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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Perspectives on this Article from Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer

Supplementary Figure S2 - PDF file 17K, ZNF423 expression in two cell lines

Supplementary Material - PDF file 131K, Provision of Supplementary material relating to methods, tables for patient characteristics, SNP-covariate interactions, SNP effects on time to breast cancer, top SNPs on chromosomes 4 and 16, and supplementary Figure legends

Objectives Oncologists estimate patients' prognosis to guide care. Evidence suggests oncologists tend to overestimate life expectancy, which can lead to care with questionable benefits. Information obtained from geriatric assessment may improve prognostication for older adults. In this study, we created a geriatric assessment-based prognostic model for older adults with advanced cancer and compared its performance to alternative models. Materials and methods We conducted a secondary analysis of a trial (URCC 13070; PI: Mohile) capturing geriatric assessment and vital status up to one year for adults age ≥ 70 years with advanced cancer. Oncologists estimated life expectancy as 0–6 months, 7–12 months, and > 1 year. Three statistical models were developed: (1) a model including age, sex, cancer type, and stage (basic model), (2) basic model + Karnofsky Performance Status (≤50, 60–70, and 80+) (KPS model), and (3) basic model +16 binary indicators of geriatric assessment impairments (GA model). Cox regression was used to model one-year survival; c-indices and time-dependent c-statistics assessed model discrimination and stratified survival curves assessed model calibration. Results We included 484 participants; mean age was 75; 48% had gastrointestinal or lung cancer. Overall, 43% of patients died within one year. Oncologists classified prognosis accurately for 55% of patients, overestimated for 35%, and underestimated for 10%. C-indices were 0.61 (basic model), 0.62 (KPS model), and 0.63 (GA model). The GA model was well-calibrated. Conclusions The GA model showed moderate discrimination for survival, similar to alternative models, but calibration was improved. Further research is needed to optimize geriatric assessment-based prognostic models for use in older adults with advanced cancer.

Objectives Physician assistants (PAs) and NPs are essential to quality care delivery. The need to demonstrate value and optimize PA and NP roles in neurology subspecialty clinics is unmet. We outline the development of a PA- and NP-led neuro-oncology procedural clinic and provide metrics to support the institutional and clinician value added. Methods We designed a PA- and NP-led Geisinger Ommaya Clinic (GOC) to manage leptomeningeal carcinomatosis (LMC) with defined clinician roles and the GOC treatment protocol. A retrospective review of 135 patients (2012-2019) compared survival outcomes for patients treated on the protocol compared with those treated off the protocol. Results Centralized care in the GOCs minimized shared physician encounters and improved PA and NP autonomy and utility. LMC therapy as part of the GOC protocol improved care continuity and survival outcomes. Conclusions PA- and NP-led procedural clinics optimize use of these clinicians and open physician availability for nonprocedural duties. This research highlights the institutional patient and financial benefit while demonstrating the operational and leadership growth potential for PAs and NPs.

ImportanceOlder adults with advanced cancer who have high pretreatment symptom severity often experience adverse events during cancer treatments. Unsupervised machine learning may help stratify patients into different risk groups.ObjectiveTo evaluate whether clusters identified from baseline patient-reported symptom severity were associated with adverse outcomes.Design, Setting, and ParticipantsThis secondary analysis of the Geriatric Assessment Intervention for Reducing Toxicity in Older Patients With Advanced Cancer (GAP70+) Trial (2014-2019) included patients who completed the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) before starting a new cancer treatment regimen and received care at community oncology sites across the United States. An unsupervised machine learning algorithm (k-means with Euclidean distance) clustered patients based on similarities of baseline symptom severities. Clustering variables included severity items of 24 PRO-CTCAE symptoms (range, 0-4; corresponding to none, mild, moderate, severe, and very severe). Total severity score was calculated as the sum of 24 items (range, 0-96). Whether the clusters were associated with unplanned hospitalization, death, and toxic effects was then examined. Analyses were conducted in January and February 2022.ExposuresSymptom severity.Main Outcomes and MeasuresUnplanned hospitalization over 3 months (primary), all-cause mortality over 1 year, and any clinician-rated grade 3 to 5 toxic effect over 3 months.ResultsOf 718 enrolled patients, 706 completed baseline PRO-CTCAE and were included (mean [SD] age, 77.2 [5.5] years, 401 [56.8%] male patients; 51 [7.2%] Black and 619 [87.8%] non-Hispanic White patients; 245 [34.7%] with gastrointestinal cancer; 175 [24.8%] with lung cancer; mean [SD] impaired Geriatric Assessment domains, 4.5 [1.6]). The algorithm classified 310 (43.9%), 295 (41.8%), and 101 (14.3%) into low-, medium-, and high-severity clusters (within-cluster mean [SD] severity scores: low, 6.3 [3.4]; moderate, 16.6 [4.3]; high, 29.8 [7.8]; P P = .046). Moderate- and high-severity clusters were associated with a higher risk of death (moderate: hazard ratio, 1.31; 95% CI, 1.01-1.69; P = .04; high: hazard ratio, 2.00; 95% CI, 1.43-2.78; P Conclusions and RelevanceIn this study, unsupervised machine learning partitioned patients into distinct symptom severity clusters; patients with higher pretreatment severity were more likely to experience hospitalization and death.Trial RegistrationClinicalTrials.gov Identifier: NCT02054741

