Risk Of Primary Breast Cancer Research Articles

Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers: A Systematic Review and Meta-Analysis

Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59-1.21) or CBC risk (RR = 0.95, 95%CI: 0.65-1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18-0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68-1.17) or CBC risk (RR = 0.85, 95%CI: 0.59-1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07-1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41-0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30-0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers.

Perceptions of Breast Cancer Risks Among Women Receiving Mammograph Screening

Breast density is an independent risk factor for breast cancer. Despite the proliferation of mandated written notifications about breast density following mammography, there is little understanding of how women perceive the relative breast cancer risk associated with breast density. To assess women's perception of breast density compared with other breast cancer risks and explore their understanding of risk reduction. This mixed-methods qualitative study used telephone surveys and semistructured interviews to investigate perceptions about breast cancer risk among a nationally representative, population-based sample of women. Eligible study participants were aged 40 to 76 years, reported having recently undergone mammography, had no history of prior breast cancer, and had heard of breast density. Survey participants who had been informed of their personal breast density were invited for a qualitative interview. Survey administration spanned July 1, 2019, to April 30, 2020, with 2306 women completing the survey. Qualitative interviews were conducted from February 1 to May 30, 2020. Respondents compared the breast cancer risk associated with breast density with 5 other risk factors. Participants qualitatively described what they thought contributed to breast cancer risk and ways to reduce risk. Of the 2306 women who completed the survey, 1858 (166 [9%] Asian, 503 [27%] Black, 268 [14%] Hispanic, 792 [43%] White, and 128 [7%] other race or ethnicity; 358 [19%] aged 40-49 years, 906 [49%] aged 50-64 years, and 594 [32%] aged ≥65 years) completed the revised risk perception questions and were included in the analysis. Half of respondents thought breast density to be a greater risk than not having children (957 [52%]), having more than 1 alcoholic drink per day (975 [53%]), or having a prior breast biopsy (867 [48%]). Most respondents felt breast density was a lesser risk than having a first-degree relative with breast cancer (1706 [93%]) or being overweight or obese (1188 [65%]). Of the 61 women who were interviewed, 6 (10%) described breast density as contributing to breast cancer risk, and 43 (70%) emphasized family history as a breast cancer risk factor. Of the interviewed women, 17 (28%) stated they did not know whether it was possible to reduce their breast cancer risk. In this qualitative study of women of breast cancer screening age, family history was perceived as the primary breast cancer risk factor. Most interviewees did not identify breast density as a risk factor and did not feel confident about actions to mitigate breast cancer risk. Comprehensive education about breast cancer risks and prevention strategies is needed.

Risk of primary breast cancer in patients with differentiated thyroid cancer undergoing radioactive iodine therapy: a systematic review and meta-analysis.

Although it has been proven that radioactive iodine (RAI) treatment is an effective and well-tolerated procedure in patients with differentiated thyroid cancer (DTC), there is still some concern regarding the risk of developing a second primary malignancy after RAI administration. We performed a systematic review and meta-analysis to investigate the risk of primary breast cancer in patients with DTC undergoing RAI therapy. A comprehensive literature search of the PubMed, Scopus, and Web of Science databases was conducted according to the PRISMA statement. The final analysis included 14 studies accounting for a total of 200,247 patients with DTC (98,368 treated with RAI and 101,879 not treated with RAI). The relative risk of primary breast cancer in patients with DTC treated with RAI to those not treated with RAI among studies ranged from 0.45 to 2.55, the pooled relative risk was 0.83 (95% confidence interval, 0.70-0.99), and the heterogeneity was 71.5%. The present meta-analysis indicates that patients with DTC treated with RAI do not have a higher risk of primary breast cancer compared to those not treated with RAI. These findings suggest that RAI therapy does not increase the risk of breast cancer.

Evaluating the Age-Based Recommendations for Long-Term Follow-Up in Breast Cancer

