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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.

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.

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.

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.

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.

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.

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.

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: 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.

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.

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.

Background: The anti-diabetic drug metformin, commonly used to treat type 2 diabetes due to its ability to reduce circulating glucose and insulin, has emerged as a potential anti-cancer agent. Observational studies have reported decreased cancer incidence and mortality in diabetics receiving metformin. Metformin's ability to reduce insulin may be particularly important for breast cancer (BC) because hyperinsulinemia is an adverse prognostic factor and most cells express the insulin receptor (IR). The anti-cancer effects of metformin are associated with both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMPK and an inhibition of mTOR signalling, while indirect effects are mediated by reductions in circulating insulin levels, leading to reduced IR-activated PI3K signalling. We conducted a neoadjuvant, single arm, “window of opportunity” trial examining the clinical and biological effects of metformin on thirty-nine locoregional BC patients awaiting definitive surgery. Methods: Non-diabetic women with newly diagnosed, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood and tumour samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, while IHC analysis of tumours was used to characterize cellular markers before and after metformin. Specifically, IR levels and the phosphorylation status of proteins involved in AMPK and PI3K/AKT/mTOR signalling, including AMPK (T172) and AKT (S473), were examined. Results: 39 patients with a mean age of 51 years received metformin for a median of 18 days (range 13–40) with minor GI toxicities. The clinical effects (previously reported) included significant (p < 0.05) decreases in body mass index (−0.5 kg/m2), weight (−1.2 kg), glucose (−0.14 mM) and HOMA (an estimate of insulin resistance, −0.21), and a decrease in insulin (−4.7 pmol/L) that approached significance (p = 0.0686). Ki67 staining in tumour tissue decreased significantly and TUNEL increased significantly. Levels of IR expression decreased significantly (from 4.39 to 3.82, p = 0.0375) as did the phosphorylation status of AKT (S473) and AMPK (T172) (from 9.82 to 7.08, p = Conclusions: Metformin impact was consistent with beneficial anti-cancer effects. Reduced AKT phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. Assessment of additional factors in BC cells, including OCT1 expression (required for metformin uptake), and the phosphorylation of ACC (a marker of AMPK activation), is underway and will be reported. Integrated analysis of these factors combined with the physiological and molecular data described above will further enhance understanding of metformin action in the clinical setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-05.

Background/Aims: Obesity is associated with a 30-50% increased risk of breast-cancer (BC) mortality, most consistently in estrogen receptor (ER) positive disease, through unclear mechanisms. Leptin is a multi-functional protein with key actions on adipose tissue. In pre-clinical studies, leptin stimulates the growth, survival, and progression of BC cells through both estrogen dependent and other (e.g. JAK/STAT, PI3K/Akt, MAPK) pathways. Leptin has also been associated with increased BC risk and poor prognosis. Our aim was to correlate tumor leptin-receptor (OB-R) expression with tissue markers of cell signaling and systemic markers of obesity, inflammation, and metabolism in a cohort of ER+/HER2- BC patients. Methods: From our biorepository, we identified ER+/HER2- BC patients having both blood and tissue samples available. Data included BMI, menopausal status, and family/cancer/medical history, tumor histology, grade, stage, and ER/PgR/HER2 status. We performed blood assays for factors related to inflammation, tumor growth, hormonal regulation, and metabolism (see below). Immunohistochemistry for OB-R, pAkt (S473), pERK (T202/Y204), and insulin-receptor (IR) was performed on archived tissue, and scored for % positive cells and intensity of staining. Allred and H-scores were calculated. Associations with OB-R scores were calculated using Pearson, Spearman, and χ2 methods. Results: 129 patients were eligible; 69.8% were post-menopausal and mean BMI was 27.8 ± 6.5 kg/m2. Most tumors were no-special-type (79%), PgR+ (90%), and node-neg (78%). The tissue expression of OB-R and other markers was scorable in 118 (91%) cases. OB-R was expressed in all 118/118 cancers (Allred score range: 3 to 8; median 7, mean 6.61). High blood leptin did not downregulate OB-R (Spearman R=0), even though leptin was strongly correlated with BMI (Pearson r=0.78, p OB-R correlated with ER (Spearman R = 0.27), PgR (R=0.29), and insulin receptor (R = 0.24), weakly correlated with estradiol (Spearman, R=0.11) and fasting glucose (R=0.18), and negatively correlated with systemic IL-2 (R=-0.11) and IL-6 (R=-0.21). OB-R was not correlated with other blood markers (insulin, HOMA, PAI-1, IL-1ẞ, IL-8, VEGF, EGF, TNF-α,hsCRP, SHBG, or estrogens) or tumor grade. Conclusions: OB-R is highly expressed in breast tumor tissue even in non-obese patients. Although leptin and BMI did not modulate OB-R expression, downstream signaling (e.g. Akt, ERK) did show a BMI-dependent effect, albeit of limited magnitude. This suggests that leptin acts on breast cancer cells through OB-R activation and downstream Akt/ERK signaling, without a coupled change in total OB-R expression. Further work is needed to elucidate the roles of inflammation, estrogens, and regulatory mechanisms within the PI3K-PTEN and Ras-MAPK cell-signaling networks. The authors wish to acknowledge the generous support of the Breast Cancer Research Foundation and Hold'Em For Life Charity Challenge. Citation Format: Chang MC, Ennis M, Dowling RJO, Stambolic V, Goodwin PJ. Leptin receptor (OB-R) in breast carcinoma tissue: Ubiquitous expression and correlation with leptin-mediated signaling, but not with systemic markers of obesity [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 P6-02-03.

