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.

Abstract Background: The 21-gene Recurrence Score (RS) Assay (Oncotype DX®) is a validated prognosticator and predictive of chemotherapy (CT) benefit in patients with hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In Israel, the RS assay has been reimbursed by Clalit Health Services (CHS, the largest HMO in Israel) since 2006, and the assay is widely used in eligible estrogen receptor (ER)+ patients. Notably, ER+ breast cancer patients have a protracted risk of recurrence with approximately half of all distant recurrences occurring after 5 years from diagnosis. The goal of the current ongoing analysis was to investigate early (≤5 years) and late (>5 years) distant recurrence in N0/N1mi ER+ HER2-negative breast cancer patients who were RS-tested through CHS. Methods: This analysis of the CHS registry included breast cancer patients with ER+ HER2-negative N0/N1mi disease who underwent RS testing from 1/2006 (CHS approval of the assay) through 1/2009. Data sources included CHS claims arms (for patient/tumor characteristics), Teva Pharmaceuticals (for tumor characteristics, RS result), and medical records (for treatment/recurrence/survival). The study was approved by the institutional review boards of the CHS Community Division and was granted a waiver for obtaining patient consent. Results: The analysis included 1026 patients with median (interquartile range) follow up of 9.3 (8.8-10.2) years. Most patients were females (99%). Median (range) age was 59 (25-84) years; 92% had N0 and 8% had N1mi disease; 14%, 52%, and 16% had grade 1, 2, and 3 tumors, respectively (grade information was not available for 18% of patients); median (range) tumor size was 1.5 (0.3-6.5) cm. The majority of patients (78%) had invasive ductal carcinoma and 12% had invasive lobular carcinoma. Overall, 489 patients (48%) had RS<18, 434 (42%) had RS 18-30, and 103 (10%) had RS≥31. The use of adjuvant CT was consistent with the RS result: 3%, 27%, and 90% of RS<18, RS 18-30, and RS≥31 patients, respectively. Overall, 25 distant recurrences were reported within 5 years of RS testing: 5 (1.0%) in RS<18 patients, 9 (2.1%) in RS 18-30 patients, and 11 (10.6%) in RS≥31 patients. In the first 5 years, breast cancer-specific death was reported in 8 patients including 3 (0.7%) with RS 18-30 and 5 (4.9%) with RS≥31 results. Among N0 patients with RS 11-25 who did not receive adjuvant CT (n = 540), 5 (0.9%) distant recurrences and one (0.2%) breast cancer death were reported within 5 years of RS testing. Analysis of 'late' recurrences and breast cancer-specific death (from 5 to 9.3 years of follow-up) is ongoing. Conclusions: These will be the first late recurrence data from over 1000 patients for whom the RS result was used in real-life clinical decision making. Consistent with previous analyses of the CHS registry, CT use was appropriately based on the RS result, and the recurrence/survival outcomes (for the first 5 years) demonstrated the prognostic performance of the RS. Distant recurrence and breast cancer death data beyond 5 years will be presented at the meeting. Citation Format: Stemmer SM, Rizel S, Steiner M, Geffen DB, Soussan-Gutman L, Bareket-Samish A, McCullough D, Svedman C, Nisenbaum B, Ryvo L, Peretz T, Fried G, Rosengarten O, Liebermann N, Ben Baruch N. Real-life analysis evaluating >1000 N0/N1mi estrogen receptor (ER)+ breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score (RS) result: Clinical outcomes with median follow up of > 9 years [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-14.

Abstract 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<0.001) and more advanced stage at diagnosis (p<0.001). These findings remained significant on multivariate analysis. Patients treated with ARB had worse 5-year breast cancer specific survival (94.7% vs. 98.8%, P=0.024) and worse 5-year overall survival (94.6% vs. 98.8%, p=0.015), but these differences were not demonstrated on multivariate analysis (p=0.251 and p=0.441. respectively). 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<0.0013763<0.001ACEI (93)1.93 (0.93)0.0048.50.86363.835.10.355MRA (14)1.88 (0.67)0.32914.30.36357.142.90.907BB (115)1.77 (0.95)0.21613.20.08766.731.60.0911Macroscopic nodes: lymph node metastases> 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.