BackgroundAfter 5 years of annual follow‐up following breast cancer, Dutch guidelines are age based: annual follow‐up for women <60 years, 60–75 years biennial, and none for >75 years. We determined how the risk of recurrence corresponds to these consensus‐based recommendations and to the risk of primary breast cancer in the general screening population.Subjects, Materials, and MethodsWomen with early‐stage breast cancer in 2003/2005 were selected from the Netherlands Cancer Registry (n = 18,568). Cumulative incidence functions were estimated for follow‐up years 5–10 for locoregional recurrences (LRRs) and second primary tumors (SPs). Risks were compared with the screening population without history of breast cancer. Alternative cutoffs for age were determined by log‐rank tests.ResultsThe cumulative risk for LRR/SP was lower in women <60 years (5.9%, 95% confidence interval [CI] 5.3–6.6) who are under annual follow‐up than for women 60–75 (6.3%, 95% CI 5.6–7.1) receiving biennial visits. All risks were higher than the 5‐year risk of a primary tumor in the screening population (ranging from 1.4% to 1.9%). Age cutoffs <50, 50–69, and > 69 revealed better risk differentiation and would provide more risk‐based schedules. Still, other factors, including systemic treatments, had an even greater impact on recurrence risks.ConclusionThe current consensus‐based recommendations use suboptimal age cutoffs. The proposed alternative cutoffs will lead to a more balanced risk‐based follow‐up and thereby more efficient allocation of resources. However, more factors should be taken into account for truly individualizing follow‐up based on risk for recurrence.Implications for PracticeThe current age‐based recommendations for breast cancer follow‐up after 5 years are suboptimal and do not reflect the actual risk of recurrent disease. This results in situations in which women with higher risks actually receive less follow‐up than those with a lower risk of recurrence. Alternative cutoffs could be a start toward risk‐based follow‐up and thereby more efficient allocation of resources. However, age, or any single risk factor, is not able to capture the risk differences and therefore is not sufficient for determining follow‐up. More risk factors should be taken into account for truly individualizing follow‐up based on the risk for recurrence.

Impact of 18F-FDG PET/MR on therapeutic management in high risk primary breast cancer patients – A prospective evaluation of staging algorithms

PurposeTo investigate whether potential differences in staging between a traditional staging imaging algorithm and 18F-FDG PET/MR lead to a change in patient management in breast carcinoma and to compare the diagnostic accuracy between the traditional staging algorithm and 18F-FDG PET/MR for the TNM classification. MethodIn this prospective cohort study from two university hospitals 56 women with newly diagnosed, therapy-naive breast cancer and increased pre-test probability for distant metastases were included. All patients were examined by a traditional staging imaging algorithm (X-ray mammography, breast ultrasonography, chest plain radiography, bone scintigraphy, and ultrasonography of the liver and axillary fossa) and whole-body 18F-FDG PET/MR including dedicated 18F-FDG PET/MR breast examinations. Each patient was discussed two times in a separate tumor board session to determine a total of three therapy recommendations based on histopathological data of the primary tumor and (1) traditional algorithm only, (2) traditional algorithm and 18F-FDG PET/MR, and (3) 18F-FDG PET/MR only. Major changes in therapy recommendations and differences between the traditional staging algorithm and 18F-FDG PET/MR for the TNM classification were evaluated. ResultsStaging by 18F-FDG PET/MR led to a difference in treatment compared the traditional staging algorithm in 8/56 cases (14%). Therapy changes included therapy of the breast, locoregional nodes and systemic therapy. A trend to staging superiority was found for 18F-FDG PET/MRI without statistical significance (p = 0.3827). ConclusionIn conclusion, for breast cancer patients with elevated pre-test probability for distant metastases a change of the therapy regiment occurs in 14 % of patients when staged by 18F-FDG PET/MR and confirmed by histopathology compared to a traditional staging algorithm. In particular with regard to the amendment of the guideline further assessment of 18F-FDG-PET/MR in this setting is necessary to assess the true value of this modality.

Bisphosphonates and primary breast cancer risk: an updated systematic review and meta-analysis involving 963,995 women.

ImportancePrevention of primary breast cancer (BCa) in women is of great public health importance. The existing results from observational epidemiologic studies focused on the association between bisphosphonates and primary BCa risk have been inconsistent.ObjectiveTo update this systematic review and meta-analysis to assess the effect of bisphosphonates on primary BCa risk.Data sourcesWe comprehensively searched MEDLINE, EMBASE, Cochrane libraries, ProQuest, and Web of Science through June 25, 2018 for relevant studies.Study selectionEpidemiological studies that assessed the effect of bisphosphonates on the risk of primary BCa in women.Data extraction and synthesisWe reported this meta-analysis according to the PRISMA guidelines. Available multivariable-adjusted effect estimates and corresponding 95% CIs were pooled with a random-effects model.Main outcomes and measuresThe prespecified main outcome was the risk of primary BCa.ResultsIn total, five cohort studies involving 657,558 women and 12,991 primary BCa patients, three population-based case-control studies involving 54,701 primary BCa cases and 237,962 healthy controls and two randomized controlled trials (RCTs) involving 13,774 women and 165 primary BCa patients were included in this meta-analysis. Bisphosphonates were associated with a 12% decreased risk of primary BCa (RR, 0.88; 95% CI, 0.83–0.94). However, when we analyzed study designs separately, the pooled results from observational studies were inconsistent with that from RCTs. The observed association of primary BCa risk with long-term use (≥1 year) of bisphosphonates seemed to be more robust and stronger than that of short-term use (<1 year) (RR, 0.75; 95% CI, 0.66–0.84; and 0.90; 95% CI, 0.84–0.97; respectively).ConclusionThis meta-analysis adds to the body of evidence for an association between bisphosphonates and a significantly decreased risk of primary BCa. However, future large-scale RCTs are required to validate this concern.