Supportive-expressive group therapy has been reported to prolong survival among women with metastatic breast cancer. However, in recent studies, various psychosocial interventions have not prolonged survival.In a multicenter trial, we randomly assigned 235 women with metastatic breast cancer who were expected to survive at least three months in a 2:1 ratio to an intervention group that participated in weekly supportive-expressive group therapy (158 women) or to a control group that received no such intervention (77 women). All the women received educational materials and any medical or psychosocial care that was deemed necessary. The primary outcome was survival; psychosocial function was assessed by self-reported questionnaires.Women assigned to supportive-expressive therapy had greater improvement in psychological symptoms and reported less pain (P=0.04) than women in the control group. A significant interaction of treatment-group assignment with base-line psychological score was found (P/=0.003 for the comparison of mood variables; P=0.04 for the comparison of pain); women who were more distressed benefited, whereas those who were less distressed did not. The psychological intervention did not prolong survival (median survival, 17.9 months in the intervention group and 17.6 months in the control group; hazard ratio for death according to the univariate analysis, 1.06 [95 percent confidence interval, 0.78 to 1.45]; hazard ratio according to the multivariate analysis, 1.23 [95 percent confidence interval, 0.88 to 1.72]).Supportive-expressive group therapy does not prolong survival in women with metastatic breast cancer. It improves mood and the perception of pain, particularly in women who are initially more distressed.

Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman’s rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69–1.52, P = 0.9 and HR 1.27, 95 % CI 0.86–1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66–1.59, P = 0.93 and HR 1.17, 95 % CI 0.76–1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome.

