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Background Obesity is a known risk factor for developing endometrial cancer. However, the association of obesity with endometrial cancer (EC) outcomes has not been clearly established. This study examined how outcomes in women with early stage EC vary with body composition measured via computed tomography (CT). Methods In this retrospective study, patients diagnosed with EC international Federation of Gynecology and Obstetrics stages I-III and available CT scans were included. Automatica software was used to assess the areas of visceral adipose tissue, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) and skeletal muscle area. Results Of 293 patient charts assessed, 199 met eligibility criteria. Median body mass index (BMI) was 32.8 kg/m2 (interquartile range [IQ] = 26.8-38.9); 61.8% had histologic subtype endometrioid carcinoma. Adjusted for age, international Federation of Gynecology and Obstetrics stage, and histologic subtype, a BMI of at least 30 vs less than 30 kg/m2 was associated with lower endometrial cancer–specific survival (ECSS) (hazard ratio [HR] = 2.32, 95% confidence interval [CI] = 1.27 to 4.25) and overall survival (OS) (HR = 2.7, 95% CI = 1.35 to 5.39). Higher IMAT 75th vs 25th percentile and SAT of at least 225.6 vs less than 225.6 cm2 were associated with lower ECSS (HR = 1.53, 95% CI = 1.1 to 2.13, and HR = 2.57, 95% CI = 1.13 to 5.88) and OS (HR = 1.50, 95% CI = 1.11 to 2.02, and HR = 2.46, 95% CI = 1.2 to 5.01), respectively. The association of visceral adipose tissue (75th vs 25th percentile) with ECSS and OS was not statistically significant (HR = 1.42, 95% CI = 0.91 to 2.22, and HR = 1.24, 95% CI = 0.81 to 1.89). Conclusion Higher BMI, IMAT, and SAT were associated with higher mortality from EC and lower OS. A better understanding of the mechanisms underlying these relationships could inform strategies to improve patient outcomes.

Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients < 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI < vs > 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-08.

Background To evaluate the potential intracranial efficacy of immunotherapy among patients with breast cancer brain metastases (BrM), we analyzed the immunohistochemical expression of programmed death-ligand 1 (PD-L1), a predictive biomarker of response to immunotherapy. Methods In this single-center retrospective cohort study, consecutive patients with breast cancer BrM (immunotherapy naïve) who underwent surgery for BrM at Sunnybrook Health Sciences Center between July 1999 and June 2013 were identified. PD-L1 expression by immunohistochemistry (IHC) was assessed on BrM samples in triplicate; PD-L1 positive status was defined as PD-L1 expression ≥1% on tumor-infiltrating cells as a percentage of tumor area using the Ventana SP142 antibody. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status was determined using 2018 ASCO/CAP guidelines. Results The median patient age at the time of BrM diagnosis was 52 (range 32–85). PD-L1 expression using the SP42 antibody was identified in 9 out of 59 (15.3%) breast cancer BrM. The frequency of PD-L1 positive BrM by subtype is as follows: TNBC (n = 3/12, 25.0%), HER2+/HR- (n = 3/14, 21.4%), HR+/HER2- (n = 2/18, 11.1%), and HER2+/HR+ (n = 1/14, 7.1%). 24-month brain-specific progression-free survival was 66.7% (95% CI 37.9%–100%) among patients with PD-L1 positive BrM versus 42% (95% CI 26.6%–67.3%) among those with PD-L1 negative BrM (log-rank P-value .142). Conclusions One in 7 patients in our cohort had PD-L1 positive BrM; this proportion was highest (25%) among those with TNBC. Intracranial efficacy of immunotherapy warrants further study, particularly among patients with treatment-naïve metastatic TNBC, for whom extracranial efficacy has already been established.

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was −1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Background Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2−), HER2 positive (HER2+), and triple negative (TNBC). Methods We searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models. Results Twenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P Conclusions Obesity was associated with modestly worse DFS and OS in all BC subtypes.

Background and Rationale: Biomarker evaluation on breast tumor tissue is an important component of clinical research. There is a concern that tissues collected at different times (pre- vs intra-op) and with different techniques (core biopsy vs. surgical excision) produce different results that may confound comparisons of patient samples. Our objective is to address the difference between tumor tissue from the same patient collected pre- vs intra-op and by core biopsy (Core Bx) vs surgical excision, with an emphasis on ER/PgR/HER2/Ki-67 and biomarkers related to insulin metabolism. Design: Following a protocol approved by the IRB, patients with Core Bx proven invasive breast cancer (BC) >1.5 cm in size by imaging underwent a peri-operative Core Bx followed by surgical excision. No neoadjuvant therapy was administered. Formalin-fixed paraffin-embedded tumor sections of the diagnostic and peri-operative Core Bx and surgical excision were immunohistochemically (IHC) stained for ER, PgR, HER2, Ki-67, insulin receptor (IR), phospho-AKT (pAKT), and phospho-AMPK (pAMPK) using standardized protocols on the same platforms. A pathologist (MCC) scored all sections in blinded order to yield H-Scores (which combine percentage of stain-positive cells and staining intensity). The level of agreement for each assay between specimens was assessed by using pairwise models based on normal theory. Results: 18 women (mean age = 66.8 years, 16/18 postmenopausal) provided all specimens. Mean (± SD) invasive tumor size was 2.7 (± 1.2) cm. 1 BC was Nottingham Grade 1 (6%), 9 Grade 2 (50%), and 8 Grade 3 (44%). An in situ component was present in 4/18 (22%) cases (all non-extensive). Lymphovascular invasion was present in 6/18 (33%) cases. 10/18 were node-negative (N0, 56%), 2/18 had isolated tumor cells (pN0[i+], 22%), 5/18 had 1 to 3 nodes (pN1, 28%), 1/18 had >9 nodes involved (pN3, 6%).There was high concordance between diagnostic Core Bx, peri-op Core Bx, and excisions for the standard prognostic markers ER, PgR, and HER2. ER was concordant in all samples including 16/18 (89%) ER-positive and 2/19 (11%) ER-negative BCs. PgR was concordant in 16/18 (89%) of cases. In the 2 discordant cases, PgR was negative in 2 of 3 tissue samples with low expression in the 3rd sample (1 diagnostic Core Bx and 1 excision). HER2 was concordant in all samples in 16/18 (89%) HER2-negative cases and in 2/18 (11%) HER2-positive cases including 1/18 cases (6%) positive by IHC, and 1/18 cases (6%) positive by ISH. Table 1 summarizes the agreement between samples for Ki-67, IR, pAKT, and pAMPK. Ki-67 scores were statistically similar between diagnostic and peri-op Core Bx and excision samples. The IR, pAKT, and pAMPK H-Scores were statistically similar between diagnostic and peri-op Core Bx, but significantly different between Core Bxs versus excisional specimens. There was a systematic tendency towards lower IHC H-Scores in the excisional specimen for IR, pAKT, and pAMPK. Conclusion: Tissue from surgical excisions are susceptible to reduced IHC staining for metabolic markers such as IR, and phosphorylated kinases, when compared to core biopsies. When evaluating non-standard biomarkers for research, core biopsies should be used when possible. Funding: This study was funded by the Hold'Em For Life Charity and the Breast Cancer Research Foundation Table 1: Concordance Between IHC Scores for Ki-67, Insulin Receptor, pAKT, and pAMPKScore: Mean ± Standard DeviationPeri-Operative Core Bx versus Diagnostic Core BxExcision versus Diagnostic Core BxDiagnostic Core BxPeri-Operative Core BxExcisionDifferenceP-valueDifferenceP-valueKi-67 (% Positive)33.5 ± 28.235.9 ± 31.034.2 ± 29.1Mean ± SD: 2.4 ± 5.60.09Mean ± SD: 0.6 ± 6.30.68Range: -7.7 to 12.3Range: -11.5 to 12.2Insulin Receptor (H-Score**)136 ± 102124 ± 9986 ± 78Mean ± SD: -13 ± 530.32Mean ± SD: -51 ± 540.001*Range: -215 to 40Range: -150 to 5Phospho-AKT (H-Score**)102 ± 70100 ± 8641 ± 41Mean ± SD: -1 ± 750.95Mean ± SD: -61 ± 520.0001*Range: -170 to 170Range: -144 to 0Phospho-AMPK (H-Score**)201 ± 79185 ± 78157 ± 86Mean ± SD: -15 ± 760.41Mean ± SD: -44 ± 690.016*Range: -225 to 120Range: -215 to 70* Statistically significant difference in pairwise values based on t-test** H-Score is the percentage of stain-positive cells multiplied by the average intensity score (0 = absent, 1 = faint, 2 = moderate, 3 = strong) Citation Format: Martin C. Chang, Marguerite Ennis, Jaime Escallon, Karina Bukhanov, Ryan JO Dowling, Vuk Stambolic, Pamela J Goodwin. Concordance of immunohistochemical assays between peri-operative and post-operative breast tumor specimens: A prospective observational study of 18 cases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-25.