Population-Based Assessment of the Association Between Magnetic Resonance Imaging Background Parenchymal Enhancement and Future Primary Breast Cancer Risk.

To evaluate comparative associations of breast magnetic resonance imaging (MRI) background parenchymal enhancement (BPE) and mammographic breast density with subsequent breast cancer risk. We examined women undergoing breast MRI in the Breast Cancer Surveillance Consortium from 2005 to 2015 (with one exam in 2000) using qualitative BPE assessments of minimal, mild, moderate, or marked. Breast density was assessed on mammography performed within 5 years of MRI. Among women diagnosed with breast cancer, the first BPE assessment was included if it was more than 3 months before their first diagnosis. Breast cancer risk associated with BPE was estimated using Cox proportional hazards regression. Among 4,247 women, 176 developed breast cancer (invasive, n = 129; ductal carcinoma in situ,n = 47) over a median follow-up time of 2.8 years. More women with cancer had mild, moderate, or marked BPE than women without cancer (80% v 66%, respectively). Compared with minimal BPE, increasing BPE levels were associated with significantly increased cancer risk (mild: hazard ratio [HR], 1.80; 95% CI, 1.12 to 2.87; moderate: HR, 2.42; 95% CI, 1.51 to 3.86; and marked: HR, 3.41; 95% CI, 2.05 to 5.66). Compared with women with minimal BPE and almost entirely fatty or scattered fibroglandular breast density, women with mild, moderate, or marked BPE demonstrated elevated cancer risk if they had almost entirely fatty or scattered fibroglandular breast density (HR, 2.30; 95% CI, 1.19 to 4.46) or heterogeneous or extremely dense breasts (HR, 2.61; 95% CI, 1.44 to 4.72), with no significant interaction (P = .82). Combined mild, moderate, and marked BPE demonstrated significantly increased risk of invasive cancer (HR, 2.73; 95% CI, 1.66 to 4.49) but not ductal carcinoma in situ (HR, 1.48; 95% CI, 0.72 to 3.05). BPE is associated with future invasive breast cancer risk independent of breast density. BPE should be considered for risk prediction models for women undergoing breast MRI.

Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers

BackgroundThe effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.MethodsThe study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.ResultsOf the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46–1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39–1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60–2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.ConclusionNo evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.

Abstract P2-07-04: Risk of primary and contralateral breast cancer in BRCA1/2 mutation carriers previously affected with ovarian cancer