Background: Elevated levels of circulating tumor cells (CTCs) are associated with adverse outcomes in metastatic breast cancer (BC). However, relationships between CTCs and various patient-related factors that may impact outcome remain undefined. Consequently, associations of CTC counts with obesity and metabolic factors were evaluated in order to gain insight into potential interactions between patient physiology and disease burden. We hypothesized that obesity and associated metabolic factors would be associated with higher CTC counts. Methods: Non-diabetic women with metastatic BC beginning a new line of treatment due to progressive disease were recruited from four Ontario cancer hospitals between February 2013 and April 2015. Patients provided blood for CTC analysis, which was completed within 72 hours of collection using the Janssen CellSearch platform. Fasting serum was also collected for assessment of metabolic factors including glucose (mmol/L), insulin (pmol/L), leptin (ng/mL) and adiponectin (ng/mL). Associations of CTC counts with these factors, as well as anthropometric measurements (height (cm), weight (kg), BMI (kg/m2)) were evaluated using Pearson correlation coefficients after transforming the variables involved to normality. For CTC counts, the log transformation with half integer correction was used. Results: 96 patients with a median age of 60.5 years completed the study. Most were post-menopausal (87, 90.6%) and exhibited grade II/III tumors (75, 78.1%). The majority of patients had hormone receptor positive disease (83, 86.5%), but 16.7% (16) were HER2 positive and 10.4% (10) were triple negative. The number of CTCs observed ranged from 0 to 1238 (median 2, geometric mean 3.63). No CTCs were detected in 29 patients (30.2%), whereas 25 patients (26 %) exhibited counts of 1 to 4 CTCs and 42 (43.8%) had 5 or more CTCs. CTCs were not significantly associated with tumor characteristics including ER/PgR, HER2, grade, stage (T/N) or lymphovascular invasion. The number of CTCs inversely correlated with BMI (r=-0.26, p=0.01), leptin (r=-0.29, p=0.004), and leptin-adiponectin ratio (r=-0.3, p=0.004). A similar trend that approached significance was noted for body weight (r=-0.19, p=0.07), insulin (r=-0.19, p=0.06) and homeostatic model assessment (HOMA, an estimate of insulin resistance, r=-0.2, p=0.055). Conversely, adiponectin (r=0.18, p=0.07) and height (r=0.18, p=0.07) were positively associated with CTC counts in correlations that neared significance. No associations were observed for age (r=0.09, p=0.4) or glucose (r=-0.09, p=0.4). Conclusions: Obesity associated metabolic factors including weight, BMI, insulin, HOMA and leptin were inversely associated (and adiponectin and height positively associated) with CTC counts. These patterns are consistent with weight loss and/or cachexia in women with elevated CTC counts who have higher disease burden. Additional analyses are underway to further characterize these associations and include assessment of serum albumin, free fatty acids, creatine kinase and hepcidin. Citation Format: Dowling RJO, Chang MC, Lohmann AE, Ennis M, Amir E, Elser C, Brezden-Masley C, Vandenberg T, Lee E, Fazaee K, Stambolic V, Goodwin PJ. Obesity associated factors are inversely associated with circulating tumor cells in metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-09.

Background: Circulating tumor cells (CTCs) are associated with prognosis in metastatic breast cancer (BC). We evaluated the association of inflammatory/tumor markers and CTCs in women with progressing metastatic breast cancer prior to commencing a new line of systemic therapy. Methods: From February 2013 to April 2015, 96 patients with metastatic BC about to start a new treatment (due to progression), without current diabetes or use of anti-inflammatory agents, were recruited from four Ontario cancer hospitals. Women provided fasting blood for inflammatory and tumor markers and CTC measurement; CTCs were assayed within 72 hours of collection using CellSearch. Blood was frozen at -80C until assays were performed in a single batch (C-reactive protein (CRP), IL-6, PAI-1, Ca15-3, Ca125, VEGF, TNFa). Associations of CTCs with blood factors were evaluated using Pearson correlation coefficients after transforming the variables to normality. For CTCs the transformation log(x+0.5) was used. Associations with categorical variables were tested using one-way analysis of variance. P values Results: Median age of patients was 60.5 years, 87 (90.6%) were post-menopausal, 83 (86.5%) had hormone receptor positive BC, 16 (16.7%) HER2 positive BC, 10 (10.4%) triple negative; 75 (78.1%) grade II/III. At the time of CTC measurement, bone, lung, liver and brain metastases were present in 79%, 44%, 40% and 6% of patients respectively, with 54%, 37%, 35% and 3% having progression at these sites respectively. PAI-1 and CA15-3 exceeded the limit of the assay in 11 and 5 cases respectively (the upper limit of the assay was used in the analysis). 33.4% of patients were starting first line therapy, 25% second line and 16.7% third line. CTC counts (per 7.5cc) ranged from 0 to 1238 (median 2, geometric mean 3.63); none were detected in 29 (30.2%) patients, 1 to 4 in 25 (26%) and 5 or more in 42 (43.8%) patients. CTCs were not associated with age, estrogen receptor, progesterone receptor, HER2, line of treatment, lymph-vascular invasion or tumor grade. Compared to metastatic disease at other sites, CTCs were higher in the presence of bone (p=0.027) and liver metastases (p=0.002) and with progressing bone (p=0.018) and liver (p=0.012) metastases. CTCs were significantly associated with CRP (R =0.25, p=0.014), IL-6 (R=0.31, p=0.002), PAI-1 (R=0.31, p=0.002), Ca15-3 (R=0.44, p= Conclusion: CTCs were associated with bone and liver metastases and with higher levels of inflammatory and tumor markers, potentially reflecting tumor burden. Additional inflammatory marker assays are underway. Future studies are warranted to confirm these findings. Citation Format: Lohmann AE, Chang M, Dowling RJO, Ennis M, Amir E, Elser C, Brezden-Masley C, Vandenberg T, Lee E, Fazae K, Stambolic V, Goodwin PJ. Association of inflammatory and tumor markers with circulating tumor cells in metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-12.

