Insulin receptor loss impairs mammary tumorigenesis in mice.

Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR's role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.

Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Body composition and endometrial cancer outcomes.

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

PD-L1 expression in breast cancer brain metastases.

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

Karnofsky Performance Status (KPS) ≤60 Is Strongly Associated With Shorter Brain-Specific Progression-Free Survival Among Patients With Metastatic Breast Cancer With Brain Metastases.

Objective: To examine the association between Karnofsky Performance Status ("KPS") and brain-specific progression-free survival ("bsPFS") among patients with breast cancer brain metastases ("BCBrM"). Methods: Using a previously compiled retrospective cohort of 683 patients who were treated for BCBrM with surgery and/or radiotherapy at the Sunnybrook Odette Cancer Centre from 2008-2018, electronic records were reviewed to impute KPS scores at the time of BCBrM diagnosis. Patients were then grouped into KPS ≤60 and KPS >60 cohorts. The dataset was analyzed to identify variables that were prognostic for bsPFS and/or overall survival ("OS") using univariable and multivariable Cox proportional hazards models. Results: The mean age of patients was 57 (range 24-93). Most patients (n=622, 91%) had extracranial metastatic disease and 174 (25%) had leptomeningeal disease. 247 patients (36%) had hormone receptor ("HR")-positive/human endothelial growth factor receptor 2 ("HER2")-negative tumours, 189 (28%) had HER2-positive disease, and 153 (22%) had triple-negative breast cancer. Of the 331 patients (48%) who could be assigned a KPS cohort, 102 (31%) had KPS ≤60. Most patients were treated with whole brain radiotherapy (n=498, 73%) and/or stereotactic radiosurgery ("SRS") (n=128, 19%). Median bsPFS was 9 months (95% CI 8-10 months) and median OS was not reached. In univariable analyses, KPS ≤60, presence of leptomeningeal disease, neurological symptoms, ≥2 brain metastases, and not undergoing SRS were factors associated with shorter bsPFS. In a multivariable analysis, KPS ≤60 was the only statistically significant determinant of bsPFS (HR 1.86, 95% CI 1.20-2.88). Although survival data was limited, KPS ≤60 was associated with shorter OS in both univariable (HR 3.12, 95% CI 1.85-5.26) and multivariable (HR 2.95, 95% CI 1.55-5.58) analyses. Conclusion: Patients with BCBrM who have a KPS ≤60 have significantly shorter bsPFS and OS than those with KPS >60. KPS should be documented routinely at the time of diagnosis of brain metastases to improve prognostication.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

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

The Futility of Futility Analyses in Adjuvant Trials in Hormone Receptor-Positive Breast Cancer.

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

Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.

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 < .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .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.

Crown-like structures in breast adipose tissue of breast cancer patients: associations with CD68 expression, obesity, metabolic factors and prognosis.

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.

Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial.

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.

Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis.

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 < .001) for HR+HER2- BC, 1.16 (95% CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2- BC HR = 1.39, 95% CI = 1.20 to 1.62, P < .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2- BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P < .001). CONCLUSIONS: Obesity was associated with modestly worse DFS and OS in all BC subtypes.

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

BACKGROUND: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. METHODS: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. CONCLUSION: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

Prognostic associations of plasma hepcidin in women with early breast cancer.

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/m2), 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.

Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study.

Studies have suggested that women with elevated BMI or 25-OH vitamin D levels may derive less benefit from AIs versus tamoxifen. We prospectively investigated whether high BMI or 25-OH vitamin D levels were associated with higher estrogen levels in post-menopausal women receiving standard adjuvant letrozole (2.5 mg/day). Furthermore, we evaluated whether an increased dose of letrozole resulted in lower serum estrogens in women with BMI > 25 kg/m2. Correlation between entry BMI and day 29 serum biomarkers (estrogens, 25-OH vitamin D, insulin, CRP, leptin) was assessed in all patients. On day 29, participants with BMI > 25 kg/m2 switched to letrozole 5 mg/day for 4-weeks and blood was drawn upon completion of the study. The change in serum estrogen levels was assessed in these patients (BMI > 25 kg/m2). 112 patients completed days 1-28. The Pearson correlations of estradiol and estrone with BMI or serum 25-OH vitamin D levels were near zero (-0.04 to 0.07, p = 0.48-0.69). Similar results were obtained for correlation with markers of obesity (insulin, CRP, and leptin) with estradiol and estrone (-0.15 to 0.12; p = 0.11-0.82). Thirty-one patients (BMI > 25 kg/m2) completed the interventional component; Increasing the dose of letrozole did not further reduce estradiol or estrone levels (change 0.1 and 0.4 pmol/L respectively; p = 0.74 and 0.36). There was no observed association between markers of obesity (BMI, insulin, leptin, and CRP), serum 25-OH vitamin D levels and estradiol or estrone levels. Additionally, an increased dose of letrozole did not further reduce estradiol or estrone levels compared to the standard dose.

A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy.

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.

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.

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.

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.

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

Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer.

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.

Sexual health in long-term breast cancer survivors.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Sexual health and uro-genital symptom counseling should be provided to BCS, particularly pre/peri-menopausal patients, even at long-term follow-up.

Metabolic factors, anthropometric measures, diet, and physical activity in long-term breast cancer survivors: change from diagnosis and comparison to non-breast cancer controls.

PURPOSE: 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. METHOD: 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. RESULTS: Median weight gain in BC survivors was 2.00 kg (p < 0.0001); BMI, glucose, insulin, homeostasis model assessment (HOMA), and total cholesterol increased modestly but significantly. Waist circumference, glucose, and triglycerides were higher in LTFU BC survivors versus controls. BC survivors had significantly greater prevalence of diabetes/pre-diabetes versus controls (33 vs. 20.4%, AE-adjusted odds ratio (OR) 1.59, p = 0.050). This effect was restricted to those with lower levels of physical activity (<56 metabolic equivalent (MET)-hours/week: OR 2.70 versus 0.94 for those with higher physical activity, interaction p = 0.034). At LTFU, BC survivors were more physically active than at diagnosis (median increase 28 MET-hours/week interquartile range -14.8 to 82), and compared to controls (median 68.2 vs. 44 MET-hours/week, p < 0.0001). CONCLUSION: The prevalence of the metabolic syndrome and diabetes/pre-diabetes was significantly higher in BC survivors than in controls group, notably in those with lower levels of physical activity. Enhanced diabetes/metabolic syndrome screening and promotion of physical activity may be warranted in BC survivors.