Abstract Introduction: BRCA1/2 mutation carriers are at increased risk of developing breast cancer (BC) and ovarian cancer (OC). However, for BRCA1/2 mutation carriers previously affected with OC, primary BC (PBC) and contralateral BC (CBC) risks might be lowered due to OC treatment, but data hereon are limited. Accurate BC risk estimates are essential for counseling and optimal decision making on BC surveillance and risk-reducing mastectomy (RRM) after diagnosis of BRCA1/2-associated OC. Methods: From the national HEBON cohort study, we selected female BRCA1/2 mutation carriers born from 1940 and at risk of PBC (n=2019; 1194 BRCA1, 825 BRCA2) or at risk of CBC (n=1276; 839 BRCA1, 437 BRCA2). Eligibility criteria for the PBC risk analyses included no history of PBC and both breasts in situ at DNA testing. For the CBC risk analyses, CBC before DNA testing was not allowed and the contralateral breast had to be unaffected at DNA testing. To estimate the association between OC and BC risk, we used the Fine and Gray regression model, with OC as a time-dependent variable and death as competing risk event. The observation started at the age of DNA testing, age 35, or – for the CBC risk analyses – age at PBC diagnosis, whichever came last. Censoring events were RRM, study closing date (i.e. 2014-12-31), and – for the CBC risk analyses – ipsilateral BC recurrence. All analyses were performed separately for BRCA1 and BRCA2 mutation carriers. Results: For the PBC analyses, we selected 236 BRCA1/2 mutation carriers with OC and 1783 BRCA1/2 mutation carriers without OC (median age at start study 53 and 41 years, respectively). During a mean follow-up (FU) of 5.2 years, 15 (6%) OC patients developed PBC after OC, while PBC was diagnosed in 262 (15%) women without OC. OC diagnosis was associated with a lower PBC risk in BRCA1 mutation carriers (HR, 0.27; 95% CI, 0.14–0.53) but not in BRCA2 mutation carriers (HR, 0.88; 95% CI, 0.34–2.27). The cumulative PBC incidence at age 70 in BRCA1 mutation carriers was 25% for OC patients and 66% for women without OC, and in BRCA2 mutation carriers 49% for OC patients and 53% for women without OC. For the CBC analyses, we selected 99 BRCA1/2 mutation carriers affected with PBC and OC, and 1177 BRCA1/2-associated PBC patients without OC (median age at start study 54 and 46 years, respectively). During a mean FU of 3.5 years, 8 (8%) PBC/OC patients developed CBC after OC, while CBC was diagnosed in 131 (11%) PBC patients without OC. In BRCA1 mutation carriers, OC diagnosis was non-significantly associated with a lower CBC risk (HR, 0.44; 95% CI, 0.19–1.03). For BRCA2 mutation carriers the HR was 1.65 (95% CI, 0.34–8.04). The cumulative CBC incidence at age 70 in BRCA1 mutation carriers was 40% for OC patients and 68% for patients without OC; for BRCA2 mutation carriers the number of CBCs was too small to obtain meaningful estimates. Conclusion:­ For BRCA1 mutation carriers affected with OC the risk of developing subsequent BC is lower than for BRCA1 mutation carriers without OC. Our data suggest that the current BC prevention strategies should be reconsidered for OC patients carrying a BRCA1 mutation, possibly including less intensive BC surveillance, and RRM being indicated only for a subgroup of OC patients. Citation Format: Heemskerk-Gerritsen BAM, Hooning MJ, van Doorn HC, Collée MJ, Koppert LB, Jager A, van den Ouweland AMW, Netherlands H, Seynaeve C, Kriege M. Risk of primary and contralateral breast cancer in BRCA1/2 mutation carriers previously affected with ovarian cancer [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 P2-07-04.

Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized ADEBAR trial

BackgroundThe recommendation for adjuvant dose-dense chemotherapy in high risk primary breast cancer is heterogeneous among guidelines. Understanding the impact on QoL is thereby a crucial factor, especially if the benefit is potentially low. This study aims to assess QoL as a secondary outcome in the prospective randomized multi-center ADEBAR trial. MethodsQoL was assessed at baseline (t1), before cycle 4 FEC and cycle 5 EC-DOC (t2), 4 weeks after chemotherapy (t3) and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). Results1306 patients were enrolled into the ADEBAR trial. 675 were assigned to the FEC and 688 to the EC-DOC arm. After the beginning of treatment, global QoL dropped in both arm by 3–4 points. In the EC-DOC arm, QoL dropped further at t3 by 7 points and stayed stable in the FEC arm. 6 weeks after radiation, QoL exceeded baseline in both arms by 6–8 points. The differences between treatment arms were strongest at t3 (53.0 vs. 49.5) but did not reach clinical relevance at any point in time. Physical functioning, nausea and vomiting, fatigue and systemic therapy side effects followed with some minor exceptions similar patterns but showed higher amplitudes. ConclusionIn conclusion, we could not detect a clinically relevant difference between the two treatment arms in global QoL, although the results consistently show that patients on EC-DOC report worse scores during the treatment.

Abstract P1-12-03: Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized Adebar trial