OBJECTIVE: One primary source of psychological distress in patients with cancer and their caregivers is uncertainty. However, the uncertainty trajectory and its relationship between older adults with advanced cancer and their caregivers have rarely been examined. This study describes the uncertainty trajectory in patient-caregiver dyads, explores the effect of geriatric assessment (GA) intervention on trajectory, and examines the interdependent relationship of uncertainty. METHODS: This secondary analysis used longitudinal data from a national cluster-randomized controlled trial examining a GA intervention compared to usual care. Participants completed the modified 9-item Mishel Uncertainty in Illness Scale at enrollment, 4–6 weeks, 3 months, and 6 months. The dyadic growth model and cross-lagged actor-partner interdependence model were used. RESULTS: A total of 397 dyads (patient age M = 76.81 ± SD5.43; caregiver age M = 66.69 ± SD12.52) were included. Both had a trend of decreased uncertainty over time (b = −0.16, p < 0.01). There was a greater decrease in uncertainty among caregivers in the GA group than those in the usual care group (b = −0.46, p = 0.02). For both patients and caregivers, their past uncertainty was a significant predictor of their own current uncertainty (i.e., actor effect, p < 0.01). The individual’s past uncertainty was a significant predictor of the other dyad member’s current uncertainty (i.e., partner effect, p < 0.05), indicating an interdependent relationship between patient and caregiver uncertainty over time. CONCLUSIONS: Findings suggest patient and caregiver function as a unit with uncertainty levels affecting each other. Future interventions could build on GA to address uncertainty for older patients with advanced cancer and caregivers.

1518 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN) but their benefit for regimens with intermediate FN risk is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) intervention for prescribing PP-CSF, we designed a substudy to evaluate the effectiveness of PP-CSF for patients receiving therapy with intermediate FN risk. Methods: TrACER was a cluster randomized trial where NCI community Oncology Research Program practices were randomized to usual care (UC) or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to a SOE of automated PP-CSF orders for NCCN-designated high FN risk chemotherapy regimens and alerts against PP-CSF orders for low FN risk regimens (intervention) versus usual care. A secondary randomization assigned intervention sites to a SOE intervention either to prescribe or not prescribe PP-CSF for patients receiving intermediate FN risk regimens. Clinicians were allowed to override the SOE. Patients age ≥18 with either breast, colorectal or non-small cell lung cancer were enrolled and followed for 12 mo. PP-CSF was defined as initiation within 24-72 hours after systemic chemotherapy. Sample size calculations were based on an FN risk reduction from 15% to 7.5%, and provided 80% power at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences between sites randomized to prescribe or not prescribe PP-CSF. Results: Between January 2016 and April 2020, 24 sites (2,287 patients) were randomized to the intervention. Among intervention sites, 12 were randomized to either SOE to prescribe or an alert to not prescribe PP-CSF for the 542 patients receiving intermediate FN risk regimens. Rates of PP-CSF use were higher among sites randomized to prescribe PP-CSF (37.1% vs 9.9%, OR = 5.90 (95% CI 1.72-20.20; p = 0.0048)). Overall, the rates of FN were low and identical between PP-CSF and no PP-CSF arms (3.7% vs 3.7%). Among patients who did not receive PP-CSF, rates of FN were also low and similar between arms (3.8% vs 4.1%). Conclusions: While implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving intermediate risk regimens, FN rates did not differ between arms. Despite SOE, 63% of patients assigned to receive PP-CSF did not receive it. FN rates overall were lower than expected and did not differ between patients that did or did not receive PP-CSF. Although this guideline-informed SOE influenced prescribing, the results suggest that neither the SOE nor PP-CSF itself provide sufficient benefit to justify their use for persons receiving intermediate FN risk regimens. Clinical trial information: NCT02728596.