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m2, p

Obesity is associated with poor survival after breast cancer diagnosis in individual studies and meta-analyses. Evidence regarding associations of obesity with breast cancer-specific survival (BCSS) and overall survival (OS) in relation to hormone receptor status, or BCSS in relation to menopausal status has not been evaluated in a previous meta-analysis. In this study, we conducted a meta-analysis of the association of obesity with OS and BCSS in relation to hormone receptor status and menopausal status. MEDLINE, EMBASE, and COCHRANE databases from the first record to December 2011 and presentations made at major international meetings in the last 5 years were searched. We included observational or interventional studies reporting hazard ratios (HRs) of obesity with OS and/or BCSS in relation to hormone receptor and/or menopausal status. Twenty-one studies qualified, meeting the above criteria. The pooled HR for OS in heavier versus lighter women was 1.31 (95 % CI 1.17-1.46) for estrogen receptor/progesterone receptor (ER/PgR) positive cancers; 1.18 (95 % CI 1.06-1.31) for ER/PgR negative cancers; and the difference between the two groups was not significant (p = 0.31). The pooled HR for OS in heavier versus lighter women was 1.23 (95 % CI 1.07-1.42) for premenopausal women and 1.15 (95 % CI 1.06-1.26) for post-menopausal women, and the difference between the two groups was not significant (p = 0.57). Comparable pooled HRs for BCSS were 1.36 (95 % CI 1.20-1.54) for ER/PgR positive cancers and 1.46 (95 % CI 0.98-2.19) for ER/PgR negative cancers; and 1.18 (95 % CI 0.82-1.70) for pre-menopausal women and 1.38 (95 % CI 1.11-1.71) for post-menopausal women, also without significant group differences. Results were similar after adjustment for BMI measurement technique, years of follow-up, or study design. These findings led us to conclude that there is no evidence showing that the association of obesity with breast cancer outcome differs by hormone receptor or menopausal status. This has implications for studies of weight loss interventions in the adjuvant BC setting.

Purpose Nonhormonal pharmacologic interventions are recommended for the treatment of hot flashes in breast cancer survivors. Antidepressants and gabapentin have been shown to be both effective and well tolerated; however, it is not clear which is preferred. Patients and Methods This was a group-sequential, open-label, randomized, cross-over trial of 4 weeks of venlafaxine (37.5 mg daily for 7 days followed by 75 mg daily for 21 days) versus gabapentin (300 mg once per day for 3 days, then 300 mg twice per day for 3 days, then 300 mg three times per day for 22 days), with patient preference as the primary outcome. Postmenopausal women with at least 14 bothersome hot flashes per week for the prior month were eligible. A 2-week baseline period and a 2-week tapering/washout time was used before the first and second treatment periods, respectively. Diaries were used to measure hot flashes and potential toxicities throughout the study. Participants completed a preference questionnaire at the end of the study. A predefined Pocock stopping rule was applied. Patient preference and hot flash and toxicity outcomes were compared between treatments. Results Sixty-six patients were randomly assigned, 56 of whom provided a preference (eight dropped out and two had no preference); 18 (32%) preferred gabapentin and 38 (68%) preferred venlafaxine (P = .01). Both agents reduced hot flash scores to a similar extent (66% reduction). Venlafaxine was associated with increased nausea, appetite loss, constipation, and reduced negative mood changes compared with gabapentin, whereas gabapentin was associated with increased dizziness and appetite compared with venlafaxine (all P < .05). Conclusion Breast cancer survivors prefer venlafaxine over gabapentin for treating hot flashes.

