Ten-year clinical outcomes in N0 ER+ breast cancer patients with Recurrence Score-guided therapy.

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.

Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?

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.

Clinical outcomes in ER+ HER2 -node-positive breast cancer patients who were treated according to the Recurrence Score results: evidence from a large prospectively designed registry.

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.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry.

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 categorization) 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.

The association between smoking and breast cancer characteristics and outcome.

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.

The Association between Treatment for Metabolic Disorders and Breast Cancer Characteristics.

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.

Factors Affecting Communication Patterns between Oncology Staff and Family Members of Deceased Patients: A Cross-Sectional Study.

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.

Earlier Age of Breast Cancer Onset in Israeli BRCA Carriers-Is it a Real Phenomenon?

Data on genetic anticipation in breast cancer are sparse. We sought to evaluate age at diagnosis of breast cancer in daughters with a BRCA mutation and their mothers. A review of all carriers of the BRCA mutation diagnosed with breast cancer at the Genetics Institute of a tertiary medical center in 2000-2013 yielded 80 women who could be paired with a mother with breast cancer who was either a carrier of the BRCA mutation or an obligate carrier according to pedigree analysis. Age at diagnosis, type of mutation (BRCA1, BRCA2), year of birth, and ethnicity were recorded. Paired t-test was used to analyze differences in age at cancer diagnosis between groups and subgroups. Mean age at diagnosis of breast cancer was 50.74 years (range 22-88) in the mothers and 43.85 years (range 24-75) in the daughters. The difference was statistically significant (p < 0.001). These findings were consistent regardless of type of BRCA mutation, ethnicity, or mother's year of birth. However, on separate analysis of pairs in which the mother was diagnosed before the age of 50 years, there was no significant difference in mean age at diagnosis between mothers and daughters (~42 years for both). Daughters who carry a BRCA mutation are diagnosed with breast cancer at an earlier age than their carrier mothers, with the exception of pairs in which the mother was diagnosed before the age of 50 years. Future breast-screening guidelines may need to target specific subpopulations of BRCA mutation carriers.

A Dedicated Follow-Up Clinic for BRCA Mutation Carriers.

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.

Long-Term Follow-Up of Chemotherapy-Induced Ovarian Failure in Young Breast Cancer Patients: The Role of Vascular Toxicity.

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.