1525 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN). Prior studies have shown that 55-95% of CSF prescribing is inconsistent with practice guidelines. We conducted a cluster randomized trial to determine if guideline-informed standing orders for PP-CSF improved prescribing and reduced the incidence of FN. Methods: Patients age ≥18 with breast, colorectal or non-small cell lung cancer initiating first cancer-directed therapy with NCCN-recommended regimens were eligible. The intervention consisted of automated PP-CSF orders for high FN risk chemotherapy regimens and an alert not to use PP-CSF for low FN risk regimens. Regimen FN risk was based on NCCN guidelines. Clinicians could override the orders. Primary and secondary outcomes were PP-CSF use among patients receiving high and low risk regimens FN incidence within 6 months of initial therapy. Sample size estimates assumed an FN risk of 25% for high-risk chemotherapy. 32 NCI Community Oncology Research Program (NCORP) practices randomized 3:1 to the order entry system (intervention) versus usual care (UC) provided 90% power to detect a 50% reduction in FN at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences among randomized sites. 13 practices with pre-existing PP-CSF order sets enrolled in a parallel cohort study. Patients and other stakeholder groups informed study design, conduct and reporting. Results: Between January 2016 and April 2020, 2,946 patients were randomized (2287 intervention, 659 UC); 718 were enrolled in the cohort. Mean age across arms was 58.1. 77% of patients were female; 61% diagnosed with breast cancer. Among patients receiving high-risk regimens, PP-CSF use did not differ between arms (89.2% intervention; 95.8% UC, adjusted p = 0.21) and was similar to the cohort patients (93.0%). The FN rate for high-risk patients was 5.7% in intervention clinics and 4.2% in UC clinics (adjusted p = 0.26); FN was 14.9% among high-risk patients who did not receive PP-CSF. Among patients receiving low-risk regimens, PP-CSF use did not differ between arms (intervention 6.3%, UC 5.5%, adjusted p = 0.74) and was slightly lower than the cohort (8.3%). FN rates did not differ between low risk groups (intervention 1.5%, UC 0.8%, adjusted p = 0.51). Conclusions: Guideline-informed standing orders did not increase PP-CSF use in high-risk patients, nor did it decrease use in low-risk patients. Adherence to guidelines in both risk groups exceeded historical reports. FN rates among patients not receiving PP-CSF were substantially below those reported in CSF guidelines. Automated standing orders for PP-CSF do not appear to be helpful or necessary. Clinical trial information: NCT02728596.

Despite strong evidence that it is efficacious, chemoprevention has been underused in eligible women. Reasons offered not to adopt and initiate strategies to reduce the risk of breast cancer include the fear of adverse effects, medication costs, lack of reasonably accurate and feasible methods for assessing an individual's personal risk, and lack of established risk thresholds that maximize benefit and minimize harms. The article by Macdonald and colleagues remind us that the problem of lack of uptake of risk-reducing medications for breast cancer remains a worldwide clinical challenge despite endorsements from national and international organizations that recommend the use of risk-reducing medications for breast cancer with level I evidence. Several strategies are suggested to improve uptake and utilization of safe and effective chemoprevention medications with high therapeutic indices. See related article by Macdonald et al., p. 131

Objectives Older self-perceived age is associated with poor health and higher healthcare utilization in the geriatric population. We evaluated the associations of self-perceived age with geriatric assessment (GA) domain impairments in older adults with cancer. Methods This was a secondary analysis of baseline data from a GA cluster-randomized trial (URCC 13070; PI: Mohile). We included patients aged ≥70 with incurable stage III/IV solid tumor or lymphoma considering or receiving treatment and had ≥1 GA domain impairment other than polypharmacy. Multivariate analyses were used to evaluate the associations of age difference between chronological and self-perceived age (categorized into “feeling younger than chronological age” vs. “feeling the same or older than their chronological age”) with GA domain impairments. Results We included 533 patients; mean age was 76.6 (SD 5.2). On multivariate analyses, compared to those who felt younger than their chronological age, those who felt the same or older were more likely to have impairments in physical performance [Adjusted Odds Ratio (AOR) 5.42, 95% Confidence Interval (CI) 1.69–17.40)], functional status (AOR 2.31, 95% CI 1.73–3.07), comorbidity (AOR 1.62, 95% CI 1.20–2.19), psychological health (AOR 2.62, 95% CI 1.85–3.73), and nutrition (AOR 1.65, 95% CI 1.20–2.28). They were also more likely to screen positively for polypharmacy (AOR 1.86, 95% CI 1.30–2.65). Conclusions Older adults with cancer who felt the same or older than their chronological age were more likely to have GA domain impairments. Further studies are needed to better understand the relationships between self-perceived age, aging-related conditions, and outcomes in this population.

Millions of women in the United States are at increased risk of breast cancer. Multiple prospective, randomized clinical trials have demonstrated both the efficacy and safety of selective estrogen receptor modulators and aromatase inhibitors in reducing substantially the risk of invasive breast cancer in women at increased risk. Published tables are available to aid clinicians in shared decision-making regarding drug interventions with their patients who are at increased risk of breast cancer. Both professional and governmental agencies have advised that these interventions should be offered to women at increased risk of breast cancer. Doing so would reduce breast cancer morbidity substantially.