Abstract Background: The grade of recommendation for adjuvant dose-dense chemotherapy in patients with high risk primary breast cancer is heterogeneous among international guidelines. Understanding the impact on quality of life (QOL) by adjuvant dose dense chemotherapy in comparison to standard adjuvant chemotherapy is thereby a crucial factor, especially if the benefit is potentially low. This study aims to assess the impact on QOL by adjuvant dose dense chemotherapy in the prospective randomized multi-center ADEBAR trial. Methods: QOL was assessed at baseline (t1), before cycle 4 FEC (Epirubicin 60mg/m2 i.v. d 1 + 8, 5-Fluoruracil 500mg/m2 i.v. d 1 + 8, Cyclophosphamide 75mg/m2 p.o. d 1–14, q4w x 6) and cycle 5 EC-DOC (Epirubicin 90mg/m2 plus Cyclophosphamide 600mg/m2 q3w x 4, sequentially followed by Docetaxel 100mg/m2 q3w x 4) (t2), 4 weeks after chemotherapy (t3), 6 weeks after radiation (t4) and 1 year after baseline (t5) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). A multivariate mixed model was fitted to test for differences between the two treatment arms. Primary endpoint was global QOL, secondary endpoints physical functioning, nausea&amp;vomiting, fatigue and systemic therapy side effects. A minimum clinically meaningful difference was considered to be 10 points. Results: 1306 patients were recruited between 3/2002 and 5/2005 675 were assigned to the FEC and 688 to the EC-DOC arm. Compliance to QOL assessment was 74% at baseline and 58% four weeks after therapy, but dropped to 11% after one year follow up. After the beginning of treatment global QOL dropped in both arm by 3 to 4 points. In the EC-DOC arm QOL dropped further at t3 by 7 points and stayed stable in the FEC arm. 6 weeks after radiation QOL exceeded baseline in both arms by 6 to 8 points. The differences between treatment arms were strongest at t3 (54.1 vs. 49.7) but did not reach clinical relevance at any point in time. Physical functioning, nausea vomiting, fatigue and systemic therapy side effects followed with some minor exceptions similar patterns, but showed higher amplitudes. Conclusion: In conclusion we could not detect a statistically significant difference between the two treatment arms in QOL parameters, indicating that dose dense adjuvant chemotherapy did not impact QOL at a clinically relevant level compared to standard adjuvant chemotherapy. Citation Format: Schwentner L, Harbeck N, Singer S, Eichler M, Rack B, Forstbauer H, Wischnik A, Scholz C, Fink V, Huober J, Friedl T, Weissenbacher T, Härtl K, Kiechle M, Janni W. Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized Adebar trial. [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 P1-12-03.

Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer.

Trials demonstrate the efficacy of medications to reduce the risk for invasive breast cancer. To summarize benefits and harms of tamoxifen citrate, raloxifene, and tibolone to reduce the risk for primary breast cancer. MEDLINE and Cochrane databases from inception to January 2009, Web of Science, trial registries, and manufacturer information. Predefined eligibility criteria were used to select articles. English-language reports of randomized, controlled trials (RCTs) for benefits and RCTs and observational studies for harms were included. Two reviewers assessed study data, quality, and applicability. Seven placebo-controlled RCTs and 1 head-to-head trial provide results for main outcomes. Tamoxifen (risk ratio, 0.70 [95% CI, 0.59 to 0.82]; 4 trials), raloxifene (risk ratio, 0.44 [CI, 0.27 to 0.71]; 2 trials), and tibolone (risk ratio, 0.32 [CI, 0.13 to 0.80]; 1 trial) reduce risk for invasive breast cancer compared with placebo by 7 to 10 per 1000 women per year. Tamoxifen and raloxifene reduce estrogen receptor-positive breast cancer but not estrogen receptor-negative breast cancer, noninvasive breast cancer, or mortality. All medications reduce fractures. Tamoxifen (risk ratio, 1.93 [CI, 1.41 to 2.64]; 4 trials) and raloxifene (risk ratio, 1.60 [CI, 1.15 to 2.23]; 2 trials) increase thromboembolic events by 4 to 7 per 1000 women per year; raloxifene causes fewer events than tamoxifen. Tamoxifen increases risk for endometrial cancer (risk ratio, 2.13 [CI, 1.36 to 3.32]; 3 trials) compared with placebo by 4 per 1000 women per year and causes cataracts compared with raloxifene. Tibolone causes strokes in older women. Bias, trial heterogeneity, and a dearth of head-to-head trials limit this review. Data are lacking on doses, duration, and timing of the medications; long-term effects; and nonwhite and premenopausal women. Three medications reduce risk for primary breast cancer but increase risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone).