543 Background: Elderly BC pts are generally undertreated, despite evidence suggesting that they may benefit from adjuvant chemotherapy (CT). We compared treatments/clinical outcomes in elderly vs younger Clalit Health Services (CHS) pts undergoing RS testing. Methods: This exploratory analysis of the CHS registry included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 (CHS approval of the test) through 12/2010 (N0) or 12/2011 (N1mi/N1). Medical records were reviewed to verify treatments/recurrences/survival. Results: The analysis included 458 elderly and 2052 younger pts, with a median (range) follow-up of 5.7 (0.9-9.6) and 6.1 (0.1-10.3) yrs, respectively. In the elderly/younger pts, median age was 73/58 yrs, 48%/52% had grade 2 tumors, median tumor size was 1.6/1.5 cm, 70%/72% were N0 and 30%/28% were N1mi/N1. RS distribution (<18, 18-30, ≥31) among elderly pts was 56%, 33%, and 11%, respectively, compared to 49%, 41%, and 10%, respectively, in younger pts. In pts with RS 18-30 and RS≥31, CT use was significantly lower in the elderly ( P<.001). Kaplan-Meier estimates for 5-yr distant recurrence and BC death risk are presented (Table). Conclusions: In elderly pts, the proportion of those with RS≥31 was very similar to younger pts; however, overall CT use was significantly lower. Within each RS group, there was no statistically significant difference in clinical outcomes between the age groups; though, numerically, in RS 18-30 pts, outcomes were worse in the elderly. In pts with RS<18, outcomes were excellent regardless of age and despite very low rates of CT use. [Table: see text]

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

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.

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.

1077 Background: Lately, updated data led the medical community to reconsider the use of intensive CT with stem-cell support for selected groups of BC patients (pts). Herein, we provide an update on a study investigating the efficacy, feasibility, and toxicity of high-dose CT with stem-cell support in pts with high-risk stage II, chemosensitive stage III and IV BC. Methods: The protocol offered adjuvant/neoadjuvant/induction doxorubicin-based CT, 75-90 mg/m2 X 4 courses followed by high-dose CT (cyclophosphamide 6000 mg/m2, carboplatin 800 mg/m2, and thiotepa 500 mg/m2) and autologous stem cell support with growth factors. Post-transplant local radiotherapy was delivered. Pts who were hormone receptor (HR) positive received Tamoxifen. Results: From 2/1994 to 11/1998, 292 BC pts were referred to the study from all Israeli oncology centers. Median follow-up from transplant was 20 (range, 18-22) years; 119 had stage 2 disease (42 with 4-9 positive nodes, 77 with ≥10 positive nodes); 87 had stage 3 disease, of whom 50 had locally advanced/inflammatory BC treated with neoadjuvant CT; and 86 had chemosensitive stage IV BC. Two acute transplant-related deaths and one death due to late transplant-related toxicity were reported. Median age at transplant was 45 (range, 24-63) years. Overall survival (OS) by HR status is presented in the table. In total, 167 of the 292 pts died (based on death status data retrieved from the Registry of the Ministry of the Interior), representing OS of 42%. The OS rates for stage II, III, and IV were 55%, 45%, and 23%, respectively. Conclusions: Long-term accurate follow-up of pts receiving well-defined treatments remains an important tool in cancer research. High-dose CT with stem-cell support could represent a therapeutic/curative option in select BC patients in all disease stages. Reintroduction of this approach should be re-examined. [Table: see text]

e12053 Background: The RS assay is widely used to guide treatment decisions in ER+ HER2-negative early BC regardless of tumor histology. However, the RS validation studies did not include an analysis by histologic subtype. We investigated treatments/clinical outcomes in RS-tested Clalit Health Services (CHS) patients (pts) by histologic subtype, focusing on invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). Methods: This exploratory analysis of the CHS cohort included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 through 12/2010 (N0) or 12/2011 (N1mi/N1). Data from medical records were analyzed to assess risks of distant recurrence and BC death by histologic subtype. Results: The cohort included 2510 pts: 2060 (82%) IDC, 298 (12%) ILC, and 152 (6%) unknown/others. Median follow up for IDC/ILC pts was 6.0/6.1 yrs. Median age in IDC/ILC pts was 60/62 yrs; median tumor size was 1.5/1.8 cm; 71%/71% were N0, and 29%/29% were N1mi/N1. RS distribution (<18, 18-30, ≥31) was 50%, 39%, and 11%, respectively for IDC pts and 48%, 48%, and 4%, respectively, for ILC pts. Chemotherapy (CT) use for each RS group was similar between IDC and ILC pts; 5-yr Kaplan-Meier estimates for the risk of distant recurrence and BC death differed significantly across RS groups in both IDC and ILC; clinical outcomes for IDC and ILC pts were similar within risk groups see Table. Conclusions: For both IDC and ILC pts, treatment was aligned with the RS results. Within each RS group, there was no difference in clinical outcomes between these histologic subtypes, however the number of pts with ILC and RS≥31 was limited. [Table: see text]