Purpose The clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility. Methods Whole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management. Results Thirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer—including a stage 1C fallopian tube cancer—via these procedures. Conclusion Screening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

Active patient partner engagement with SCOREboard – a diverse group of older patients with cancer, caregivers of older patients with cancer, survivors, and patient advocates – to conduct the largest randomized geriatric assessment clinical trial to date, has been shown to be feasible and resulted in tangible and invaluable benefits for both the research team and patient partners alike. Actively engaging patient partners should be an essential component in the development, conduct, and completion of all clinical research.

In women at increased risk of breast cancer age ≥35 years, the selective estrogen receptor modulator (SERM) tamoxifen should be discussed as an option to reduce the risk of estrogen receptor (ER)-positive breast cancer. In postmenopausal women, raloxifene, anastrozole, and exemestane should also be discussed as options for breast cancer risk reduction. Risk reduction with SERMs continues for at least 10 years in both premenopausal and postmenopausal women. Tamoxifen is not recommended for women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. Chemoprevention with a SERM may be particularly beneficial to women with atypical hyperplasia, a 5-year risk of more than 5 %, in women with increased mammographic density, or in women with lobular carcinoma in situ. Aromatase inhibitor therapy is of value in high-risk postmenopausal women. Toxicity with tamoxifen is minimal in premenopausal women and is less with either raloxifene or an aromatase inhibitor in postmenopausal women.

7051 Background: Long-term use of aromatase inhibitor (AI) therapy has been shown to decrease bone mineral density (BMD) and is associated with at least twice the fracture risk when compared to an age-matched healthy population. AI’s are a common treatment in hormone receptor-positive breast cancer for post-menopausal women. Similarly, tamoxifen has been shown to decrease BMD in premenopausal women. As a result, the National Comprehensive Cancer Network (NCCN) recommends BMD screening for women being treated with anti-estrogen therapy (AET), typically via Dual-energy X-ray absorptiometry (DEXA) scan. Previous studies have shown poor adherence to BMD screening with AI therapy, but no known study has evaluated compliance with tamoxifen therapy. Methods: We evaluated a retrospective cohort (December 2015 – July 2019) of all women with a breast cancer diagnosis initiating AET using data from the electronic health records of patients throughout a rural integrated health system. We assessed non-adherence to baseline and annual BMD screening using descriptive statistics along with preliminary data regarding fractures associated with AET therapy. Results: A total of 3,693 health records of women with a breast cancer diagnosis and documented prescription for AET were evaluated. In the year before AET initiation, 16% of women received BMD screening. Overall, 1,189 women treated with AET had a DEXA scan ordered at any point after drug initiation: 37% for AI’s and 12% for tamoxifen. Of those treated with AI, 84% had no DEXA ordered within 12 months of starting drug after a minimum of 9 months of continuous use; this value was 96% for tamoxifen use. Patients complied with the ordered DEXA scan within the first year 81% of the time. Repeat DEXA scans were ordered 34% of the time, and patient compliance decreased to 55%. There was no significant difference in the number of patient co-morbidities between patients who did and did not have a DEXA scan ordered. After starting an AI, 131 fractures were documented; 44% occurred within the first year following starting drug treatment with an average of 5 months from drug start to diagnosis. Conclusions: A significant proportion of breast cancer patients treated with AET did not receive guideline-recommended BMD screening. These findings should raise awareness of the importance of BMD screening by responsible providers, including oncologists, primary care physicians, care managers and insurance companies in order to decrease avoidable morbidity.

This chapter reviews 20 years of randomized, prospective clinical research on the use of selective hormone receptor modulators and aromatase inhibitors for the reduction of breast cancer risk in high-risk women. The findings from the trials are summarized using data from the individual trials themselves and published meta-analyses. Also included are recommendations from both US national organizations and international consensus groups that outline the approved agents for specific patients to reduce women's risk of breast cancer. Data are also included for carriers of predisposing genetic mutations.

Multiple studies provide estimates of the risk of breast cancer for women. Dense breasts on mammography or having first-degree relatives with breast cancer are associated with at least a 2-fold increase in risk of breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts are associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth are associated with a 1.0- to 1.5-fold increased risk. Predisposing genetic mutations, lobular carcinoma in situ, and atypical hyperplasia increase risk markedly. These risk factors, as well as environmental exposures, are reviewed in this chapter. Identification of these risk factors may be useful for personalized management of breast cancer risk.

