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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. [ABSTRACT FROM AUTHOR]

The 21-gene Recurrence Score (RS) assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in early-stage estrogen receptor (ER)-positive breast cancer (BC). Long-term data from real-life clinical practice where treatment was guided by the RS result are lacking. We performed exploratory analysis of the Clalit Health Services (CHS) registry, which included all CHS patients with node-negative ER+ HER2-negative BC who underwent RS testing between 1/2006 and 12/2009 to determine 10-year Kaplan-Meier estimates for distant recurrence/BC-specific mortality (BCSM) in this cohort. The analysis included 1365 patients. Distribution of RS results: RS 0-10, 17.8%; RS 11-25, 62.5%; RS 26-100, 19.7%. Corresponding CT use: 0, 9.4, and 69.9%. Ten-year distant recurrence rates in patients with RS 0-10, 11-25, and 26-100: 2.6% (95% confidence interval [CI], 1.1-6.2%), 6.1% (95% CI, 4.4-8.6%), and 13.1% (95% CI, 9.4-18.3%), respectively ( P  < 0.001); corresponding BCSM rates: 0.7% (95% CI 0.1-5.1%), 2.2% (95% CI, 1.3-3.7%), and 9.5% (95% CI, 6.0-14.9%) ( P  < 0.001). When the analysis included patients treated with endocrine therapy alone (95.5/87.5% of patients with RS 0-10/11-25), 10-year distant recurrence and BCSM rates for RS 0-10 patients were 2.7% (95% CI, 1.1-6.5%) and 0.8% (95% CI, 0.1-5.3%), respectively, and for RS 11-25 patients, 5.7% (95% CI, 3.9-8.3%) and 2.0% (95% CI, 1.1-3.7%), respectively. For RS 11-25 patients, no statistically significant differences were observed in 10-year distant recurrence/BCSM rates between CT-treated and untreated patients; however, this should be interpreted cautiously since the number of events was low and patients were not randomized. In conclusion, in node-negative ER+ HER2-negative BC patients, where treatment decisions in real-life clinical practice incorporated the RS, patients with RS 0-25 (~80% of patients, <10% CT use) had excellent outcomes at 10 years. Patients with RS 26-100 had high distant recurrence risk despite CT use and are candidates for new treatment approaches., Competing Interests: Competing interestsS.M.S. reports receiving grant funding from Teva; receiving travel expenses from Genomic Health, Inc.; conducting research funded by Teva. N.B. reports receiving honoraria from Teva, and serving on the speaker’s bureau of Genomic Health. D.M.J., J.B., and S.S. report being employed by Genomic Health. D.M.J., J.B., and S.S. report having stock ownership in Genomic Health. S.S. reports having intellectual property interest in Genomic Health and a leadership role at Genomic Health. L.S.G. reports being employed by and holding stock options in Teva Pharmaceutical Industries Ltd. A.B.S. reports being a consultant/medical writer for Teva Pharmaceutical Industries Ltd., Genomic Health Inc. (including for the purpose of the current study), Bayer, and Roche. M.S., S.R., B.U., G.F., O.R., A.I., B.N., D.K., M.L., M.T., N.L., and D.B.G. declare no competing interests., (© The Author(s) 2019.)

Purpose: Though former evidence implies a correlation of breast cancer susceptibility gene ( BRCA ) mutation with reduced ovarian reserve, the data is yet inconsistent. Our aim was to investigate biomarkers of ovarian aging in a cohort of young healthy carriers of the BRCA mutation. We hypothesized that the role played by BRCA genes in aging pathways is not exclusive to the ovary., Experimental Design: Healthy female BRCA carriers, 40 years or younger and healthy male BRCA carriers, 50 years or younger, were enrolled in the study. Serum anti-mullerian Hormone (AMH), fibroblast growth factor-23 (FGF-23), Klotho and IL-1 were measured by enzyme-linked immunosorbent assay (ELISA). Ovarian AMH and protein kinase B (AKT) mRNA from BRCA carriers who underwent prophylactic oophorectomy and from age-matched, healthy, non-carriers who underwent partial oophorectomy due to benign conditions were analyzed by qPCR., Results: Thirty-three female (median age 35y) and 20 male (44y) BRCA carriers were enrolled into the study and matched to control non-carriers (34y and 43y, respectively). Serum AMH level was significantly lower in BRCA female carriers than in both non-carrier controls and age-matched nomograms. The levels of ovarian AMH and AKT mRNA were significantly lower in carriers than in controls. The systemic aging cytokines FGF-23, klotho and IL-1 displayed a differential expression in carriers of both genders. FGF-23 level was higher in carriers (P=0.06)., Conclusions: Our results suggest a link between BRCA mutation, accelerated ovarian aging and systemic aging-related pathophysiology., Competing Interests: CONFLICTS OF INTEREST The authors declare that there is no conflicts of interest.