Abstract S3-04: The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer

Abstract Background: Although approximately 50% of newly diagnosed breast cancers arise in women above 65 years old they are underrepresented in clinical trials. The ICE study was designed to investigate if a mono-chemotherapy with capecitabine in addition to the third generation bisphosphonate ibandronate will improve the outcome compared to ibandronate alone in elderly breast cancer patients with medium and high risk primary breast cancer not suitable for standard chemotherapy. Methods: This is a prospective, multi-center, controlled, open-label, randomized phase III trial. Female patients ≥ 65 years with unilateral or bilateral breast cancer who are either node-positive or high-risk node-negative (tumor size ≥2 cm, grade &amp;gt;I, and/or ER-and PR-negative); and a Charlson Comorbidity Index (CMI) ≤2 received either ibandronate alone for 2 years, 50 mg p.o. daily alternatively 6 mg i.v. every 4 weeks or the same ibandronate regimen together with capecitabine 2000 mg/m2 on day 1 – 14 q day 22 for 6 cycles to be started within 6 months after axillary dissection. Patients with hormone-sensitive disease received an endocrine therapy according to guidelines. The primary objective is disease-free survival. A total of 1,394 patients were needed (5-year DFS improvement from 65% with ibandronate to 71.5% with ibandronate/capecitabine; α=0.05, ß=80%) and we expected 497 events during a median 5 year follow up. Results: Between 06/2004 and 08/2008, 1409 patients were randomized to ibandronate (N=702) or ibandronate/capecitabine (N=668) in 172 German centers, of whom 1380 patients started treatment (689 and 691 respectively). Median age was 71 (range 74-80) years; 58.6% of patients had a CMI≥1, 48.2% had N+, 35.2% grade 3, and 19.2% had ER/PgR negative disease. 83.8% of patients received all 6 capecitabine cycles. Capecitabine grade 3/4 toxicities were &amp;lt;2% except hand-foot-syndrome (6.8%). 3 patients died in relation with capecitabine treatment. Final DFS analysis will be presented at the meeting. Conclusion: CALGB 49907 showed that AC or CMF was superior to capecitabine in patients aged ≥65 years but was associated with twice as many moderate to severe toxic effects (64% vs 33%) (Muss H et al, NEJM 2012). The ICE study will provide evidence if capecitabine monotherapy is as active as adjuvant treatment and if it might be an option for frail and/or elderly patients where standard chemotherapy is considered to be too toxic. Citation Format: Gunter von Minckwitz, Toralf Reimer, Jochen Potenberg, Bettina Conrad, Ulrike Schürer, Holger Eidtmann, Marianne Just, Stefan Paepke, Elmar Stickeler, Georg Heinrich, Michael Untch, Volker Moebus, Christoph Thomssen, Christian Jackisch, Jens Huober, Sibylle Loibl, Valentina Nekljudova, Ulrike Nitz. The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-04.

Flax and Breast Cancer

Flax is a food and dietary supplement commonly used for menopausal symptoms. Flax is known for its lignan, α-linolenic acid, and fiber content, components that may possess phytogestrogenic, anti-inflammatory, and hormone modulating effects, respectively. We conducted a systematic review of flax for efficacy in improving menopausal symptoms in women living with breast cancer and for potential impact on risk of breast cancer incidence or recurrence. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to January 2013 for human interventional or observational data pertaining to flax and breast cancer. Of 1892 records, we included a total of 10 studies: 2 randomized controlled trials, 2 uncontrolled trials, 1 biomarker study, and 5 observational studies. Nonsignificant (NS) decreases in hot flash symptomatology were seen with flax ingestion (7.5 g/d). Flax (25 g/d) increased tumor apoptotic index (P< .05) and decreased HER2 expression (P< .05) and cell proliferation (Ki-67 index; NS) among newly diagnosed breast cancer patients when compared with placebo. Uncontrolled and biomarker studies suggest beneficial effects on hot flashes, cell proliferation, atypical cytomorphology, and mammographic density, as well as possible anti-angiogenic activity at doses of 25 g ground flax or 50 mg secoisolariciresinol diglycoside daily. Observational data suggests associations between flax and decreased risk of primary breast cancer (adjusted odds ratio [AOR] = 0.82; 95% confidence interval [CI] = 0.69-0.97), better mental health (AOR = 1.76; 95% CI = 1.05-2.94), and lower mortality (multivariate hazard ratio = 0.69; 95% CI = 0.50-0.95) among breast cancer patients. Current evidence suggests that flax may be associated with decreased risk of breast cancer. Flax demonstrates antiproliferative effects in breast tissue of women at risk of breast cancer and may protect against primary breast cancer. Mortality risk may also be reduced among those living with breast cancer.

