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Background: The gut microbiome modulates response and resistance to immune checkpoint inhibitors (ICI) across different cancer types. The objective of this study was to explore the association between fecal microbiome profiles and clinical outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with eribulin (E) + pembrolizumab (P) or E alone as part of a randomized phase II study (NCT03051659). Patients and Methods: Metagenomic shotgun sequencing was performed on fecal samples collected prior to randomization from a subset of 26 participating patients (E+P, n = 15; E, n = 11) collected prior to randomization. Sequencing data were processed with MetaPhlAn3 to obtain diversity scores and taxonomic composition profiles. Associations between microbiome diversity, taxonomic composition, and clinical outcomes including survival metrics were assessed using Kaplan-Meier estimation methods and Cox proportional hazard models. Results: In this subset, median follow-up was 21.6 months and median overall survival (OS) was 17.9 months. OS was not statistically significant between two treatment arms as observed in the overall cohort. Metagenomic microbiome analysis revealed higher alpha diversity by inverse Simpson Index values associated with longer survival among all patients (p = 0.004), and in patients in the E + P arm (p = 0.006) but not in the E arm (p = 0.2). At the taxonomic level, longer OS among all patients was associated with a baseline lower relative abundance of Blautia wexlerae (≤0.2%vs >0.2%) (22.1 vs 16.6 months; p = 0.01) and a higher relative abundance of Odoribacter splanchnicus, a common short-chain fatty acid producing gut bacterium (>0.35% vs ≤0.35%) (22.3 vs 11.3 months; p < 0.0001). These associations remained significant after controlling for age, ECOG-PS status, and use or not of prior lines of chemotherapy in the metastatic setting. Conclusions: These results suggest high diversity and composition of the gut microbiome are associated with prolonged OS in HR+ MBC pts receiving eribulin with pembrolizumab. Additional and larger clinical studies are needed to validate these findings and preclinical models are needed to interrogate the mechanisms by which gut microbiome diversity and composition may impact therapeutic response and clinical outcomes in this patient population. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Ashish V. Damania, Molly K. DiLullo, Tanya Keenan, Gerburg M. Wulf, Laura M. Spring, Elizabeth A. Mittendorf, Jennifer A. Ligibel, Nadim J. Ajami, Jennifer Wargo, Nabihah Tayob, Sara Tolaney. PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-05.

Background: Tumor characteristics such as grade, stage and receptor status are associated with breast cancer (BC) prognosis. Less is known about modifiable factors and BC prognosis. Advanced glycation end-products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism, generated in conditions of increased oxidative stress. AGEs irreversibly accumulate in our tissues over time with pathogenic effects on genetic fidelity, protein function, cell signaling pathways, and chronic inflammatory diseases. The total body AGE pool is composed of endogenous AGEs and exogenous AGEs (consumed mainly through processed foods and those cooked at high temperatures). Serum AGE (sAGE) levels, a reflection of total body AGE, are higher in people with poor diet quality, lower levels of physical activity, and in women with BC compared to healthy controls. AGEs promote growth, migration and invasion in BC cell lines and activate prognostic inflammatory mediators such as interleukin-6 and C-reactive protein. Dietary AGEs have been associated with increased BC risk and increased mortality after BC diagnosis whereas lifestyle interventions can lower dietary and sAGE levels. The impact of sAGE levels, a better estimate of total body AGE than dietary AGE, on BC prognosis has not been previously evaluated. Methods: The Women’s Healthy Eating and Living (WHEL) study randomized 3088 BC patients stage I-III who completed their primary therapy to a high-vegetable, low-fat diet or control and followed for a median of 7.3 years. Main outcomes were invasive BC events (recurrence or new primary N=518), death due to BC (N=262) and deaths from any cause (N=315). sAGE was measured as the AGE metabolite carboxymethyllysine (ug/ml) from WHEL fasting blood specimens at study entry. sAGE was logged and corrected for plate batch effect via linear regression and analyzed in continuous scale and in quintiles. The Kaplan-Meier method and Cox regression model were performed for risk impact of sAGE on overall survival (OS), recurrence free survival (RFS), breast cancer specific survival (BCSS) and distant metastasis free survival (DMFS). We additionally adjusted in Cox models for potential confounding variables (age, race, BMI, smoking, alcohol use, physical activity, tumor characteristics). Results: 2564 participants had sAGE available. After excluding samples for excessive variabilities, 2315 samples were analyzed. Raw corrected sAGE ranged from 0.0-48.15 ug/ml (median 7.39); logged and corrected range -5.04-1.67. sAGE was positively associated with BMI (p Citation Format: Lindsay L. Peterson, Yu Tao, Jingqin Luo, Graham A. Colditz, Yikyung Park, Jennifer A. Ligibel, David Turner. PD12-09 Serum Advanced Glycation End-Products are Associated with Breast Cancer Prognosis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-09.