The Recurrence Score® is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 ( N  = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors ≤ 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18-30, and 10.2% Recurrence Score ≥ 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18-30, and ≥ 31 group, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant-recurrence rates for N1mi/1 positive node/2-3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated ( n  = 27) and 2.9% in chemotherapy-untreated patients ( n  = 352); P  = 0.245. In Recurrence Score 18-30, recurrence rate in chemotherapy-treated patients ( n  = 102) was significantly lower than in untreated patients ( n  = 156) (1.0% vs. 9.7% P  = 0.019); in Recurrence Score ≤ 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated ( n  = 89) and 4.4% in chemotherapy-untreated patients ( n  = 488); P  = 0.521. In conclusion, our findings support using endocrine therapy alone in ER+ HER2-negative breast cancer patients with micrometastases/1-3 positive nodes and Recurrence Score < 18.

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 ( n  = 304) and 11-25 ( n  = 1037) (TAILORx categorizatio n ) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.

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.

Objective: Perceptions of the role of oncology medical staff in supporting bereaved families have evolved with the transition to interdisciplinary cancer care. We investigated the interactions between oncology professionals and bereaved families., Methods: This cross-sectional study involved all oncology medical staff at the Davidoff Center. Participants were given a questionnaire relating to bereavement follow-up. Responses were measured using a 5-point Likert scale., Results: Of 155 staff members, 107 filled questionnaires with <20% missing data and were included in the analysis (α = 0.799; corrected, α = 0.821). Respondents included physicians (35%), nurses (46%), social workers (7%), psychologists (4%), or unspecified (8%); 85% were Jewish, and 60% had ≥10 years of oncology experience. Most respondents thought that contacting bereaved families was important (73%), and that it provided closure for staff (79%); 41% indicated that they contacted >50% of the families of their deceased patients. Contacting bereaved families was considered the responsibility of the physicians (90%), nurses (84%), or social workers (89%). The main barriers to contacting bereaved families were emotional overload (68%) and lack of time (63%); 60% indicated a need for additional communication tools for bereavement follow-up. In a multivariate analysis, profession (physician vs. nurse), primary workplace (outpatient setting vs. other), and self-defined religion were significant variables with respect to the perceived importance of contacting bereaved families and to actually contacting them. Other factors (e.g., age, gender) were non-significant., Conclusions: Perspectives regarding bereavement actions differ significantly across medical professions, work settings, and self-defined religions. Additional guidance and education regarding bereavement actions is warranted., Competing Interests: The authors have declared that no competing interests exist.

Background: Women who carry the BRCA gene mutation have an up to 80% chance of developing cancer, primarily of breast and ovarian origin. Confirmation of carrier status is described by many women as an overwhelming, life-changing event. Healthy individuals harboring a BRCA mutation constitute a high risk population with unique needs, often overlooked by health authorities. As such, we felt the need to create a specialized service dedicated specifically to this high risk population. The clinic staff comprises an experienced multidisciplinary team of health professionals who can support the medical and emotional needs of this population. Since its inception in 2001 the clinic has served 318 women. The mean age of patients is 46 years. With a median follow-up of 46 months, 21 women have developed malignancies, including 17 breast cancers, 1 ovarian cancer and 3 additional cancers. All but one of the patients above the age of 40 underwent bilateral salpingo-oophorectomy (BSO). The median and mean ages at BSO were 46.5 and 48 years, respectively (range 33-68). However, only 28.3% underwent bilateral preventive mastectomy. A multidisciplinary clinic for BRCA mutation carriers provides a "home" for this unique population with unmet needs. The high rate of BSO in women before natural menopause indicates that both the medical community and this population are aware of international guidelines supporting this procedure. We believe that a dedicated clinic, with a multidisciplinary team, is likely to contribute to the health, quality of life and survival of BRCA carriers.

BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells.The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy.These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants.

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: We previously reported that chemotherapy-induced ovarian toxicity may result from acute vascular insult, demonstrated by decreased ovarian blood flow and diminished post-treatment anti-Müllerian hormone (AMH) levels. In the present study, we report the continuous prospective evaluation of ovarian function in that cohort., Methods: Patients (aged <43 years) with localized breast cancer were evaluated by transvaginal ultrasound prior to initiation of chemotherapy, immediately at treatment completion, and at 6 and 12 months after treatment cessation. Doppler flow velocity indices of the ovarian vasculature (resistance index [RI], pulsatility index [PI]) were visualized. Hormone markers of ovarian reserve were assessed at the same time points., Results: Twenty patients were enrolled in the study. Median age was 34 ± 5.24 years. Ovarian blood flow was significantly reduced immediately following chemotherapy (both RI and PI; p = .01). These parameters were partially recovered at later points of assessment (6 and 12 months after treatment); patients aged <35 years significantly regained ovarian blood flow compared with patients aged >35 years (p < .05). AMH dropped dramatically in all patients following treatment (p < .001) and recovered in only 10 patients. Hormone markers of ovarian reserve shortly after chemotherapy depicted a postmenopausal profile for most patients, accompanied by related symptoms. Follicle-stimulating hormone (FSH) levels recovered in 14 of 20 patients and significantly returned to the premenopausal range in patients aged <35 years (p = .04); 10 of 20 resumed menses at 12 months. The pattern of vascular impairment was lessened in patients treated with a trastuzumab-based protocol, although results did not reach statistical significance (p = .068)., Conclusion: Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Age may affect whether patients regain ovarian function, whereas recovery of blood flow and premenopausal FSH levels at later assessment was notable in patients aged <35 years., Implications for Practice: This study explored the role of vascular toxicity in mediating ovarian impairment and recovery following chemotherapy. Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Future studies are warranted to further characterize patterns of vascular toxicity of various chemotherapies in clinical practice and to assess the role of chemotherapy-induced vascular toxicity for specific end organs such as the ovary with systemic vascular effect. Elucidating the cause of impairment may facilitate development of measures to minimize vascular toxicity and consequences of acute vascular insult., (©AlphaMed Press.)