BACKGROUND Currently available prognostic models for noncancer patients lack high levels of discrimination. Therefore, the quest for additional prognostic factors must continue. To date, none have utilized the occurrence of wounds as a prognostic factor. METHODS As a prospective observational study, based on a sequential case series of 189 advanced noncancer patients, all wounds were documented. One hundred seventy patients were followed until their deaths. Univariate and multivariate survival analyses were performed using hazard ratios (HRs) derived from Cox proportional hazard models. RESULTS Seventy-eight percent of patients presented with at least one wound at referral. Patients with wounds displayed worse overall survival than those without wounds (p = 0.009). Survival analysis for the full postreferral period revealed a violation of the proportional hazards assumption for pressure ulcers and the Palliative Performance Scale version 2 (PPSv2). In order to address this finding, early deaths (within 14 days of referral) were assessed separately from later deaths (more than 14 days after referral). After controlling for the co-occurrence of wounds, age, gender, Charlson comorbidity index, and PPSv2, pressure ulcers were associated with statistically significant increased risk of death for patients of sufficient health to survive at least 2 weeks after referral (HR 2.42, p = 0.003), while other wounds were associated with greater levels of mortality over the full postreferral period (HR 1.96, p = 0.0001). DISCUSSION The occurrence of pressure ulcers and other wounds are correlated with reduced survival in patients with advanced noncancer illness. These data merit incorporation into existing prognostic models or used in conjunction with them to enhance prognostic accuracy.

The mechanism of the association between breast cancer and obesity remains unknown. To investigate this mice over-expressing HER2/Neu in the mammary gland (MMTV-HER2/Neu) were fed either a high-fat diet (45% of calories) (HFD) or low-fat diet (10%) (LFD) from 4 weeks of age and followed for up to 1 year, or sacrificed when a mammary tumor reached 1.5 cm. There was a small but significant increase in body weight on HFD (P < 0.05) and the HFD mice displayed a greater fat mass determined by MRI (P < 0.01). Mild glucose intolerance was observed from 3 months of age on HFD, but insulin levels were not elevated. While the time of onset of a first tumor and tumor growth rates were not altered, mice on HFD had an earlier onset of a second tumor and a twofold greater incidence (LFD 25%, HFD 54%) and a greater absolute number of multiple tumors (tumors/mouse, LFD 1.5 ± 0.25 vs. HFD 2.7 ± 0.23, P < 0.01). Consistent with a lack of hyperinsulinemia, immunoblotting of skeletal muscle lysates from mice injected with insulin showed no insulin resistance determined by the phosphorylation of Akt/PKB. Similarly, there was no difference in basal or maximum insulin-stimulated phosphorylation of IRS-1/2, Akt/PKB, or p70 S6K in tumor cell lysates from HFD and LFD groups. Immunohistochemistry revealed no difference in tumor tissue staining for the proliferative marker, Ki67, between diets. These data indicate that HFD, in the absence of significant insulin resistance, mediates a tumor promoting, but not a tumor growth effect in this model of mammary carcinogenesis.

A number of validated and objectively based prognostic models are available for use in cancer care. The quest for additional prognostic factors continues in order to increase their accuracy. To date, none has considered the effect that wounds may contribute to assessing survival. This study serves to demonstrate that certain wound classes affecting cancer patients carry associations with survival. As a prospective observational study, based on a sequential case series of 418 advanced cancer patients, all cutaneous and wound issues were documented and monitored. Three hundred and seventy seven patients were followed until their deaths. Univariate and multivariate survival analyses were performed using hazard ratios (HRs) derived from Cox-proportional hazard models. Forty-four percent of patients presented with at least one wound at referral. Patients with wounds displayed worse overall survival than those without wounds (por = 0.0001). A significant interaction was seen between pressure ulcers (PU's) and sex (p=0.0005). After controlling for the co-occurrence of wounds, age, sex, Charlson comorbidity index and PPSv2, statistically significant increased risk of death was observed for female patients with PU's (HR 2.00, p=0.0002), but not for males with PU's (HR 0.83, p=0.328). Malignant wounds were not associated with decreased survival (HR 1.17, p=0.285). The presence of all other wounds was associated with decreased survival (HR 1.48, p=0.002). In summary, the presence of PU's in female cancer patients and 'other' wounds in all cancer patients correlates with reduced survival. Therefore, this data should be incorporated into existing prognostic models or used in conjunction with them in order to enhance prognostic accuracy.