Despite FDA approval of drugs to reduce the risk of breast cancer in women at increased risk, uptake of these drugs has been poor despite the publication of numerous studies that demonstrate both their effectives and safety. National organizations have made recommendations for their use, but both physicians and their patients do not fully understand either breast cancer risk factors or risk assessment or the indications for using risk-reducing agents. Histologically predisposing conditions, such as ductal or lobular atypia and lobular carcinoma in situ, impart particularly high risks of developing subsequent invasive breast cancer. Resources should be committed to both provider and patient education to reduce the risk of breast cancer in women who are at increased risk. Cancer Prev Res; 10(8); 431–3. ©2017 AACR.

e12099 Background: The purpose of this retrospective case series was to assess pCR rate, progression-free survival and prognostic factors in TNBC. Methods: We reviewed medical records for 33 consecutive female patients with TNBC (41% node+) treated between July 2015 and April 2018 with neoadjuvant paclitaxel 80 mg/m2 IV weekly plus concurrent carboplatin (AUC 4) every 3 weeks for a total of 12 weeks followed by dose-dense doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for a total of 4 cycles. Surgical pathology was studied to determine the presence or absence of residual disease at surgery. Age at treatment, tumor stage, subsequent hospitalizations, and genetic testing were recorded. Patients with residual disease were treated with adjuvant capecitabine 1500 mg PO BID, one week on, one week off, for 6 monthly cycles ± radiation; some patients with a complete pathological response also received postoperative radiation. Results: Among 33 patients, 17 patients had pCR (52%, median age 58 yrs), 10 had a partial response and 6 had no response or progression (median age 63.5). After surgery 24 patients received radiation therapy (XRT). There were 6 hospitalizations, 3 that were treatment related, 2 for neutropenic fever and one for renal failure induced by carboplatin; all 3 resulted in chemotherapy dose reductions; all 3 had pCR. 3 progressions/recurrences were recorded: 2 after treatment and 1 progression during treatment. Two deaths occurred, 1 secondary to progressive disease. Median progression free survival time was 8.5 months (range 0.1 to 24.0 mos). Median time since diagnosis is 16.7 months (range 8.1 to 37.6 mos). There was no significant difference in the median age of patients who had a pCR compared with patients with residual disease. Conclusions: We observed pCR in patients with TNBC treated with a pre-operative carboplatin-containing regimen (superior to historical pCR rates in patients receiving taxanes and anthracyclines only). Although there are insufficient data to demonstrate increased overall survival, we show an improvement in prognosis with a carboplatin-containing regimen for TNBC.

Purpose To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committee's review of the literature. Results Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole. Recommendations In women at increased risk of BC age ≥ 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) –positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC ≥ 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent.

Purpose To provide recommendations on the follow-up and management of patients with breast cancer who have completed primary therapy with curative intent. Methods To update the 2006 guideline of the American Society of Clinical Oncology (ASCO), a systematic review of the literature published from March 2006 through March 2012 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed the evidence to determine whether the recommendations were in need of updating. Results There were 14 new publications that met inclusion criteria: nine systematic reviews (three included meta-analyses) and five randomized controlled trials. After its review and analysis of the evidence, the Update Committee concluded that no revisions to the existing ASCO recommendations were warranted. Recommendations Regular history, physical examination, and mammography are recommended for breast cancer follow-up. Physical examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For women who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. The use of complete blood counts, chemistry panels, bone scans, chest radiographs, liver ultrasounds, pelvic ultrasounds, computed tomography scans, [18F]fluorodeoxyglucose–positron emission tomography scans, magnetic resonance imaging, and/or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination.

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.

Pregnancy-associated breast cancer (PABC) has been defined as breast cancer diagnosed during pregnancy or within one year of delivery. It is believed that after adjusting for age and stage, the 5-year survival rates are the same in both pregnant and nonpregnant women. We conducted a retrospective case-control study among patients treated at our institution between 1990 and 2005 to compare the 5-year survival outcomes for PABC with women treated for breast cancer who were not pregnant. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method, and log rank tests were used to assess the associations between OS, DFS and pregnancy status, HER-2 status, ER/PR status, and family history. The median age was 33 years (range 24-42) for both groups. Twenty-two (55%) patients with PABC were ER/PR receptor positive compared with 20 (50%) for the controls. Ninety percent of patients with PABC received chemotherapy compared with 87.5% in the nonpregnant group. 91.5% of patients with PABC had breast-conserving surgery and 8.5% had mastectomies compared with 86% and 14%, respectively, for the control group. The median OS was 4.9 years in the PABC group compared with 6 years for the controls (p = 0.02). The median DFS was 2.7 years for the PABC group compared with 5.1 years for the controls (p = 0.01). The most common site of relapse was bone for the PABC group (27%) and local recurrence (33%) for the controls. Univariate analysis revealed that OS and DFS were associated with pregnancy status, family history, ER/PR status, and stage. After adjusting for age and stage, PABC patients had higher risk of both death (p = 0.01) and recurrence (p = 0.02) compared with nonpregnant controls. Women with PABC had significantly shorter OS and DFS compared with nonpregnant age and stage-matched controls.

