinical trials. All other authors have declared no conflicts of interest.