Recent outcome data including those from the prospective TAILORx trial strongly confirmed the RS role in node negative (N0) ER+ BC. The prospective WSG PlanB study showed excellent outcomes in high-risk N0 and node-positive (N+) pts with RS ≤ 11 and no adjuvant chemotherapy (CT). Physicians are increasingly using the RS for treatment decisions in N+ BC. We evaluated treatment and clinical outcomes in N+ pts undergoing RS testing through Clalit Health Services (CHS). Medical records of all CHS pts with N+ ER+ HER2- BC who were tested between 1/2008 and 12/2011 were reviewed to verify treatment given and recurrence/death status. Interim results are presented herein. Final cohort results (>700 pts) will be presented at the meeting. The current analysis includes 627 pts. Median age, 61 (34-87) yrs; 270 (43%) were N1mi, whereas 231 (37%) and 126 (20%) had 1 and 2-3, positive nodes, respectively. Grade 1 (15%), 2 (53%), 3 (16%), N/A (16%); histology, IDC (82%), lobular (12%), other (6%). With a median follow-up of 5.7 yrs, proportion of patients with distant recurrence (DR)/BC death by Paik et al and TAILORx RS categorization and by nodal status are presented in the Table. As pts were not randomized to treatment, analysis of DR/BC death by CT use is only exploratory: within the RS 18-30 group, CT-untreated pts (60%) had DR rate and BC death rate of 9.6% and 3.7%, respectively, whereas in CT-treated pts (40%) these rates were 2.2% and 1.1%; within the RS 11-25 group, CT-untreated pts (82%) had DR rate and BC death rate of 4.1% and 1.2%, respectively, whereas in CT-treated pts (18%) these rates were 2.7% and 0%. Tabled 1CT use, %DR rate, %BC death rate, %Paik et al RS categorizationRS < 18N1mi (n = 146)50.70.71 positive node (n = 128)104.70.02-3 positive nodes (n = 65)86.23.1Total (n = 339)73.20.9RS: 18-30N1mi (n = 93)3710.83.21 positive node (n = 81)473.72.52-3 positive nodes (n = 53)383.81.9Total (n = 227)406.62.6RS ≥ 31N1mi (n = 31)9719.416.11 positive node (n = 22)8618.213.62-3 positive nodes (n = 8)750.00.0Total (n = 61)9016.413.1TAILORx RS categorizationRS < 11N1mi (n = 45)42.22.21 positive node (n = 37)145.40.02-3 positive nodes (n = 20)010.05.0Total (n = 102)74.92.0RS: 11-25N1mi (n = 169)144.11.21 positive node (n = 152)203.30.02-3 positive nodes (n = 90)224.42.2Total (n = 411)183.91.0RS > 25N1mi (n = 56)8216.110.71 positive node (n = 42)8314.311.92-3 positive nodes (n = 16)690.00.0Total (n = 114)8113.29.6 Open table in a new tab CT use was aligned with the RS results. Pts with N1mi or 1-3 positive nodes and RS ≤ 25 had very good outcomes, even when selected for endocrine therapy alone. Updated data will be presented at the meeting.

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.

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

Abstract Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha'emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of <18, 18-30, ≥31): low (51%), intermediate (38%), and high (11%), with chemotherapy (CT) use of 1%, 26%, and 89%, respectively. Distant recurrence was reported in 17/813, 33/612, and 24/169 patients in the low, intermediate, and high Recurrence Score groups, respectively. In the high Recurrence Score group, distant recurrence was reported in 20/150 (13.3%) of CT-treated patients and in 4/19 (21.1%) of untreated patients. In the intermediate Recurrence Score group, the respective values were 9/162 (5.6%) and 24/450 (5.3%). The 5-year KM estimate for distant recurrence rate was 1.4% (95% CI: 0.9-2.3%) for the entire cohort, and 0.5% (95% CI: 0.2-1.6%), 1.2% (95% CI: 0.6-2.8%), and 6.9% (95% CI: 3.7-12.9), for the low, intermediate, and high Recurrence Score groups, respectively. The 5-year KM estimate for breast cancer specific survival was 98.4% (95% CI: 97.6-98.9%) for the entire cohort, and 99.9% (95% CI: 99.0-99.98%), 98.5% (95% CI: 97.1-99.2%) and 90.6% (95% CI: 84.5-94.4%), for the low, intermediate, and high Recurrence Score groups, respectively. Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-02.