Importance Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration ClinicalTrials.gov Identifier: NCT01101438.

Breast cancer (BC) prognosis and outcome are adversely affected by increased body weight, obesity and the obesity-associated type 2 diabetes. Hyperinsulinemia, which is commonly seen as part of metabolic reprograming in the obese state, has been associated with higher risk of death and recurrence in BC. Up to 80% of breast cancers overexpress the insulin receptor (INSR) de novo, which correlates with worse prognosis. To directly probe the role of insulin signaling in mammary tumorigenesis in the mouse, we generated the MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC models, respectively, with coordinate mammary epithelium-restricted deletion of the INSR. In both models, deletion of either one or both copies of the INSR in the mammary gland led to a marked delay in tumor onset and burden, including in mice fed to mimic conditions of human obesity. Longitudinal monitoring of generated mouse models revealed that tumor initiation, rather than progression and metastasis, were impacted by INSR deletion. The similarity of phenotypes elicited by the deletion of one or both copies of INSR raises the possibility that there is a dose-dependent threshold for the contribution of INSR to mammary tumorigenesis.

PURPOSE: Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown. METHODS: Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4–12 weeks post-operatively, prior to treatment with chemotherapy or tamoxifen. RESULTS: Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30 kg/m(2)), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04–3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01). CONCLUSIONS: Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.

Crown-like structures of the breast (CLS-B), defined by the clustering of macrophages (identified using CD68 immunohistochemical staining) to surround a dying adipocyte, are a sign of adipose-tissue inflammation. In human cohorts, CLS-B positively correlates with older age, obesity, dyslipidemia and higher levels of glucose, insulin, C-reactive protein and IL-6. In an existing cohort of early-stage breast cancer patients, CLS-B were identified using H&E stained histologic sections (hCLS-B), and by CD68 immunohistochemistry (CD68 + CLS-B). We examined associations of H&E and CD68-detected CLS-B with clinicopathologic features using χ2 tests, with metabolic factors using Wilcoxon rank sum tests and with disease free and overall survival using Cox regression models. hCLS-B were detected in 59 of 163 patients with slides (36.2%) and CD68 + CLS-B in 37 of 119 patients with paraffin blocks (31.1%). hCLS-B were positively correlated with higher weight (p = 0.003), BMI (p = 0.0008) and C-reactive protein (p = 0.045). CD68 + CLS-B were positively correlated with higher weight (p = 0.006), BMI p = 0.001), leptin (p = 0.034), insulin (p = 0.008) and Homeostasis Model Assessment (p = 0.027). CD68 + CLS-B were associated with poor distant disease-free with a hazard ratio (HR) of 2.81, 95% confidence interval (CI) 1.20–6.57, and overall survival with HR 3.97 (1.66–9.48), while hCLS-B were not associated with either: HR for distant recurrence 0.59 (0.26–1.30); HR for death 1.04 (0.50–2.16). The presence of hCLS-B and of CD68 + CLS-B were associated with obesity; CD68 + CLS-B were associated with insulin resistance and adverse prognosis. Similar patterns were not seen for hCLS-B. Research is needed to understand the biologic basis for these differences.

An interim analysis is commonly used in phase III superiority trials to compare treatment arms, with the goal of terminating exposure of patients to ineffective or unsafe drugs or to identify highly effective therapies for earlier public disclosure. Traditionally, interim analyses have been designed to identify early evidence of extremely large benefit of the experimental approach, potentially leading to early dissemination of effective treatments. Increasingly, interim analysis has also involved analysis of futility, which may lead to early termination of a trial that will not yield additional useful information. This presents an important challenge in early stage hormone receptor–positive breast cancer, where recurrence often occurs late, with a steady annual event rate up to 20 years. Early analysis of events may miss late treatment effects that can be observed only with longer follow-up. We discuss approaches to futility analysis in adjuvant clinical trials in hormone receptor–positive breast cancer, the role of the Data Safety Monitoring Committee in such analyses, considerations of the potential harms vs benefits of treatment, and the risks of continuing vs early termination of a trial.

Background Circulating levels of cancer antigen (CA) 15–3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15–3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15–3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15–3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor–positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15–3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15–3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15–3 = 7.7% vs 2.0%, P .11). Conclusions Our observation that metformin reduces CA 15–3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15–3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

Research objectives: To conduct a prospective observational study of patient and tumor-related factors in women with high risk hormone receptor (HR)+/HER2- breast cancer (BC) following at least 5 years of adjuvant hormonal therapy, in order to identify risk factors for imminent recurrence. Rationale: Many of the life-threatening BC recurrences in women with HR+HER2- BC take place more than 5 years post-diagnosis, often after completion of adjuvant hormonal therapy. The identification of a biomarker(s) for late BC recurrence could lead to interventional trials to evaluate preventive therapies. We will evaluate whether the presence of blood-based biomarkers [(i) Circulating Tumor Cells (CTCs), (ii) circulating tumor DNA (ctDNA), (iii) tumor markers (CA 15-3, CEA)] and patient factors may predict BC recurrence. Trial design: A prospective cohort of eligible women with previously treated HR+HER2- BC who have not experienced a distant recurrence will be enrolled; patient and circulating factors will be measured annually until distant recurrence or study completion. Host factors (including BMI, lifestyle, medical illness, surgery, trauma and stress, as well as circulating PlGF, VEGF-1 and inflammatory markers) that may contribute to exit of BC cells from dormancy will also be assessed. The primary outcome is distant BC recurrence. Any BC event, including loco-regional recurrence, new breast or other primary cancer will be evaluated as a secondary endpoint. Outcomes will be ascertained by regular self-report (via annual telephone calls) and/or physician report and confirmed by medical record review. Key eligibility criteria: i) Diagnosis of ER and/or PR positive (either or both 10% positive), HER2 negative invasive BC, ii) predicted >1.5-2% annual risk of recurrence (T2, T3 or T4 with any N+;T1 N2+; T2N0 or T1 N1 cancers with high risk genomic scores), iii) receipt of adjuvant endocrine therapy for at least 4 years, with discontinuation planned in the next 12 months or completion of endocrine therapy within the last 5 years, iv) prior adjuvant chemotherapy, targeted therapy and bone targeted therapies are allowed provided they have been completed. Specific aims: 1) Determine if the presence of (i) CTCs, (ii) ctDNA, (iii) CA15-3 and CEA are associated with imminent risk (within 1-2 years) of distant recurrence in the study population. 2) Identify host factors associated with these blood-based biomarkers, as well as clinical outcomes. Statistical methods: A matched case control design (matching for time since completion of adjuvant hormone therapy, baseline T, N and grade) will be used to investigate associations of key study variables with imminent risk of distant recurrence within the next 1-2 years. Measurements of patients who do versus do not recur will be compared over the 1-2 years prior to relapse. Each variable will be allocated one third of a study-wide type one error of 0.05 (2-sided). ROC analyses and multivariable modelling will be used to optimize sensitivity, specificity, PPV and NPV. Available questionnaire data will be summarized at all time-points to generate descriptive survivorship data. Accrual: Starting in August 2018, we plan to recruit 1,000 patients over 2 years at selected Canadian cancer centres. Citation Format: Jerzak KJ, Cescon DW, Chia SK, Bratman S, Ennis M, Stambolic V, Chang M, Dowling R, Goodwin PJ. Exploration of factors associated with imminent risk of late recurrence in hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-01.