Background High insulin levels have been associated with poor outcomes in breast cancer. Our goal was to investigate whether hyperinsulinemia was associated with insulin resistance in a cohort of newly diagnosed locoregional breast cancer patients and to examine associations of hyperinsulinemia with the broader insulin resistance syndrome (IRS). Methods Five hundred and four women with T1-3, N0-1, M0 breast cancer provided fasting blood that was analyzed for glucose, insulin and lipids. They underwent anthropomorphic measurements and provided information on diet, exercise and sleep. Relationships of insulin with three validated indices of insulin resistance and with attributes of the IRS were examined. Results High insulin levels were strongly correlated with insulin resistance calculated using the three indices of insulin resistance/sensitivity (Spearman r = 0.83–0.98). Hyperinsulinemia was also associated with other components of the IRS (obesity, high waist–hip ratio, lipid profile). Conclusions High insulin levels in women with locoregional breast cancer reflect the presence of insulin resistance and are associated with other components of the IRS. These observations have implications for the development of therapies that target hyperinsulinemia in early stage breast cancer and for the long-term management of breast cancer survivors.

7521 Background: Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with NSCLC. Methods: Tissue from 200 patients with NSCLC at the Pri...

The objective of this study was to examine the association of: (i) diagnosis at age/=35, (ii) first-degree family history of breast or ovarian cancer (BOC) and (iii) a research based definition of genetic risk, with tumor characteristics, treatment and survival in breast cancer (BC).Consenting female participants in the population-based Ontario Familial Breast Cancer Registry diagnosed with primary invasive BC between 1996 and 1998 were followed prospectively until 2005.Among 967 women, 105 were/=35 years old at diagnosis and 686 were classified as genetic risk cases, including 349 with a first-degree family history. Individuals diagnosed at age/=35 were more likely to self-detect tumors, to present with inflammatory BC, to have invasive ductal carcinoma of no special type, high T stage, and tumors with lymphovascular invasion (LVI), high grade and negative estrogen receptors. Younger women were more likely to receive chemotherapy and less likely to receive hormonal therapy. Diagnosis/=35 years old was associated with significantly reduced distant recurrence free survival, an effect that did not persist after adjustment for tumor and treatment related variables. Poor outcomes were restricted to younger women with hormone responsive BC. Family history was associated with increased rates of mammographic detection of BC, lower tumor stage and less frequent inflammatory BC, but had no association with BC outcomes.Women diagnosed with BC at age/=35 have more aggressive tumors; these adverse tumor characteristics, rather than age, lead to poor outcomes. Family history was not associated with survival.

Metastatic breast cancer is associated with psychological distress in one-third of patients. We examined the impact of group psychosocial support on health care costs in metastatic breast cancer. Psychosocial interventions have been shown to reduce psychological distress in these patients. In other diseases, depression and anxiety have been associated with higher health care system resource utilization.Data on health care system resources utilization were collected as part of a Canadian multicenter randomized controlled trial of a supportive-expressive group support in metastatic breast cancer. Costs were obtained from one tertiary care hospital in Toronto. A cost minimization analysis was conducted since there was no survival difference; the primary endpoint of the study. Cost-effectiveness analyses were conducted for mood and pain.Total health care utilization costs (including costs of the group therapy intervention) for the intervention and control groups were $31,715 and $28,189, respectively per patient. The difference in total costs between groups ($3,526) was not statistically significant (P = 0.53). The cost-effectiveness analysis for mood showed the intervention group to have an increased cost of $5,550 per patient for an effect size of 0.5 on the POMS scale. The corresponding cost for pain was $4,309. An exploratory analysis on patients who were more distressed at baseline showed a non-significant decrease in cost in favor of the intervention arm (difference of $3,911 P = 0.66).Psychosocial intervention, in the form of supportive-expressive group support for metastatic breast cancer, does not lower health care system resource utilization.