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case–control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3, *4, *5, and *6), reduced (*10, *17, and *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46–1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575–1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669–1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy. Clin Cancer Res; 17(21); 6944–51. ©2011 AACR.

Women who are at increased risk of breast cancer can be identified using individual risk factors or by using validated quantitative risk assessment models. There are millions of such women in the US population alone, and many additional millions of women at increased risk worldwide. Decades of randomized, prospective studies of these women using selective estrogen receptor modulators (SERMs) have shown that risk can be reduced safely and effectively by 50% for all invasive breast cancer and by nearly 70% or more for estrogen receptor–positive breast cancer. Safety and tolerability of the SERMs are acceptable in the published studies, and two SERMs, tamoxifen and raloxifene, are approved by the US Food and Drug Administration for breast cancer risk reduction. Nevertheless, the drugs are not widely used despite reasonable cost per year of life saved (or morbidity avoided). Clinicians must endeavor to identify women who are suitable candidates for these drugs and educate them about their safety and utility.

The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls ( n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis -platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.

Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further.

Selective estrogen receptor modulators (SERMs) are established in the treatment of estrogen receptor (ER)-positive breast cancer, and four decades of basic and preclinical research have shown them to be ideal agents for the reduction of the risk of breast cancer in high- risk pre- and postmenopausal women. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has conducted many clinical trials that used SERMs for the treatment and prevention of breast cancer. The trials were designed to assess a number of clini- cal and pathological outcomes including both invasive and in situ breast carcinomas. Here, we summarize the previously published data from two of those trials and also highlight the most recent data related to in situ events in the Study of Tamoxifen and Raloxifene (STAR) NSABP breast cancer risk reduction trial using tamoxifen. Background In the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT), the reduction in risk of noninvasive breast cancer was 50%. There were 93 cases in women receiving placebo and 60 in those receiving tamoxifen (P = .008). Through 7 years of follow-up, the cumulative incidence of noninva- sive breast cancer among the placebo group was 15.8 per 1000 women vs 10.2 per 1000 women in the tamoxi- fen group. In the initial report of the Study of Tamoxifen and Raloxifene (STAR trial), the rate for noninvasive breast cancer was 1.51 per 1000 women assigned to tamoxifen and 2.11 per 1000 women assigned to raloxifene (risk ratio, 1.40; 95% confidence interval = 0.98 to 2.00). Methods Additional follow-up of the NSABP STAR trial through March 31, 2009 is reported with a focus on noninvasive breast cancer events. Results Through 81 months of median follow-up in the NSABP STAR trial, there are 137 cases of noninvasive breast cancer in the raloxifene group compared with 111 cases in the tamoxifen group (risk ratio = 1.02, 95% confi- dence interval = 0.61 to 1.70). The occurrence of ductal carcinoma in situ with raloxifene was seen more fre- quently among women with lower baseline Gail scores and no atypical hyperplasia than in women taking tamoxifen therapy. Raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive breast cancer. Conclusions Although these data indicate that raloxifene offers less protection than tamoxifen for postmenopausal women who are at increased risk for both invasive and noninvasive breast cancer, the favorable risk-benefit profile for raloxifene affords acceptable clinical reduction in the risk of in situ cancers among postmenopausal women.

Key Points Question Can population-level genomic screening identify those at risk for disease? Findings In this cross-sectional study of an unselected population cohort of 50 726 adults who underwent exome sequencing, pathogenic and likely pathogenic BRCA1 and BRCA2 variants were found in a higher proportion of patients than was previously reported. Meaning Current methods to identify BRCA1/2 variant carriers may not be sufficient as a screening tool; population genomic screening for hereditary breast and ovarian cancer may better identify patients at high risk and provide an intervention opportunity to reduce mortality and morbidity., Importance Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2. Main Outcomes Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers. Results Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P, This cross-sectional study investigates the ascertainment of pathogenic and likely pathogenic BRCA1/2 variants among US adults enrolled in the MyCode Community Health Initiative.

Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer. The effectiveness of concurrent versus sequential regimens is not known.We randomly assigned 5351 patients with operable, node-positive, early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent ACT). The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen. The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women.At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-year overall survival, 83%) as compared with the doxorubicin-docetaxel group (overall survival, 79%; hazard ratio for death, 0.83; P=0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P=0.09). Disease-free survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the doxorubicin-docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or death, 0.80; P=0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P=0.01). The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio, 0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status.Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin-docetaxel. Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status. (ClinicalTrials.gov number, NCT00003782.)