Background: MET treatment of diabetes is associated with improved BC outcomes. Hirsch et al (Cancer Res 2009;69:7505-7511) suggested MET may act synergistically with CXT in BC rodent models. We conducted a double-blind Phase II RCT of CXT plus MET vs placebo in LABC/MBC. Methods: Non-diabetic BC patients (pts) about to commence 1st-4th line CXT (prespecified anthracycline, taxane, vinorelbine, platinum or capecitabine; HER2 Rx permitted) for MBC or refractory LABC (any ER, PgR, HER2) were eligible if (i) age 18-75, (ii) ECOG 0-2, (iii) adequate hepatic, renal, bone marrow, cardiac function and (iv) measurable or evaluable disease. Those with CNS metastases, recent MET use or radiotherapy to target lesions, intake of ≥ 3 alcoholic drinks/day, history of lactic acidosis or current/planned pregnancy or lactation were ineligible. Randomization was to MET 850 mg po bid (or identical PLAC bid) with a 2 day ramp up of one tablet/day; dose was reduced/drug discontinued in a pre-specified manner for grade 2-4 toxicity. Disease status and toxicity/HRQOL were assessed at baseline and q9 weeks until progression. Primary outcome was progression-free survival (PFS); secondary outcomes included survival (OS), response and toxicity. With 40 subjects and type one error 0.2 (1-sided), a PFS HR of 0.58 could be detected with 80% power. PFS was analyzed using Cox proportional hazards regression. Results: 40 pts were randomized (22 MET, 18 PLAC). Mean age 55.4 vs 56.9 years; ER/PgR+ in 86.4 vs 83.3%; time from 1st metastases to randomization 297 vs 405 days, in MET vs PLAC respectively. MET pts were more likely to have visceral metastases (95.5% vs 72.2% PLAC) and less likely to be HER2+ (9.1% vs 23.5% PLAC). CXT was 1st line in 68.2% MET and 66.7% PLAC pts. Toxicity - # events: Gr 4: 0 MET vs 1 PLAC, Gr 3: 14 MET vs 14 PLAC; Gr 1 or 2: 193 MET (mainly GI) vs 53 PLAC. Best response: PR 18.2% MET vs 22.2% PLAC, SD 31.8% MET vs 11.1% PLAC, PD 45.4% MET vs 50.0% PLAC, P = 0.41. Mean PFS 164 days MET vs 192 days PLAC; HR (MET vs PLAC) 1.14 (95% CI 0.59-2.2), 1-sided p=0.65. Mean OS 645 MET vs 831 PLAC days; HR (MET vs PLAC) 1.6, 95% CI 0.72-3.54, 1-sided p=0.88. Conclusion: In these BC pts receiving 1st-4th line CXT, MET (vs PLAC) did not improve response rates, PFS or OS. Gr 1 and 2 toxicity was higher with MET than PLAC. These results do not support use of MET with CXT in refractory LABC/MET BC. MA32, an adjuvant trial of MET vs PLAC in early BC will provide information on MET in the adjuvant setting. Funded by the Breast Cancer Research Foundation (New York) and Hold'em for Life Charity (Toronto) Citation Format: Goodwin PJ, Ennis M, Cescon DW, Elser C, Haq R, Hamm CM, Lohmann AE, Pimentel I, Chang MC, Dowling RJ, Stambolic V. Phase II randomized clinical trial (RCT) of metformin (MET) vs placebo (PLAC) in combination with chemotherapy (CXT) in refractory locally advanced (LABC) or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-03.

Background Significant sexual dysfunction is reported in women with breast cancer (BC) in the years following diagnosis. It is unclear whether symptoms persist over time in BC survivors (BCS) as long-term data compared to healthy controls is lacking. We compared sexual functioning in long-term BCS to controls and explored the impact of adjuvant therapy on sexual health. Methods A cohort of women with localized BC recruited from 1989 to 1996 was prospectively followed as previously described. BCS without recurrence and controls without BC were contacted between 2005 and 2007 and answered self-reported quality of life questionnaires. Sexual health was measured with the Sexual Activity Questionnaire (SAQ). Vasomotor, gynecological and bladder symptoms were scored using the Menopausal Symptom Scale (scale ranges 0-4) based on the Breast Cancer Prevention Trial Symptom Checklist. Regression analysis was used to compare groups, with and without adjustment for age (quadratic) and menopausal status. P values Citation Format: Soldera SV, Ennis M, Lohmann AE, Goodwin PJ. Sexual health in long-term breast cancer survivors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-22.

Background: Intra-tumor RNA expression of hepcidin has been linked to adverse metastasis-free survival in women with early BC, but the prognostic implications of this inflammatory marker and iron-regulating peptide are unknown. Methods: Using an ELISA assay, we measured plasma hepcidin in the banked blood of 518 women who were recruited from 1989-1996 for a prospective cohort study regarding diet and lifestyle factors in BC. Blood had been obtained 4-12 weeks post-operatively and prior to treatment with radiation, chemotherapy or hormonal therapy. Women ages 18 to 75 with T1-3, N0-1, M0 BC who underwent surgery and axillary dissection were included; those with metabolic disorders were excluded. Tumor size, grade and ER/PR expression were abstracted from pathology reports; HER2 status was unknown. Median follow-up was 12.1 years (range, 0.2 to 17 years). Univariable Cox regression models were used to determine the association between hepcidin and i) time to distant BC recurrence (primary outcome), and ii) time to death due to any cause. Multivariable Cox proportional hazards models were adjusted for age (continuous), T stage (T2, T3, Tx vs T1), tumor grade (3 vs 2 or 1), N stage (node positive vs negative), ER/PR expression (both ER and PR negative vs either positive) a-priori. Associations between hepcidin and CRP, IL6, insulin, cholesterol, glucose, vitamin D, total iron, transferrin, and soluble transferrin receptor; sTfR were explored (Pearson's coefficients). Results: Hepcidin ranged from 4.70-190.70 ng/L (median 16.25; IQR 16.40 ng/L). To ensure normal distribution, a transformed [-1/sqrt (x)] hepcidin variable was used for prognostic analyses. Average age was 50.3±9.7 years. 16% were obese [body mass index (BMI) >30kg/m2], 30% (n=156) were node positive, 35% (n=181) had grade 3 tumors and 71% (n=370) had ER and/or PR positive tumors. 77% underwent a lumpectomy, 73% (n=380) received adjuvant radiotherapy and 39% (n=203) received adjuvant chemotherapy. Plasma hepcidin was not univariably associated with either time to distant BC recurrence (HR for 75th percentile versus 25th 1.20; 95%CI 0.79-1.32) or time to death due to any cause (HR 1.23; 95%CI 0.95-1.59) in the overall cohort; multivariable results were similar. In pre-planned analyses, the prognostic association of hepcidin differed by BMI (≤30 vs >30 kg/m2; interaction p-values Conclusion: Higher plasma hepcidin was independently associated with a shorter time to distant BC recurrence in obese women but not in the overall cohort. Further investigation of hepcidin and mechanisms linking it to adverse BC outcomes is warranted. Citation Format: Jerzak KJ, Lohmann AE, Ennis M, Nemeth E, Ganz T, Goodwin PJ. Prognostic associations of plasma hepcidin in early breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-08.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.

Objectives Pre-clinical data suggest metformin might enhance the effect of chemotherapy in breast cancer (BC). We conducted a Phase II randomized trial of chemotherapy plus metformin versus placebo in metastatic breast cancer (MBC). Material and methods In this double blind phase II trial we randomly assigned non-diabetic MBC patients on 1st to 4th line chemotherapy to receive metformin 850 mg po bid or placebo bid. Primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), response rate (RR), toxicity and quality of life (QOL). With 40 subjects and a type-one error of 0.2 (one-sided), a PFS hazard ratio (HR) of 0.58 could be detected with 80% power. Results 40 patients were randomized (22 metformin, 18 placebo) with a mean age of 55 vs 57 years and ER/PR positive BC in 86.4% vs 83.3% off metformin vs placebo, respectively. Mean BMI was 27kg/m2 in both arms. The majority of patients were on 1st line chemotherapy. Grade 3–4 toxicity occurred in 31.8% (metformin) vs 58.8% (placebo). Best response: Partial response 18.2% metformin vs 25% placebo, stable disease 36.4% metformin vs 18.8% placebo, progressive disease 45.4% metformin vs 56.2% placebo. Mean PFS was 5.4 vs 6.3 months (metformin vs placebo), HR 1.2 (95% CI 0.63–2.31). Mean OS was 20.2 (metformin) vs 24.2 months (placebo), HR 1.68 (95% CI 0.79–3.55). Conclusion In this population metformin showed no significant effect on RR, PFS or OS. These results do not support the use of metformin with chemotherapy in non-diabetic MBC patients.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