Purpose. The prognosis of women with early-stage breast cancer is influenced by insulin and body mass index (BMI). High levels of serum insulin and obesity often coexist with dyslipidemia in the insulin resistance syndrome (IRS), but the contribution of lipids to breast cancer outcome is unclear. Here, we examine whether serum levels of total cholesterol (TC) and triglycerides (TG) influence breast cancer outcome. Patients and methods. A cohort of 520 women without known hyperlipidemia or diabetes, with stage T1–T3, N0–N1, M0 breast cancer, was assembled from July 1989 to June 1996. Fasting blood was collected at baseline. Subjects were followed prospectively, for recurrence (local, regional, distant) and death. Cox models were used to calculate the prognostic effect of TC and TG levels. Two-sided significance levels were set at 0.025. Results. TC was correlated with age (Spearman’s r = 0.44) and low tumor grade (p = 0.01), while TG was correlated with insulin (r = 0.43) and BMI (r = 0.45). At a median follow-up of 8.7 years, TC and TG were not associated with breast cancer recurrence or death before of after adjustment for age, tumor-related variables, BMI or fasting insulin levels. In multivariate analysis adjusting for age, tumor-related variables and BMI, a trend towards an adverse effect of TC on disease recurrence was seen (HR recurrence = 1.62 for the 4th versus. 1st quartile, 2-sided p = 0.03). Conclusions. Fasting TG was not associated with outcome. A trend towards risk of recurrence was seen with higher TC in multivariate analysis. This potential association should be explored in future studies.

Purpose Leptin, an adipocyte-derived cytokine that is elevated in obesity, has been associated with carcinogenesis, tumor migration and invasion, enhancement of angiogenesis, and increased aromatase activity. It has been suggested that leptin may mediate adverse prognostic effects of obesity in breast cancer. Patients and Methods Four hundred seventy-one women with surgically resected T1-3, N0-1, M0 breast cancer were studied. Leptin was assayed in stored fasting blood specimens obtained before adjuvant therapy. Women were followed prospectively for distant disease-free survival (DDFS) and overall survival (OS). Results Patients ranged from 26 to 74 years of age, and staging was as follows: T1 = 262, T2 = 151, T3 = 23, TX = 35, N0 = 323, and N1 = 148. Estrogen receptor was positive in 286 patients, and progesterone receptor was positive in 259 patients. One hundred forty-five patients received adjuvant chemotherapy, 146 received adjuvant tamoxifen, 46 received both, and 134 received neither. Mean leptin was 15.2 ± 10.1 ng/mL. Univariately, leptin was associated with OS (overall P = .049; P = .014 postmenopausal). Leptin was not associated with DDFS overall or in any menopausal subgroup (P ≥ .19). In multivariate Cox modeling, leptin was not significantly associated with DDFS or OS (P = .11 and 0.075, respectively). Adjustment for insulin or body mass index further reduced the association of leptin with outcome. Conclusion Although leptin is strongly correlated with obesity and insulin, we could not show that it is independently associated with prognosis in early-stage breast cancer. Because we cannot rule out modest prognostic effects, we recommend additional research to explore this potential association, particularly in postmenopausal women.

Purpose Evidence that psychosocial status and health-related quality of life (HRQOL) are associated with breast cancer (BC) outcomes is weak and inconsistent. We examined prognostic effects of these factors in a prospective cohort study. Patients and Methods Three hundred ninety-seven women with surgically resected T1 to T3, N0/N1, M0 BC completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30 items), Profile of Mood States, Psychosocial Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer Scale, and the Courtauld Emotional Control Scale 2 months after diagnosis and 1 year later. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records, and Cox survival analyses were performed. Results Mean age was 52.0 ± 9.9 years. Two hundred twenty-five women had T1, 136 women had T2, 16 women had T3, and 20 women had TX tumors; 127 were N1. One hundred thirteen women received adjuvant chemotherapy, 130 received hormone therapy, 45 received both, and 109 received neither. We investigated 140 prognostic associations; four were found to be statistically significant at a P value of ≤ .05 (three fewer than expected by chance). Two were in the hypothesized direction of effect, and two were in the opposite direction. All arose from measurements 1 year after diagnosis, which were most susceptible to confounding by treatment. There was no evidence of consistency of associations across outcomes or questionnaires. These results are in keeping with chance as the explanation for our statistically significant findings. Conclusion HRQOL and psychosocial status at diagnosis and 1 year later are not associated with medical outcome in women with early-stage BC.