Informed choice about breast cancer prevention: randomized controlled trial of an online decision aid intervention

IntroductionTamoxifen and raloxifene are chemopreventive drugs that can reduce women's relative risk of primary breast cancer by 50%; however, most women eligible for these drugs have chosen not to take them. The reasons for low uptake may be related to women's knowledge or attitudes towards the drugs. We aimed to examine the impact of an online breast cancer chemoprevention decision aid (DA) on informed intentions and decisions of women at high risk of breast cancer.MethodsWe conducted a randomized clinical trial, assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention. Women (n = 585), 46- to 74-years old old, completed online baseline, post-test, and three-month follow-up questionnaires. Participants were randomly assigned to either an intervention group, a standard control group that answered questions about chemoprevention at baseline, or a three-month control group that did not answer questions about chemoprevention at baseline. The main outcome measures were whether women's intentions and decisions regarding chemoprevention drugs were informed, and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA, using a dichotomous composite variable 'informed choice' (yes/no) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman's decision and relevant attitudes.ResultsAnalyses showed that more intervention than standard control participants (52.7% versus 5.9%) made informed decisions at post-test, P <0.001. At the three-month follow-up, differences in rates of informed choice between intervention (16.9%) and both control groups (11.8% and 8.0%) were statistically non-significant, P = 0.067.ConclusionsThe DA increased informed decision making about breast cancer chemoprevention, although the impact on knowledge diminished over time. This study was not designed to determine how much knowledge decision makers must retain over time. Examining informed decisions increases understanding of the impact of DAs. A standard for defining and measuring sufficient knowledge for informed decisions is needed.Trial registrationClinicalTrials.gov: NCT00967824

Use of Medications to Reduce Risk for Primary Breast Cancer: A Systematic Review for the U.S. Preventive Services Task Force

Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer. MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists. English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment. Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria. Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer. Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking. Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates. Agency for Healthcare Research and Quality.

Black Cohosh and Breast Cancer

Many women use black cohosh as a natural treatment for menopausal symptoms. However, controversy exists around safety in breast cancer, because of its purported estrogenic activity. We conducted a systematic review of black cohosh use in women with or at risk of breast cancer. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to July 2012 and October 2012 for human interventional or observational data pertaining to the safety and efficacy of black cohosh in patients with or at risk of breast cancer, including an assessment of the effect of black cohosh on estrogen responsive tissues. Of 450 records, we included 26 articles: 14 randomized controlled trials, 7 uncontrolled trials, and 5 observational studies.The evidence on efficacy for ho t flashes is divided, with some benefits seen when compared with baseline, but not when compared with placebo. Two observational studies found no association between black cohosh and risk of breast cancer, whereas 2 studies reported significant reductions in risk of primary breast cancer among postmenopausal women (adjusted odds ratio = 0.47, 95% confidence interval = 0.27-0.82), and risk of recurrence (adjusted hazard ratio = 0.75, 95% confidence interval = 0.63-0.89). Seventeen trials showed no significant impact on circulating hormone levels or proliferation in estrogen responsive tissues. Current evidence does not support an association between black cohosh and increased risk of breast cancer. There is a lack of evidence supporting the efficacy of black cohosh for reduction of hot flashes in breast cancer patients. Given conflicting but promising results, and apparent safety, further research is warranted.

Abstract P3-13-04: Skeletal related Events and Bone Metastasis Patients with Breast Cancer in Japan. A Retrospective Study