Background: Some studies have suggested that women with high BMI have less benefit from aromatase inhibitors (AI) vs. tamoxifen as adjuvant treatment for early breast cancer. One possible mechanism for this observation is that complete suppression of estrogen is not achieved in these women with the standard flat dose of AI. We evaluated whether a doubling of letrozole to 5 mg/day for 4 weeks affected residual estrogen levels in this population. Methods: Post-menopausal women with early breast cancer and BMI>25 already taking adjuvant letrozole for at least 3 months were recruited from medical oncology clinics at 4 sites in Toronto, Canada. Fasting blood samples were collected 24 hours following the last dose at baseline (routine use of own letrozole), after 28 days of monitored adherence to a provided supply of letrozole (Femara) 2.5 mg/day (Part A), and after an additional 28 days of letrozole (Femara) 5 mg/day (Part B). Symptom/quality of life questionnaires were completed at the same timepoints. Estradiol and estrone were measured using a high sensitivity liquid chromatography-tandem mass spectrometry assay. One interim analysis for futility and efficacy was planned after 31 eligible patients had completed the study, using estradiol and O'Brien-Fleming boundaries with an inner wedge. Results: 36 patients were enrolled and started on study, and 31 eligible patients completed Parts A and B. The 5 non-completers withdrew because of adverse events (n=4, unlikely related to drug) or withdrawal of consent (n=1). Median age was 62 (range 48 to 77) and BMI 28.3 kg/m2 (Range 25.2 to 42.2 kg/m2). One patient had non-postmenopausal estrogen levels at Day 29 and Day 57 and one patient's blood assay was unsuccessful; both were excluded from further analyses. The predetermined stopping rule for futility was met. Estradiol levels (mean±standard deviation) changed from 2.68±0.40 pg/mL at baseline to 2.67±0.59 pg/mL at Day 29 to 2.70±0.53 pg/mL at Day 57. Mean change from Day 29 to Day 57 was 0.03±0.48 pg/mL (95% confidence interval -0.15 to 0.21 pg/mL). Four patients reported new or increased arthralgias (to NCI CTCAE Grade 2 or 3) while taking letrozole 5 mg/day in Part B. There was no association between changes in estradiol levels and either study non-completion or the development of arthralgias. Estrone results were similar. Conclusion: Increasing letrozole from 2.5 to 5 mg/day did not further suppress estrogen levels in women with BMI>25. It is unlikely that letrozole dosing tailored to body size would improve clinical outcomes. The letrozole 5 mg/day intervention was terminated based on the results of the interim analysis for futility. Citation Format: Cescon DW, Ennis M, Pritchard KI, Townsley C, Warr D, Elser C, Rao L, Stambolic V, Sridhar S, Goodwin PJ. Effect of 5 vs 2.5 mg/day letrozole on residual estrogen levels in post-menopausal women with high BMI - A prospective crossover study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-02.

Introduction: The association of breast cancer (BC) with obesity is complex and multifactorial, depending partly on diet and related metabolic imbalances. Previous reports have shown that local inflammation in adipocytes can be seen in tissue sections as rings of macrophages of macrophages around necrotic adipocytes (“Crown-Like Structures of the Breast”, CLS-B). We and others have shown that CLS-B have higher prevalence and density within the adipose tissue of obese patients. Our goal was to examine the association of CLS-B with survival in participants enrolled at one center (Mount Sinai Hospital, Toronto) of a multicenter prospective cohort study designed to investigate obesity-related prognostic factors in early stage BC. Design: Archived H&E sections of breast adipose tissue were retrieved from Mount Sinai (Toronto) participants (N=163). All specimens were from breast excisions for invasive carcinoma. A CLS-B was defined as a ring of macrophages surrounding an adipocyte in otherwise normal breast tissue. In a subset (N=119), immunostains for CD68 were performed on a representative block to highlight macrophages. Sections containing tumor, fat necrosis, and mastitis were excluded. Slides were pathologist-reviewed, recording the number of CLS-B, slides containing CLS-B, and slides with normal tissue. Serologic markers of metabolism and inflammation were previously performed in a central laboratory. Correlations with clinical and serologic markers were examined using descriptive statistics and Wilcoxon tests. Survival analysis was performed with Cox proportional hazards models. Results: CLS-B were identified in routine H&E sections of normal fat in 59 out of 163 cases (36%). In the representative subset stained for CD68 (N=119), 22 cases were identified as positive for CLS-B by both H&E and CD68, 15 cases by CD68 alone and 24 by H&E alone, giving a CLS-B prevalence of 39% as detected by H&E, 31% by CD68 and 51% when combining the two. Both i) CD68-positive and ii) H&E-positive CLS-B showed similar positive relationships with BMI (median BMI 27 versus 24 kg/m2, P Univariable Cox model hazard ratios (HRs) for CD68-positive CLS-B were 2.79 (95% confidence interval (CI) 1.31-5.95) and 3.74 (CI 1.73-8.07) for disease-free and overall survival respectively, and after adjustment for age, nodal status, tumour grade, stage, ER/PR status, adjuvant treatment and BMI, HRs were 2.43 (CI 1.01-5.81) and 3.19 (CI 1.3-7.79). In the same subset, H&E-positive CLS-B had univariable HRs of 0.66 (CI 0.29-1.52) and 1.18 (CI 0.55-2.54) respectively and adjusted HRs of 0.31 (CI 0.11-0.82) and 0.57 (CI 0.23-1.39). Combining H&E and CD68 did not improve prediction over using CD68 alone. Conclusion: CLS-B visualized by the macrophage immunostain CD68 were associated with poor outcome, independent of patient BMI and tumour characteristics. Detection of CLS-B using H&E alone was not associated with poor outcome. Our results demonstrate that although CLS-B are a phenotype of obesity, they may also reflect a tissue-specific risk of adverse BC outcome. This risk may relate to localized tissue inflammation with higher prevalence in obese individuals. Although we do not advocate the clinical use of the CD68 stain, further work is warranted to clarify the connection between tissue inflammation and poor breast cancer outcome. Acknowledgement: The authors wish to acknowledge the Hold'Em For Life Charity Challenge for Cancer Research for their generous support. Citation Format: Martin C. Chang, Marguerite Ennis, Zohreh Eslami, Pamela J. Goodwin. CD68-positive crown-like structures of the breast are independently associated with adverse survival: A retrospective analysis of cases from a prospective cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-02.

Sexual dysfunction is reported in women with breast cancer (BC). It is unclear whether symptoms persist over time as data comparing long-term survivors to controls are lacking. We compared sexual functioning in long-term breast cancer survivors (BCS) to controls and determined the impact of adjuvant therapy on sexual health. A cohort of women with localized BC (1989–1996) was prospectively followed. BCS and controls (2005–2007) completed self-reported questionnaires. Sexual health was measured with the Sexual Activity Questionnaire (SAQ). Vasomotor, gynecological, and bladder symptoms were scored using the Menopausal Symptom Scale. Regression analysis was used to compare groups, with adjustment for age and secondly menopausal status. BCS (n = 248, 87%) and controls (n = 159, 95%) completed the SAQ at a median time from diagnosis of 12.5 years. BCS were older (62 vs 59 years, p = 0.0004) and more likely to be menopausal (94 vs 86%, p = 0.0025). Sexual activity did not differ significantly between BCS and controls, but when adjusted for menopausal status, pre/peri-menopausal BCS were less likely to be sexually active than pre/peri-controls (odds ratio OR 0.12, p = 0.012). In those sexually active, no significant differences were noted on the SAQ Pleasure, Discomfort, and Habit scales. BCS reported worse gynecological symptoms and pre/peri-menopausal patients had more bladder complaints (standardized effect size 0.36 p = 0.002 and 1.11, p = 0.011). Adjuvant treatments were not significantly associated with sexual function, but BCS treated with chemotherapy reported worse gynecological symptoms. Sexual health and uro-genital symptom counseling should be provided to BCS, particularly pre/peri-menopausal patients, even at long-term follow-up.

Background Circulating tumor cells (CTCs) are associated with worse prognosis in metastatic breast cancer (BC). We evaluated the association of metabolic, inflammatory, and tumor markers with CTCs in women with metastatic BC before commencing a new systemic therapy. Methods Ninety-six patients with newly diagnosed or progressing metastatic BC without current diabetes or use of anti-inflammatory agents were recruited from four Ontario hospitals. Women provided fasting blood for measurement of metabolic, inflammatory, and tumor markers and CTCs. CTCs were assayed within 72 hours of collection using CellSearch. Other blood was frozen at –80°C, and assays were performed in a single batch. Associations between CTC counts with study factors were evaluated using Spearman correlation, and the chi-square or Fisher exact test. All statistical tests were two-sided and P value ≤ .05 was considered statistically significant. Results The median age was 60.5 years; 90.6% were postmenopausal. The cohort included hormone receptor–positive (87.5%), HER2–positive (15.6%), and triple-negative (10.4%) BCs. Patients were starting firstline (35.5%), second-line (26.0%), or third-or-later-line therapy (38.5%). CTC counts (per 7.5 mL of blood) ranged from 0 to 1238 (median 2); an elevated CTC count, defined as five or more CTCs, was detected in 42 (43.8%) patients. Those with liver metastases (vs not) more frequently had an elevated CTC count (59.0% vs 33.3%, P = .02). CTCs were significantly associated with C-reactive protein (R = .22, P = .02), interleukin (IL)-6 (R = .25, P = .01), IL-8 (R = .38, P = .0001), plasminogen activator inhibitor 1 (R = .31, P = .001), carcinoembryonic antigen (R = .31, P = .002), and cancer antigen 15-3 (R = .40, P = .0001) and inversely associated with body mass index (R = –.23, P = .02) and leptin (R = –.26, P = .01). Conclusions CTC counts were positively associated with tumor and inflammatory markers and inversely associated with some metabolic markers, potentially reflecting tumor burden and cachexia.