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.

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.

Abstract Endocrine therapy targeting Estrogen receptor alpha (ERα) is a key therapeutic strategy for hormone-driven breast cancer. Resistance to endocrine therapy may be intrinsic, arising from different clones or acquired by evolution influenced by selective pressure conditioned by therapy. Emerging evidence points to the role of acquired ERα mutations in driving resistance, when detected in the metastases but were absent from primary tumor. Here we studied tumor genomic evolution in a patient who developed two distinct recurrent consequences. The first recurrence was located at the lung and developed 14 years from diagnosis. In the adjuvant setting, the patient was treated with chemotherapy and had no endocrine therapy incorporated. On initial recurrence, the patient was treated with aromatase-inhibitor which resulted in complete response and the site is free of tumor now for 5.7 years. However, 2 years into endocrine therapy with aromatase-inhibitor the patient developed a single hepatic metastasis and treatment was changed to fulvestrant for 8 months with slow ongoing progression. The patient had partial hepatectomy, cholecystectomy and metastatectomy 3 months after fulvestrant was stopped. Histology and immunohistochemical stains confirmed breast origin, ER +2, 100%, PR +3, 100%. The endocrine therapy resistant hepatic lesion was sequenced by hybrid capture Next Generation Sequencing (NGS) and ERα (D538G) mutation was detected along with PIK3CA and GATA3 typical for hormone+ breast cancer. We have studied the primary tumor by same NGS method and detected only the PIK3CA and GATA3 mutations. In the lung lesions, responsive for endocrine therapy when sequenced by NGS the ERα (D538G) resistant mutation was absent. Clinical data for treatment of ERα (D538G) mutation driving endocrine resistance is lacking. The patient could not tolerate tamoxifen and failed treatments with aromatase-inhibitor and chemotherapy, losing 14 kg in weight. Treatment with megestrol acetate 160 mg was initiated and patient achieved partial response confirmed by hepatic MRI and an improved performance status which is now ongoing for 8 months. This case represents the first evidence of heterogeneous response to endocrine therapy explained by presence/absence of ERα (D538G) resistant mutation along with evidence for an active treatment in not an uncommon scenario. Citation Format: Rizel S, Dvir A, Soussan-Gutman L. Spatial and temporal genomic heterogeneity of estrogen receptor and clinical impact in a patient with advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-15.

e12000 Background: Data regarding the impact of antihypertensive medications on breast cancer are inconsistent. We evaluated the association between antihypertensive medications on tumor characteristics and outcome for patients with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative early breast cancer, whose tumors were sent to Oncotype DX analysis. Methods: This was a retrospective, single center study. Patients' Charts were reviewed for demographics, clinicopathological parameters, chronic medications, treatment and outcome. Patients were grouped according to antihypertensive medications usage during the time of breast cancer diagnosis. Every group was compared to the rest of the cohort. Results: A total of 671 patients were included. Treatment with β-blockers (BB), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) were recorded in 17.5%, 14.2%, 7%, and 2.1% of the study population, respectively. Patients treated with ARB had different histological subtype distribution (p = 0.009), higher incidence of macroscopic nodal involvement (p < 0.001) and more advanced stage (p < 0.001). Interestingly, mean Ki67 was lower for these patients (p = 0.005). ACEI usage was associated with larger tumors (p = 0.004). Patients treated with either ARB or ACEI had larger tumors (p < 0.001), more macroscopic lymph node involvement (p = 0.03) and presented with more advanced stage (p < 0.001). They also had less intense progesterone receptor staining (p = 0.04) and different histological subtype distribution (p = 0.007). Patients treated with BB had higher incidence of angiolymphatic invasion (p = 0.002). MRA usage had no impact on examined characteristics. None of the medications evaluated in the study influenced disease free survival. Conclusions: ARB and ACEI usage was associated with worse tumor characteristics at presentation for patients with ER positive, HER2 negative early breast cancer. Further research is needed to validate our finding and to elucidate the effect of anti-hypertensive treatment in breast cancer.

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.

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.