High percent mammographic breast density is strongly associated with increased breast cancer risk. Though body mass index (BMI) is positively associated with risk of postmenopausal breast cancer, BMI is negatively associated with percent breast density in cross-sectional studies. Few longitudinal studies have evaluated associations between BMI and weight and mammographic breast density. We studied the longitudinal relationships between anthropometry and breast density in a prospective cohort of 834 pre- and perimenopausal women enrolled in an ancillary study to the Study of Women's Health Across the Nation (SWAN). Routine screening mammograms were collected and read for breast density. Random intercept regression models were used to evaluate whether annual BMI change was associated with changes over time in dense breast area and percent density. The study population was 7.4% African-American, 48.8% Caucasian, 21.8% Chinese, and 21.9% Japanese. Mean follow-up was 4.8 years. Mean annual weight change was +0.32 kg/year, mean change in dense area was -0.77 cm(2)/year, and mean change in percent density was -1.14%/year. In fully adjusted models, annual change in BMI was not significantly associated with changes in dense breast area (-0.17 cm(2), 95% CI -0.64, 0.29). Borderline significant negative associations were observed between annual BMI change and annual percent density change, with percent density decreasing 0.36% (95% CI -0.74, 0.02) for a one unit increase in BMI over a year. This longitudinal study provides modest evidence that changes in BMI are not associated with changes in dense area, yet may be negatively associated with percent density.

Background Postmenopausal women with osteoporosis had a 66% relative risk reduction for invasive breast cancer over 8 years of raloxifene therapy in the randomized, placebo-controlled 4-year MORE (Multiple Outcomes of Raloxifene Evaluation) trial and the CORE (Continuing Outcomes Relevant to Evista) trial, a 4-year follow-up to MORE. Patients and Methods The first post hoc analysis examined the effects of raloxifene on the cumulative incidence of invasive breast cancer on a yearly basis. Another analysis compared the incidence of invasive breast cancer in 3967 patients who continued raloxifene for 8 years (RLX-C, n = 2280), discontinued raloxifene after 4 years in MORE (RLX-D, n = 401), or took placebo (n = 1286) for a mean 2.9 years' treatment duration (57,338 patient-years). Results The unadjusted breast cancer incidence rate was 5.39 per 1000 patient-years in the placebo group compared with 2.26 in the RLX-C group (hazard ratio [HR], 0.41 [95% CI 0.21–0.81]) and 3.59 in the RLX-D group (HR, 0.69 [95% CI 0.23–2.01]). Because the choice of taking the study drug was not randomized in CORE, propensity scores were used to adjust for potential imbalances in baseline characteristics before CORE. Results after adjustment by the propensity score method were similar to the unadjusted results. Conclusion This analysis suggests a persistent effect for breast cancer risk reduction in patients who discontinued raloxifene, although this conclusion is limited by the small sample size.

Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case-control study of 407 pre- and postmenopausal women (n = 203 cases, n = 204 controls). Logistic regression was used to model the breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy (HT) use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/ml) than controls (291.4 pg/ml; p = 0.21). In a multivariable model, the odds of breast cancer was 37% higher for women with VEGF levelsor =314.2 pg/ml compared to those with levels below 314.2 pg/ml, albeit not significantly (p = 0.16). There was no interaction between VEGF and menopausal status (p = 0.52). In this case-control study, VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.

Purpose Patients with early-stage, hormone receptor–positive breast cancer have considerable residual risk for recurrence after completing 5 years of adjuvant tamoxifen. In May 2001, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated accrual to a randomized, placebo-controlled, double-blind clinical trial to evaluate the steroidal aromatase inhibitor exemestane as extended adjuvant therapy in this setting. Patients and Methods Postmenopausal patients with clinical T1-3N1M0 breast cancer who were disease free after 5 years of tamoxifen were randomly assigned to 5 years of exemestane (25 mg/d orally) or 5 years of placebo. Our primary aim was to test whether exemestane prolongs disease-free survival (DFS). In October 2003, results of National Cancer Institute of Canada (NCIC) MA.17 showing benefit from adjuvant letrozole in this setting necessitated termination of accrual to B-33, unblinding, and offering of exemestane to patients in the placebo group. Results At the time of unblinding, 1,598 patients had been randomly assigned; 72% in the exemestane group continued on exemestane and 44% in the placebo group elected to receive exemestane. With 30 months of median follow-up, original exemestane assignment resulted in a borderline statistically significant improvement in 4-year DFS (91% v 89%; relative risk [RR] = 0.68; P = .07) and in a statistically significant improvement in 4-year relapse-free survival (RFS; 96% v 94%; RR = 0.44; P = .004). Toxicity, assessed up to time of unblinding, was acceptable for the adjuvant setting. Conclusion Despite premature closure and crossover to exemestane by a substantial proportion of patients, original exemestane assignment resulted in non–statistically significant improvement in DFS and in statistically significant improvement in RFS.