Background: The metabolic syndrome is associated with poor breast cancer (BC) outcome. We evaluated changes from diagnosis in metabolic factors and BMI in long-term survivors and compared their status at long-term follow-up (LTFU) to that of age-matched women with no history of BC. Methods: A total of 535 women with early breast cancer were enrolled between 1989 and 1996 and followed prospectively. From 2005 to 2007, those alive without distant recurrence were re-contacted to participate in a long-term followed-up study and 285 agreed. A control group of 167 age-matched women without cancer history was recruited from women presenting for screening mammograms. Mean changes in metabolic factors from diagnosis to long-term follow-up were assessed with paired t-tests. In spite of matching, controls were younger and had higher income than survivors and the comparison to controls was made using age-adjusted regression models. Variables were transformed to normality before statistical testing. Results: With a median follow-up of 12.5 years, BC survivors gained on average 2.35 kg and BMI, waist and hip circumference, waist-hip ratio, glucose, insulin, HOMA, total cholesterol and its components (but not triglycerides) increased significantly. After age adjustment, waist circumference, glucose, HOMA and total triglycerides were significantly higher in BC survivors compared to controls Comparison of LTFU BC survivors to non-cancer controls Unadjusted mean ± standard deviationUnadjusted mean ± standard deviation BC patientscontrolsP-value for age-adjusted differencewaist circumference (cm)85 ± 1281 ± 10.01Glucose (mmol/L)5.5 ± 1.05.2 ± 0.9.01Insulin (pmol/L)60.9 ± 50.547.1 ± 28.3.06HOMA2.25 ± 2.241.64 ± 1.24.03Triglycerides (mmol/L)1.28 ± 0.641.10 ± 0.57.01BMI (kg/m2)26.3 ± 4.925.4 ± 4.5.26 Despite exclusion of BC patients with diabetes at study entry, 24.9% of BC survivors self reported diabetes or pre-diabetes (1.99%/year) versus 12.6% in controls (OR 2.3, p= .0017). Conclusion: The metabolic status of long-term BC survivors deteriorated over time and age-adjusted at LTFU were worse with respect to a number of factors compared to the control group. Citation Format: Ana Elisa Lohmann, Marguerite Ennis, Pamela J Goodwin. BMI and metabolic factors in long-term breast cancer survivors: Changes from diagnosis and comparison to non-breast cancer controls [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 P1-09-02.

We studied metabolic factors, diabetes, and anthropometric measurements at diagnosis and long-term follow-up (LTFU), mean 12.5 years post-diagnosis, in breast cancer (BC) survivors, and compared their status at LTFU to that of age-matched women without BC. Diet and physical activity were also assessed. 535 non-diabetic BC patients treated at three University of Toronto hospitals were followed prospectively; 285 surviving patients, without distant recurrence, participated in a LTFU study. A control group of 167 age-matched women without BC was recruited from a mammogram screening program at one of the hospitals. Change over time was analyzed using paired t tests, and comparisons between BC survivors and controls used age and education (AE)-adjusted regression models. Median weight gain in BC survivors was 2.00 kg (p

11557 Background: Obesity at breast cancer (BC) diagnosis is associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. Here we report on the association of obesity at BC diagnosis with disease-free (DFS) and overall survival (OS) in the following subtypes: (i) hormone receptor (ER/PgR) +ve, HER2-ve, (ii) HER2+ve, any ER/PgR and (iii) triple negative (TN). Methods: We searched MEDLINE, EMBASE and COCHRANE databases to December 31, 2018 and meeting presentations (past 5 years) using predefined search terms. Study eligibility, data abstraction were performed independently by two authors; those reporting hazard ratios (HR) for obesity and DFS/OS in BC subtypes were included. Using Review Manager pooled HRs were computed and weighted using generic inverse variance in fixed and random effects models (results were similar, random effects are presented). Results: Of 10,702 titles, 26 studies (108,793 patients) were included. Pooled HR for DFS for obese vs non-obese were (i) ER/PgR+ve HER2-ve 1.21 (95% Confidence interval, CI; 1.12-1.31, p < 0.00001), (ii) HER2+ve, any ER/PgR 1.16 (95%CI, 1.06-1.26; p = 0.0006) and (iii) TN, 1.13 (95%CI; 1.05-1.22 p = 0.002). Pooled HRs for OS were (i) ER/PgR+ve, HER2-ve 1.45 (95%CI; 1.30-1.62 p < 0.00001), (ii) HER2+ve any ER/PgR 1.21 (95%CI; 1.10-1.34 p = 0.0001) and (iii) TN 1.13 (95%CI, 1.04-1.23, p = 0.003).PooledHR for OS (but not DFS) were somewhat higher in observational vs interventional studies in (i) ER/PgR+ve, HER2-ve 1.57 vs 1.36, HER2+ve any ER/PgR (ii) 1.37 vs 1.09 but not (iii) TN 1.12 vs 1.22 (p = 0.21, 0.03 and 0.48, respectively). Conclusions: Obesity was associated with a worse outcome in all BC subtypes. Higher HR for OS in observational studies in (i) ER/PgR+ve, HER2- and (ii) HER2+ve any ER/PgR BC may reflect selection of healthier patients for intervention trials.

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or > 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = < 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = < 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.

Vitamin D regulates expression of genes important in development and progression of breast cancer. The association of vitamin D with breast cancer outcomes among breast cancer patients is controversial. We conducted a systematic review and meta-analysis of this association in early stage breast cancer outcome. We searched MEDLINE (1982-May 1, 2013), the American Society of Clinical Oncology (2009-2012), and the San Antonio Breast Cancer Symposium (2010-2012) for abstracts, using the following keywords: "breast cancer" and "prognosis" or "survival", and "vitamin D" or" calcitriol" to identify studies reporting the associations of blood vitamin D levels (drawn close to diagnosis) with breast cancer outcomes. Meta-analyses were performed using an inverse-variance weighted fixed-effects model with Stata Version 12. Eight studies including 5,691 patients were identified. Vitamin D deficiency was variably categorized across studies; a median of 36.8 % of patients were classified as deficient. Low vitamin D levels were associated with a pooled hazard ratio of 2.13 (95 % CI 1.64-2.78) and 1.76 (95 % CIs 1.35-2.30) for recurrence (six studies) and death (four studies), respectively, with no evidence of significant heterogeneity across studies. There was potential evidence of a publication bias in studies examining associations with death (but not in those examining associations with recurrence). These findings support an association of low levels of vitamin D with increased risk of recurrence and death in early stage breast cancer patients. Given the observational nature of the included studies, it cannot be concluded that this association is causal. Further research is warranted to investigate the potential beneficial effects of vitamin D in breast cancer.

Low serum vitamin D levels have been associated with poor outcomes in women diagnosed with early breast cancer. However, no randomized controlled trials (RCTs) have been performed to determine whether vitamin D supplementation might be an effective intervention in this population. We prospectively evaluated vitamin D adequacy and supplementation rates in a contemporary cross-sectional sample of breast cancer patients from 2 large urban centers and examined the feasibility of an RCT of vitamin D supplementation. Women with recently diagnosed early breast cancer were prospectively identified and recruited in Toronto and Los Angeles between March 2009 and January 2010. Anthropometric measurements, dietary, lifestyle, and medication histories were obtained by means of structured questionnaires and interviews. Tumor and treatment characteristics were abstracted from clinical records and blood samples were collected for analysis of 25-OH vitamin D. 173 eligible patients (median age 57) were enrolled. Clinical and treatment characteristics were similar between centres. 84.4 % of women reported use of vitamin D-containing supplements with median daily doses of 1,400 IU. Median 25-OH vitamin D levels were 85.5 and 98.5 nmol/L (P = 0.1), and levels of deficiency (50 nmol/L), insufficiency (50-72 nmol/L), and adequacy (72 nmol/L) were 3.8, 23.8, 72.5 % (Toronto) and 4.3, 20.7, 75 % (Los Angeles). 25-OH vitamin D levels were strongly correlated with vitamin D supplement use (r = 0.41, P0.0001). 68 % of women expressed willingness to participate in a vitamin D supplementation RCT; however, only 12.7 % of the study population met the pre-specified feasibility criteria (25-OH vitamin D72 nmol/L, willing to participate, and taking ≤1,000 IU vitamin D supplement/day). Both vitamin D levels and supplementation rates are higher than in previous reports. While the majority of women would be willing to participate in an RCT of vitamin D supplementation, low levels of deficiency/insufficiency and high rates of supplement use would limit the feasibility of such a study.