Abstract Objective: Since skeletal related events (SRE) worsen QOL, the information relating to the SRE is important in the patient's care. We have examined the incidences of bone metastasis (BM) and SRE in Japan and explored the prognostic factors which may affect the BM or SRE free period or survival. Patients and Methods: A retrospective, multicenter (21 institutes) study was performed. Patients with node positive or node negative with moderate to severe recurrence risk primary breast cancer were included. The primary endpoint was SRE-free period, and the secondary endpoints were BM-free period and the over-all survival period. By using a proportional hazard model (Cox regression), factors which affect these endpoints were examined in the population excluding stage IV patients. Results: 1,779 patients were registered and 1,708 patients' data were used for analysis. The median follow-up duration was 5.71 years. SRE occurred in 133 (68.9%) of 193 patients who developed BM. The median SRE-free period from the initial treatment was 1,006 days. The SRE-free rate and SRE-free survival rate at 5-years were 92.6% and 85.4%, respectively. The median period from the initial SRE to the second one was 112 days, and the second to the third one was 147 days. The median BM-free period was 767 days. The BM-free and BM-free survival rates at 5-years were 89.2% and 83.7%, respectively. The over-all survival rate at 5-years was 89.4%. The SRE-free period was significantly affected by the number of lymph node metastasis (LN mets) (Hazard Ratio; HR [95%CI]; 1.09 [1.042–1.143], p = 0.0002) and clinical stage (when stage I was assumed as reference, HR in stage II; 4.54 [1.296–15.933], stage III; 7.36 [1.171–31.539], p = 0.0262). SRE-free survival period was affected by the number of LN mets (HR; 1.10 [1.066–1.131], p &amp;lt; 0.0001), stage (stage I as reference, HR in stage II: 2.93 [1.349–6.349], and stage III: 4.28 [1.694–10.815], p = 0.008), and tumor phenotype (Luminal [L] A as reference, HR in LB; 1.89 [0.868–4.117], L-HER2: 2.81 [1.334–5.923], HER2: 2.68 [1.266–5.659], Triple negative (TN); 5.38 [3.031–9.537], p &amp;lt; 0.0001). The BM-free period was affected by the number of LN mets (HR; 1.09 [1.048–1.125], p &amp;lt; 0.0001), stage (stage I as reference, HR in stage II; 3.24 [1.219–8.619], stage III; 6.37 [2.080–19.485], p = 0.0045), and BMI (HR; 0.92 [0.854–0.987], p = 0.0213). BM free-survival period was affected by the number of LN mets (HR;1.10 [1.067–1.129], p &amp;lt; 0.0001), stage (stage I as reference, HR in stage II; 2.80 [1.344–5.825], stage III; 4.43 [1.853–10.609], p = 0.0037), phenotype (LA as reference, HR in LB; 2.23 [1.097–4.534], L-HER2; 3.10 [1.557–6.191], HER2; 2.57 [1.344–5.324], TN; 5.02 [2.887–8.738], p &amp;lt; 0.0001), and BMI (HR; 0.92 [0.872–0.981], p = 0.0090). Over-all survival period was affected by the number of LN mets (HR; 1.11 [1.075–1.147], p &amp;lt; 0.0001), stage (stage I as reference, HR in stage II; 2.32 [1.000–5.381], stage III; 4.24 [1.551–11.573], p = 0.01777), and phenotype (LA as reference, HR in LB; 2.26 [0.850–6.013], L-HER2; 3.58 [1.393–9.184], HER2; 4.22 [1.719–10.347], TN; 10.05 [4.810–21.004], p &amp;lt; 0.0001). Conclusion: Tumor phenotype appears to have an impact on SRE-free, BM-free and overall survival period, but not on SRE-free and BM-free period. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-13-04.

Abstract P4-13-12: Identifying women at increased risk for breast cancer using the electronic health record in an integrated health system

Abstract Women at increased risk for breast cancer (BC) are eligible to take selective estrogen receptor modulators (SERMs) to reduce their risk; Food and Drug Administration (FDA) approval of tamoxifen or raloxifene for BC risk reduction and American Society of Clinical Oncology (ASCO) guidelines for the use of SERMs recommend the two drugs for any woman over the age of 35 years with a 5-year risk of 1.67% or greater, but identifying those women can be both challenging and costly. We used an electronic database (Centricity RIS-IC) from the Geisinger Health System (GHS) Department of Radiology with 77,000 women ages 35–90 years to calculate 5-year and lifetime risks of developing invasive BC using National Cancer Institute's (NCI) Breast Cancer Risk Assessment Macro (BrCa RAM). BrCa RAM calculates risk based on patient age, number of biopsies, did a biopsy ever display atypical hyperplasia (Yes/No), age at menarche, age at first live birth, number of first degree relatives with breast cancer, and patient race. Demographic information (age, race, sex) was obtained from the electronic health record (EpicCare), pathology information (number of biopsies, atypical hyperplasia) was obtained from the pathology application (CoPath), and personal history (number of first degree relatives with breast cancer) were obtained from RIS. Age at menarche and age at first live birth could not be obtained, but makes a small relative contribution to the risk of BC. Sensitivity analysis explored implications of missing data; imputing ages for age at first live birth and age at menarche showed that the absence of this data did not overestimate the five-year and lifetime risks. There were 5,897 patients with calculated 5-year breast cancer risk 2; mean age was 65.8 years, mean 5-yr risk of BC = 3.05% (max 18.2%). The number of patients by 5-year risk score category were: risk 2–2.5% (n = 1728); 2.5%–3% (n = 3188); 3%+ (n = 981). There were 4,196 patients with a GHS primary care physician (PCP); 5,086 patients had seen any Geisinger physician within the past year; 4,113 women had seen their PCP in the past year. Only 239 patients ever received a prescription for tamoxifen or raloxifene, and some received raloxifene for prevention or treatment of osteoporosis and not for BC risk reduction. Only 40 were currently taking tamoxifen or raloxifene. These data from an integrated health system with an electronic health record validate the under-utilization of SERMs for primary BC risk reduction. Strategies are being designed to increase their use in GHS by using the risk score to identify the population and attempt to intervene using a risk modification clinical program. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-12.

Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101

The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity. Between 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS). A total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P=.77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P=.44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS. For women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.