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.

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.

Background: The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC., Methods: RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled., Results: Thirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81-1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival., Conclusions: Our meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.

Background: Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer., Methodology/principal Findings: Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m(2) twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%)., Conclusions/significance: External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted., Trial Registration: ClinicalTrials.gov NCT01784393NCT01784393.

Background: Chemotherapy-related amenorrhea is a frequent side effect observed in young breast cancer patients. Studies in mice revealed that chemotherapy-induced gonadal toxicity may result from vascular damage. We prospectively evaluated ovarian blood flow and function in young breast cancer patients following chemotherapy., Methods: Young female patients with localized breast cancer undergoing adjuvant or neoadjuvant anthracycline- or taxane-based chemotherapy were evaluated using transvaginal ultrasound prior to initiation of and immediately after cessation of chemotherapy. Doppler-flow velocity indices of the ovarian vasculature-resistance index (RI), pulsatility index (PI)-and size measurements were visualized. Hormonal profiles, anti-Müllerian hormone (AMH) levels, and menopausal symptoms were assessed at the same time points., Results: Twenty breast cancer patients were enrolled in the study. The median age was 34 ± 5.24 years. Ovarian blood flow was significantly reduced shortly following chemotherapy: RI decreased by 52.5% and PI decreased by 24.2%. The mean ovarian size declined by 19.08%. Patients who were treated with sequential chemotherapy experienced further reductions in ovarian blood flow and ovarian size after the second sequence. AMH levels dropped dramatically in all patients following treatment. Hormonal profiles after treatment depicted a postmenopausal profile for most patients, accompanied by related symptoms., Conclusions: Our results may imply a mechanism of chemotherapy-induced ovarian toxicity manifested by decreased ovarian blood flow accompanied by a reduction in ovarian size and diminished post-treatment AMH levels. Based upon our former preclinical studies, we assume that this may derive from an acute insult to the ovarian vasculature and may represent an initial event triggering a generalized phenomenon of end-organ toxicity.

Background: Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries., Methods: Female mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin., Results: A single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment., Conclusions: Our results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.

Background: Post-mastectomy loco-regional radiation to the chest wall and draining lymphatics, combined with adjuvant chemotherapy and hormonal therapy, significantly improve survival in patients with node-positive breast cancer. However, the actual benefit of post-mastectomy radiotherapy and the desired extent of treatment are still debatable., Objectives: To examine the effect of postoperative loco-regional radiotherapy on local and regional recurrence and survival in breast cancer patients with four or more involved lymph nodes or extracapsular tumor extension., Methods: This controlled clinical trial included 258 breast cancer patients with four or more involved nodes or ECE. Eighty-nine patients in the control group had modified radical mastectomy and received adjuvant chemotherapy with melphalan and 5FU, but no radiation therapy. The 169 patients in the study group (87 with MRM and 82 with lumpectomy and axillary dissection) received various adjuvant chemotherapy regimes and radiation therapy to the chest wall/breast, supraclavicular region and full axilla., Results: With an average follow-up of more than 5 years, loco-regional radiation significantly reduced local and regional disease recurrence. The median disease-free survival was significantly longer in radiated patients (59.2 months and 63.3 months in the MRM and L+AXLND groups, respectively, vs. 28.4 months in the control group; P < 0.01). There was no difference in the rate of systemic recurrence and overall survival. The median overall survival was 71.2 and 67.5 months in the study groups (MRM and L+AXLND, respectively) and 70.5 months in the control group (P = 0.856)., Conclusions: Radiotherapy to the breast/chest wall and to the draining lymphatics, in addition to surgery and adjuvant therapy, significantly reduced the risk of local and regional recurrence in high risk breast cancer patients with four or more involved lymph nodes or ECE.

Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients., Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls., Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212 sporadic and 56 carriers of either a BRCA1 or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent autoradiography., Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only (3/536, 0.6%)., Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.

The site of the first detectable recurrence was recorded in 17 consecutive stage II-IV ovarian carcinoma patients who, after a negative second-look laparotomy, received intraperitoneal chemotherapy with cisplatin and thiosulfate kidney protection. Although the progression-free interval and survival were favorable, 11 patients eventually had a recurrence and in six (54.5%) of these it was extraperitoneal. Brain metastases were detected in three patients. The appearance of extraperitoneal metastases is not always ominous.