A prospective case series was studied to assess the potential for complete healing of wounds among patients with advanced illness referred to a regional palliative care program in Toronto, Canada. Two hundred and eighty-two patients, of which 148 were primarily diagnosed with cancer and 134 with non cancer advanced illness, were assessed and followed until their deaths. On the baseline initial referral date, 823 wounds were documented. The wound classes assessed included pressure ulcers, malignant wounds, skin tears, venous leg ulcers, diabetic foot ulcers and arterial leg/foot ulcers. Proportions of patients showing complete healing of at least one wound were calculated, stratified by patient's survival time post-baseline (1 week, 1 month, 3 months and 6 months). Proportions of patients showing complete healing of at least one wound increased the longer patients lived and ranged between 12·9% and 43·5% for stage I pressure ulcers, 0% and 60% for stage II pressure ulcers, 2·4% and 100% for skin tears, 10% and 100% for venous leg ulcers and 0% and 50% for diabetic foot ulcers. Only one person showed complete healing of a stage III pressure ulcer and no complete healing was observed with stage IV pressure ulcers, unstageable pressure ulcers, malignant wounds and arterial leg/foot ulcers.

Purpose To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time. Patients and Methods Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model. Results There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses. Conclusion Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.

Purpose To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease. Patients and Methods An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed. Results Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64). Conclusion Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

Background: Numerous clinical studies have reported that diabetic patients receiving metformin exhibit decreased cancer incidence and cancer related mortality. Metformin's mechanism of anti-tumor action has been attributed to both direct effects on cancer cells and systemic changes in insulin metabolism. Indeed, metformin reduces circulating insulin levels, which may be integral to its effectiveness in the breast cancer (BC) setting where hyperinsulinemia is associated with both recurrence and death. While the impact of metformin on blood glucose and insulin is well documented, its effects on other systemic physiologic and inflammatory factors are unknown. We completed a neoadjuvant "window of opportunity" study of metformin in non-diabetic women with BC and a series of analyses were performed on plasma samples to assess the impact of metformin on circulating inflammatory markers, growth factors, and tumor associated antigens. Methods: Non-diabetic women with early stage, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood was collected at diagnosis and surgery to assess circulating markers pre- and post-metformin administration. Plasma was isolated from blood samples and evaluated for CRP, TNF-alpha, IL-6, IL-8, VEGF, EGF, PlGF (placenta growth factor), CA15-3, and SHBG (sex hormone binding globulin). Change scores (post-metformin minus pre-) were calculated and the degree of change characterized by the median change and the rank-biserial correlation. The Wilcoxon signed-rank test was used to test the null hypothesis that the change scores were symmetrically distributed around zero versus more positive or negative change. Results: A total of 39 patients (mean age 51 years) completed the study and received metformin for a median of 18 days (range 13-40). Metformin was associated with changes in the levels of growth factors, with increases seen in EGF (median increase 1.1 pg/mL, r=0.42, p=0.027) and VEGF (1.7 pg/mL, r=0.31, p=0.09). A reduction in PlGF levels (-0.18 pg/mL, r=-0.6, p=0.0028) was also observed. The tumor associated antigen CA15-3 was significantly reduced after metformin treatment (-0.4 pg/mL, r=-0.56, p=0.0024) and a marker of sex hormone bioavailability (SHBG) was increased (2 nM, r=0.30, p=0.1). For circulating inflammatory markers, a significant increase in the levels of IL-8 (0.8 pg/mL, r=0.36, p=0.048) was observed, but changes in TNF-alpha and IL-6 were minimal (TNF-alpha 0.2 pg/mL, r=0.20, p=0.29; IL-6 0.1 pg/mL, r=0.14, p=0.46) and no change was seen in CRP (0 mg/L, r=-0.05, p=0.93). Conclusions: Short-term metformin administration was associated with alterations in systemic physiologic and inflammatory factors. Such increases in circulating cytokines and growth factors indicate possible alterations in the inflammatory state of the host and/or tumor. Of note, the reduction seen in the tumor antigen CA15-3 may reflect a disease-modifying effect of metformin in BC. The authors wish to acknowledge the generous support of the Hold'Em For Life Charity Challenge and the Breast Cancer Research Foundation. Citation Format: Dowling RJ, Niraula S, Chang MC, Ennis M, Stambolic V, Goodwin PJ. Circulating inflammatory markers, growth factors, and tumor associated antigens in women with early stage breast cancer receiving neoadjuvant metformin [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 P1-02-03.

Background: Cognitive deficits and fatigue have been reported in breast cancer (BC) patients undergoing a variety of treatments, including chemotherapy; in some studies these concerns persist after completion of treatment. We examined these factors over time (median 11 yrs) in a longitudinal study of BC patients and compared the status of long-term BC survivors to non-BC controls. Methods: 535 T1-3, N0-1, M0 BC patients were enrolled 1989–96; 260 women survived without metastases to participate in long-term follow-up (LTFU) measurements in 2006–8. 161 controls without BC were enrolled 2007–8. Questionnaires examined a range of QOL attributes; here we focus on items related to cognition and fatigue including: EORTC QLQ C30 (cognitive functioning, fatigue), Profile of Mood States (POMS — confusion/bewilderment, fatigue/inertia, vigor/activity), Fatigue Symptom Inventory (FSI — average fatigue past week, total disruption index), Everyday Problems (EDP — forgetfulness, difficulty concentrating, easily distracted). 166 of the BC patients had also completed EORTC and POMS at diagnosis and 1 year, and change in items on these questionnaires was calculated. Age and income adjusted differences between BC (LTFU) and controls were analyzed. Clinical significance was defined as ≥5% of the scale range or an effect size of ≥0.2 and statistical significance as P≤ 0.05. Results: BC cases were older than controls (62.3 vs 59.1 yr), had lower education (24.6 vs 10.2% high school only) and family income (38.2 vs 19.8% < $60,000 annually) (all P Conclusions: Fatigue items, as well as some cognitive items, improved over time in BC patients and scores were comparable to scores in non-BC controls at LTFU. However, scores on some cognitive items were worse in LTFU BC patients than in non-BC controls raising concerns that BC diagnosis and treatment may be associated with long-term adverse effects on some aspects of self-reported cognitive attributes. (Funded by The Breast Cancer Research Foundation) Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-09.

Objective We sought to determine the incidence of cancer and to compare pathologic outcomes in bleeding and non-bleeding postmenopausal patients who underwent hysteroscopy. Methods We conducted a retrospective chart review of 294 postmenopausal women with abnormal uterine bleeding and 142 postmenopausal women without symptoms who underwent hysteroscopy. An 11mm cut-off for asymptomatic women was applied to determine whether this endometrial thickness threshold would differentiate women with and without endometrial cancer in the asymptomatic group. Results In symptomatic patients, 14 were found to have endometrial cancer and 10 were found to have endometrial hyperplasia. In the asymptomatic group, two women (1. 4%) were found to have endometrial cancer with average thickness 17 . 5mm, and one (0 . 71%) was found to have endometrial hyperplasia . Logistic regression models showed the risk of a bleeding patient developing endometrial cancer at an endometrial thickness of 4mm was the same as the risk in a non-bleeding patient at a thickness of 15mm. Conclusion Asymptomatic postmenopausal women have a low risk of having significant endometrial pathology . Cancer was approximately four times more prevalent in women with bleeding than in women with no bleeding