Laboratory and epidemiologic evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may be inversely related to the risk of breast cancer; however, the mechanism by which NSAIDs may protect against the development of this disease is uncertain. The objective of this observational study was to assess the relationship between current NSAID use and endogenous estradiol levels, an established breast cancer risk factor. To evaluate this aim, we conducted a cross-sectional investigation among 260 postmenopausal women who were not recently exposed to exogenous hormones. Information on current NSAID use (aspirin, cyclooxygenase-2 inhibitors, and other NSAIDs combined) was collected using a questionnaire at the time of blood draw. Estradiol was quantified in serum by radioimmunoassay. General linear models were used to evaluate the association between NSAID use and serum total estradiol. The age-adjusted and body mass index–adjusted geometric mean serum estradiol concentration among NSAID users (n = 124) was significantly lower than nonusers of NSAIDs (n = 136; 17.8 versus 21.3 pmol/L; P = 0.03). Further adjustment for additional potential confounding factors did not substantially alter estimates (17.7 versus 21.2 pmol/L; P = 0.03). To our knowledge, this report is the first to examine the relationship between NSAID use and serum estradiol in postmenopausal women. These cross-sectional findings suggest that NSAID use may be associated with lower circulating estradiol levels, potentially representing one mechanism through which NSAIDs exert protective effects on breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(3):680–7)

Purpose National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS. Patients and Methods Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T. Results Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not. Conclusion B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.

Purpose The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process. Methods We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. The clinical community has become accustomed to a certain amount of adjudication and may criticize trials that lack adjudication. Limitations It is difficult to document the value of adjudication in trials that have reported adjudicated and nonadjudicated event rates and related treatment effects. Making rationale decisions about when and how to adjudicate is hampered by the lack of published study of when and how central adjudication is helpful to improve the quality and validity of trials and at what cost. Conclusions Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication — which trials, which outcomes, what methods — deserves scrutiny and further study. Clinical Trials 2008; 5: 56—60. http://ctj.sagepub.com

Objective: Hormones have been implicated as modulators of cognitive functioning. For instance, results of our previous work in women with breast cancer showed that cognitive impairment was more severe and involved more memory domains in those who received adjuvant tamoxifen therapy compared with women who received chemotherapy alone or no adjuvant therapy. Recently aromatase inhibitors such as anastrozole have been used in lieu of tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor-positive, early-stage breast cancer. Plasma estrogen levels are significantly lower in women who receive anastrozole compared with those who receive tamoxifen. We hypothesized, therefore, that anastrozole would have a more profound effect on cognitive function than tamoxifen, a mixed estrogen agonist/antagonist. Design: To test this hypothesis we compared cognitive function in women with early-stage breast cancer who received tamoxifen with those who received anastrozole therapy in a cross-sectional study. We evaluated cognitive function, depression, anxiety, and fatigue in 31 postmenopausal women with early-stage breast cancer who were between the ages of 21 and 65 years and treated with tamoxifen or anastrozole for a minimum of 3 months. Results: The results showed that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen. Conclusions: Additional, prospective studies are needed to validate and confirm the changes in cognitive function associated with hormone therapy for breast cancer.

Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs.

Background: Few data are available on the safety and efficacy of once-weekly oral bisphosphonate therapy in breast cancer survivors. Objective: Our objective was to determine whether risedronate, 35 mg weekly, is efficacious and safe in preventing bone loss associated with chemotherapy-induced menopause. Design: The study was a randomized, double-blind, placebo-controlled clinical trial over 12 months. Setting and Participants: Participants included 87 newly postmenopausal women with status post chemotherapy, recruited from a breast cancer clinic in an academic medical center. Intervention: Participants were randomly assigned to receive risedronate 35 mg/wk or placebo. Main Outcome Measures: The primary outcomes were the 12-month changes in spine and hip bone mineral density. Secondary outcomes included changes in markers of bone resorption (urine N-telopeptide cross-linked collagen type I) and formation (osteocalcin, N-terminal propeptide of type I procollagen, and bone-specific alkaline phosphatase). Results: After 12 months, bone mineral density increased by 1.2% at the spine and 1.3% at the hip in women on risedronate vs. significant decreases for women in the placebo group of 0.9% at the spine and 0.8% at the hip (P < 0.01, difference between groups). N-telopeptide cross-linked collagen type I, a marker of bone resorption, decreased by 19.3%, and N-terminal propeptide of type I procollagen, a marker of bone formation, decreased by 26.6% in participants on active therapy compared with increases in the control group. Risedronate was well tolerated, and the retention rate was 95% at 1 yr. Conclusions: Risedronate once weekly prevented bone loss and reduced bone turnover in women with breast cancer treated with chemotherapy. Early measures to prevent bone loss should be considered in this cohort of breast cancer survivors.