Background: Vitamin D (Vit D) supplementation is an area of interest in the primary and secondary prevention of many cancers. We previously reported a high prevalence of Vit D insufficiency and deficiency in newly diagnosed breast cancer (BC) patients. Low Vit D levels were associated with poor BC outcomes. Here we evaluate the state of Vit D adequacy and supplementation in a more recently diagnosed cohort of BC patients from 2 large urban centres, and we examine the feasibility of a placebo-controlled randomized trial (RCT) of supplementation in this population. Patients and Methods: Women diagnosed with T1-3, N0-3, M0 invasive BC within the previous 2 years were prospectively identified from institutional registries and recruited from Mount Sinai Hospital, Toronto and UCLA, Los Angeles (LA), between March 2009 and January 2010. Anthropometric measurements were performed, and dietary, lifestyle and medication histories were obtained using structured questionnaires and interviews. Tumor and treatment characteristics were obtained from clinical records; blood samples were collected for analysis of Vit D levels. The pre-specified feasibility criteria for a Vit D (vs placebo) RCT were: ≥30% of patients with (i) deficient or insufficient Vit D levels, (ii) taking ≥1000 IU Vit D/day and (iii) willing to participate in such a trial. Results: 173 eligible patients were enrolled (80 Toronto, 93 LA). Median age at enrollment was 57 years; 73.4% were post-menopausal. Median tumor size (1.8 cm), lymph node involvement (39%), ER (80%), PR (65%) and Her2 (15%) positivity were similar between centres. Treatment characteristics including rates of mastectomy (44%), adjuvant chemotherapy (56%), radiation (68%), hormonal therapy (69%) and trastuzumab (14%) did not differ between centres. 84.4% of women reported use of Vit D containing supplements, with median daily doses of 1200 IU (Toronto) and 1400 IU (LA) (p=0.3) among users. Respective median 25-OH Vit D levels were 85.5 nmol/L (34.3 ng/mL) and 98.5 nmol/L (39.5 ng/mL) (p=0.04), and rates of deficiency, insufficiency and adequacy were 3.8%, 23.8%, 72.5% (Toronto) and 4.3%, 20.7%, 75.0% (LA) (p=0.88). No Vit D levels were in the toxic range. 25-OH Vit D levels correlated with Vit D supplement use (r=0.41, P Conclusions: Vit D levels and supplementation rates are substantially higher in these BC patients than in previous cohorts, though more than 25% of women do not have adequate levels. Rates of adequacy did not differ between patients recruited in Toronto and LA. While the maj ority of women would be willing to participate in an RCT of Vit D supplementation, low levels of deficiency/insufficiency and high rates of supplement use may limit the feasibility of such a study. Funded by the Breast Cancer Research Foundation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-09.

Background: Numerous epidemiological and pre-clinical studies have associated potential antineoplastic activity with the antidiabetic drug metformin in various tumor types including breast cancer (BC). We are conducting a neoadjuvant “window of opportunity” study to examine biologic and clinical effects of metformin in early stage BC. Data from a planned interim analysis are presented here. Materials and methods: 15 of planned 40 non-diabetic women < 75 yo with newly diagnosed untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until definitive surgery. Fasting blood and tumor tissue were obtained, anthropometric measurements performed and the EORTC QLQ C-30 administered pre-metformin and on the day of surgery. Clinical (weight, symptoms, EORTC QLQ C-30) and biologic characteristics were compared pre-metformin and at the end of metformin treatment as were Ki67 (our primary end-point), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), cleaved caspase 3, physiologic markers (insulin, HOMA,TNF-alpha) and molecular markers [phosphorylated 4E-BP1, phosphorylated protein kinase B (P-PKB/Akt), phosphorylated AMPK (P-AMPK), insulin receptor(IR), Insulin-like growth factor 1 receptor(IGF-1R)]. Analysis of Ki67, cleaved Caspase 3 and TUNNEL were performed on a blinded fashion. Ki-67 was scored by manual count selected by and expressed as percentage of cells with positive nuclear staining. Results: Mean age was 51.7 years. 73.3% (11/15) and 26.7% (4/15) had T1 and T2 BC respectively; 40% (6/15) were node positive, 86.7% (13/15) were ER and PR positive and 26.6% (4/15) were HER-2 +. Metformin was administered for a median of 21 days (range 14 - 40). Gastrointestinal (GI) side effects were most frequent and usually self-limiting — mild diarrhoea 60% (9/15), anorexia 53% (8/15) and nausea 46% (7/15). EORTC30 QLQ scores were stable. Weight decreased (mean change -0.81 kg; Mann-Whitney U p-value 0.057). HOMA (a marker of insulin sensitivity) and C-reactive protein improved, mean change -0.32 and -0.21mg/L respectively. Ki67 decreased significantly after metformin treatment (from 27.6 to 22.7, Wilcoxon signed-rank test p-value = 0.043); TUNEL staining increased significantly (from 0.43 to 1.48, p=0.03) and cleaved Caspase 3 increased non-significantly (from 1.01 to 3.96, p=0.31). Conclusion: Preoperative metformin was well tolerated with mild GI toxicities, but no significant QOL effects; it was associated with improved insulin resistance. A short term administration of metformin significantly reduced breast cancer cell proliferation (as measured by change in Ki67 index) and induced apoptosis (reflected by TUNEL). Metformin administration elicited potential physiologic and cellular effects in breast cancer that are in keeping with beneficial anti-cancer effects. Updated results and the impact of metformin on IR/IGF1R/PI3K and AMPK/mTOR signaling pathways within the cancers will be reported. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-06.

557Background: The diabetes drug metformin may improve BC outcomes through enhanced obesity-related physiology or direct anti-tumor effects. We studied the effect of metformin on CA15-3 (the solubl...

OBJECTIVE To formulate a patient-rated assessment tool that facilitates the measurement of pain and polysymptom distress directly related to all classes of wounds. DESIGN A prospective observational study derived from a sequential case series of patients with advanced illness was carried out to determine the most common symptoms associated with wounds from 9 distinct classes (malignant, pressure ulcers, iatrogenic, traumatic, diabetic foot ulcers, venous ulcers, arterial ulcers, infections/inflammatory lesions, and ostomies). Ten wound-related symptoms were identified and used to create a patient-scored assessment tool. The Toronto Symptom Assessment System for Wounds (TSAS-W) was then developed and used in a pilot trial during which patients completed TSAS-W at baseline and 7 days later. PARTICIPANTS Five hundred thirty-one patients either presented with wounds at baseline or developed them during the 24-month follow-up period. Patients affected by any type of wound were asked to report on the top 3 symptoms directly attributable to their wounds. The pilot trial of TSAS-W involved 103 wounds afflicting 83 sequential patients. MAIN RESULTS The most prevalent wound-related symptoms included pain, exudation, odor, itching, bleeding, aesthetic concern, swelling, and mass and bulk effects from the wound and associated dressings; 78.6% of the TSAS-W assessments were carried out by the patient alone, 14.6% were carried out by the patient assisted by a caregiver, and 6.8% were carried out entirely by a caregiver. The summation of all 10 TSAS-W parameters, the global wound symptom distress score (GWSDS), resulted in a mean for all wounds of 34.47 at baseline and decreased to a mean of 28.40 at 7 days later. Cosmetic or aesthetic concern and/or distress was associated with the highest mean scores of all symptoms. Malignant wounds and wounds involving the perineum and genitalia were associated with the highest GWSDSs. CONCLUSION The TSAS-W is a new tool for systematically assessing the degree of pain and polysymptom distress associated with all classes of wounds. It is modeled after the Edmonton Symptom Assessment System that is widely used and validated in the palliative care arena. TSAS-W is composed of 10 symptom parameters that are individually assessed on 11-point numeric rating scales (0-10). The summation of all of the element symptom scores equates to a GWSDS. It may be used in the clinical setting to guide wound-related pain and polysymptom management. In addition, TSAS-W may be useful as a tool in facilitating clinical audit and future wound care research.

Purpose Vitamin D has been linked to breast cancer risk, but prognostic effects are unknown. Such effects are biologically plausible given the presence of vitamin D receptors in breast cancer cells, which act as nuclear transcription factors to regulate gene activity. Patients and Methods The study was conducted in a prospective inception cohort of 512 women with early breast cancer diagnosed 1989 to 1996. Vitamin D levels were measured in stored blood. Clinical, pathologic, and dietary data were accessed to examine prognostic effects of vitamin D. Results Mean age was 50.4 years, mean vitamin D was 58.1 ± 23.4 nmol/L. Vitamin D levels were deficient (< 50 nmol/L) in 37.5% of patients, insufficient (50 to 72 nmol/L) in 38.5% of patients, and sufficient (> 72 nmol/L) in 24.0% of patients. There was little variation in mean vitamin D levels between summer and winter months. Mean follow-up was 11.6 years; 116 women had distant recurrences, and 106 women died. Women with deficient vitamin D levels had an increased risk of distant recurrence (hazard ratio [HR] = 1.94; 95% CI, 1.16 to 3.25) and death (HR = 1.73; 95% CI, 1.05 to 2.86) compared with those with sufficient levels. The association remained after individual adjustment for key tumor and treatment related factors but was attenuated in multivariate analyses (HR = 1.71; 95% CI, 1.02 to 2.86 for distant recurrence; HR = 1.60; 95% CI, 0.96 to 2.64 for death). Conclusion Vitamin D deficiency may be associated with poor outcomes in breast cancer.

Context.—Measuring the extent of nonpalpable ductal carcinoma in situ (DCIS) in a breast specimen is challenging but important because it influences patient management. There is no standardized method for estimating the extent of DCIS, although serial sequential sampling with mammographic correlation is considered an accurate method. Objective.—To estimate the extent of DCIS using various methods and to compare these estimations with the extent as determined by the serial sequential sampling method. Design.—A total of 78 primary breast excisions with DCIS were retrospectively reviewed. All specimens had been sampled using the serial sequential sampling method, which involved mapping the location of each block on the sliced specimen radiograph and calculating the extent through 3-dimensional reconstruction. The other measures for estimating extent included (1) calculating size based on areas of calcification, (2) recording the number of blocks involved by DCIS and multiplying that number by 0.3 cm, and (3) measuring the largest extent of DCIS on a single slide. Results.—All 3 alternative methods tended to underestimate the DCIS. Discrepancies became more pronounced as size increased. The percentage of cases estimated to within 1 cm of the serial sequential sampling method were 81%, 72%, and 50%, respectively, for the calcification, blocks, and single-slide methods; differences of more than 2 cm were seen in 9%, 8%, and 30% of cases, respectively. Conclusions.—The single-slide method performed poorly and should be used only when DCIS is limited to a single slide. Although the calcification and the blocks methods gave better estimates, both produced substantial underestimates and/or overestimates that could affect clinical decision making.

Obesity has been associated with poor breast cancer outcomes. Insulin may mediate this effect, interacting with insulin receptors on breast cancer cells. Metformin, a biguanide derivative used in the treatment of diabetes, reduces insulin levels in subjects with type 2 diabetes and other insulin-resistant states. If metformin lowers insulin levels in women with breast cancer, it may also improve breast cancer outcomes.We administered metformin (1500 mg per day) to 32 women with early breast cancer whose baseline insulin levels were at least 45 pmol/L to determine its effect on insulin levels.Twenty-two (69%) women completed the 6-month intervention. Four women (12.5%) dropped out because of gastrointestinal side effects; the others withdrew for reasons not related to toxicity. Completers were similar to noncompleters for all baseline characteristics apart from global health, overall physical condition, overall quality of life, physical function, and social function (HRQOL), which was decreased in noncompleters. Metformin significantly lowered fasting insulin levels by 15.8 pmol/L (22.4%; P=.024) and improved insulin sensitivity by 25.6% (P=.018), total cholesterol by 5.3%, and low-density lipoprotein (LDL) cholesterol by 9.1%. Metformin reduced weight by 1.9 kg (2.5%; P=.01), and it had no significant effects on HRQOL or specific gastrointestinal symptoms (appetite, nausea/vomiting, diarrhea, constipation).Metformin significantly lowers insulin levels, and it improves insulin resistance in nondiabetic women with breast cancer. A phase III randomized trial to evaluate its effects on breast cancer outcomes is recommended.

Pres de 60% des patients atteints d'un accident vasculaire cerebral (AVC) presentent une hyperglycemie. Les lignes directrices recommandent de surveiller le glucose apres un AVC, mais elles fournissent peu de recommandations de traitement. Nous avons examine les pratiques des medecins a ce sujet. Methodes : La population de l'etude etait constituee des urgentologues, des medecins de famille, des internistes, des intensivistes et des neurologues de l'Ontario. Nous avons distribue par la poste un questionnaire a completer au sujet de leur attitude therapeutique concernant le glucose. Nous presentons les reponses aux questions de l'enquete sous forme de proportions. Le test du chi-carre a ete utilise pour comparer les groupes de medecins. Resultats : Des questionnaires ont ete postes a 2 280 medecins ; 26,8% ont retourne le questionnaire. Deux cent soixante-dix-huit repondants ont rapporte qu'ils traitaient des patients porteurs d'AVC. Parmi ceux qui traitaient le glucose chez les patients porteurs d'un AVC, 16,6% ciblaient un glucose entre 4,0 et 6,0 mmol/L, 52% ciblaient un glucose entre 6,1 et 8,0 mmol/L, 13,6% ciblaient un glucose entre 8,1 et 12,0 mmol/L, 0,8% ciblaient un glucose entre 12,1 et 15,0 mmol/L et 7,5% etaient indecis. Si nous comparons les reponses par specialite, 32% des intensivistes, 17,5% des neurologues, 13% des internistes, 14% des urgentologues et 0% des medecins de famille ont rapporte une cible de 4,0 a 6,0 mmol/L (p = 0,026). Dans l'ensemble, 44% ont rapporte un chiffre cible pour le glucose dans les 12 heures et 77% dans les 24 heures de l'arrivee du patient a l'hopital. Les intensivistes etaient ceux qui traitaient le glucose de la facon la plus agressive et 20% d'entre eux traitaient les patients non diabetiques avec un glucose initial de 6,0 a 8,0 mmol/L par une infusion d'insuline. Les urgentologues etaient les plus conservateurs dans le traitement du glucose chez les patients porteurs d'un AVC. Conclusion : II existe une certaine variabilite dans l'attitude therapeutique de differents groupes de specialistes concernant le glucose chez les patients presentant un AVC. Cette constatation reflete l'absence de donnees pour guider le traitement de l'hyperglycemie dans ce contexte et souligne une lacune importante dans les connaissances et les recommandations therapeutiques sur l'AVC qu'on devra combler pour optimiser le pronostic des patients atteints d'AVC.

A prospective observational sequential case series was studied in order to ascertain an accurate inventory of the various wound types, their point prevalence and incidence rates and their anatomic locations in patients with advanced illness. Five hundred and ninety‐three patients were serially assessed until their deaths. Forty‐three individual wound types were identified and grouped into nine distinct classes. Data were stratified between patients suffering from malignant and non malignant disorders. One thousand and thirty‐six individual wounds (average 1·8 wounds per patient) were identified at baseline. Eight hundred and ninety‐one individual wounds (average 1·5 wounds per patient) were identified between baseline and their date of death. Pressure ulcers constituted the most commonly occurring wound class affecting more than 50% of all patients. Malignant wounds were observed only in cancer patients. Baseline point prevalence for pressure ulcers, traumatic wounds, venous ulcers and arterial ulcers in non cancer patients exceeded that in cancer patients. At baseline, iatrogenic wounds were more prevalent in cancer patients than in non cancer patients. Incidence rates for pressure ulcers, traumatic wounds, diabetic ulcers, arterial ulcers and ostomies in non cancer patients exceeded those in cancer patients. The broad range of wounds along with high rates of prevalence and incidence, identified in this study, reflects that wounds represent a significant management issue for patients with advanced illness. Therefore, there exists a need for advancement in modalities and measures aimed at risk assessment, prevention and appropriate goal‐oriented management.

Fasting insulin is related to outcome in early breast cancer. We evaluated the expression of insulin receptor (IR) and its prognostic significance in patients with early stage breast cancer. Tumors from 191 patients with T1-3, N0-1, M0 breast cancer who were enrolled at a single center of a multicenter cohort study were used to construct microarrays with subsequent immunohistochemical evaluation of IR, IGF-IR, ER, PgR and HER2/neu. Correlation of biomarker expression with traditional prognostic factors, serum biochemistry (notably insulin) and clinical outcome was assessed. IR was strongly positive (Allred score = 8) in 54% of tumors. High IR expression significantly correlated with favorable prognostic markers (low tumor grade, lymph node negativity and progesterone receptor positivity) but not with fasting levels of circulating insulin. At a median follow-up of 9.1 years, high vs. low IR expression (an Allred score of 8 vs. 0-7) was associated with statistically significant improved distant disease-free survival (multivariate hazard ratio (HR) = 0.4; P = 0.027) and overall survival (multivariate HR = 0.26; P = 0.005). IR is highly expressed in the majority of early stage breast cancers but this expression is not clearly down-regulated in the presence of high insulin levels. Furthermore, high expression of IR is independently and significantly associated with more favorable clinical outcomes. Follow-up intervention research is recommended.

Although prophylactic cranial irradiation (PCI) has been the standard of practice for patients successfully treated for limited stage small cell lung cancer for decades, subsequent changes in patient selection, updated brain imaging guidelines, an increased understanding of the mechanisms underlying the deleterious effects of whole brain irradiation as well as ongoing investigations into improving radiation treatment delivery have begun to question the current role of PCI. Who should be treated and how? This review attempts to gather together evidence for improving patient selection and describe potential improvements in treatment delivery.