Background: Neoadjuvant chemotherapy is available to women with locally advanced breast cancer where chemotherapy is given prior to surgery. By examining resected tissue following neoadjuvant chemotherapy pathological complete response (pCR) can be determined. pCR is a favorable prognostic factor associated with longer survival compared to residual disease after neoadjuvant chemotherapy. Physical activity and diet may improve some side effects during treatment, but less is known about their effect on chemotherapy completion and more specifically on pCR in the neoadjuvant setting. Utilizing data from a randomized trial of diet and physical activity with a primary endpoint of chemotherapy completion in women with newly diagnosed breast cancer initiating chemotherapy, we evaluated the effect of a lifestyle intervention on pCR among the subset of women in the trial who received neoadjuvant chemotherapy. Methods: The Lifestyle, Exercise and Nutrition Early after Diagnosis (LEANer) Study enrolled 173 women with Stage I-III breast cancer who were randomized to usual care (n = 86) or a yearlong, 16-session, in-person or telephone-administered diet and physical activity intervention (n = 87) delivered by registered dietitians. Among study participants, 73 women received neoadjuvant chemotherapy and of these, 72 (98.6%) had complete follow-up pCR data (intervention = 40; usual care = 32). pCR, dates, doses and reason for dose-adjustments/delays of chemotherapy were abstracted from electronic medical records and confirmed with treating oncologists. A Chi-square test was used to examine the effect of the intervention versus usual care on pCR. Results: The 72 women receiving neoadjuvant chemotherapy with complete follow-up pCR data in LEANer were 49.4±11.6 years old, had a body mass index of 30.0+6.7 kg/m2, and 37.0% and 49.3% had stage I or II breast cancer, respectively. Just over half (52.1%) of women had ER/PR positive cancers and 32.9% of tumors were HER2 positive, with no statistically significant differences in tumor type by study arm. 92.7% of the women randomized to intervention adhered to all of the counseling sessions during their neoadjuvant chemotherapy and had statistically significant improvements in mean physical activity (161 minute increase versus 40 minute increase, p-value = < 0.001) and fiber intake (0.21 gram/day increase versus -5.17 g/day decrease, p-value = 0.020), as well as median fruit and vegetable intake (0.6 serving/day increase versus -0.5 serving/day decrease, p-value = 0.041) compared to usual care. There was a benefit of the intervention on pCR compared to usual care (52.5% with pCR in the intervention arm versus 28.1% with pCR in the usual care arm, p-value = 0.037). The intervention effect on pCR did not appear to be impacted by chemotherapy completion (relative dose intensity of 92% in intervention versus 90% in usual care) or chemotherapy dose delays as these were similar in the two study arms. In mediation analyses, results suggested that the changes in physical activity mediated, at least partially, the intervention effect on pCR. Conclusions: A primarily telephone-based diet and physical activity intervention led to improved pCR compared to usual care among the subset of women with breast cancer in the LEANer Study who received neoadjuvant chemotherapy. As pCR is an important prognostic factor for breast cancer, additional lifestyle interventions focusing on the neoadjuvant treatment setting with pCR as the primary outcome are necessary to confirm the potential benefits of lifestyle changes on pCR. Citation Format: Leah Ferrucci, Tara B. Sanft, Maura Harrigan, Brenda Cartmel, Fangyong Li, Michelle Zupa, Courtney McGowan, Leah Puklin, Thai Hien Nguyen, Anna M. Tanasijevic, Marian L. Neuhouser, Dawn Hershman, Karen Basen-Engquist, Beth Jones, Tish Knobf, Anees B. Chagpar, Andrea L.M. Silber, Jennifer A. Ligibel, Melinda L. Irwin. PD12-08 Randomized trial of exercise and nutrition on pathological complete response among women with breast cancer receiving neoadjuvant chemotherapy: the Lifestyle, Exercise and Nutrition Early after Diagnosis (LEANer) Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-08.

PURPOSE: Factors associated with improving exercise in ovarian cancer survivors remain unknown. We explored characteristics associated with exercise adherence among women treated for ovarian cancer in the Women’s Activity and Lifestyle Study in Connecticut (WALC) randomized controlled trial. METHODS: We evaluated adherence among women randomized to the WALC exercise intervention (N=74). Women had to be exercising ≤ 90 min/week and post-treatment. The intervention included 25 telephone-based exercise counseling sessions over 6 months. Adherence was defined as 150 min/week of moderate/vigorous-intensity exercise. We evaluated factors associated with exercise adherence and duration using multivariate logistic and linear regression. The number of sessions sufficient to achieve 150 min/week was modeled with an unadjusted receiver operating characteristic (ROC) curve. RESULTS: Women were 57.3 ±8.8 years old and 1.7 ± 1.0 years since diagnosis. The mean exercise time over 6 months was 166.0 ± 66.1 min/week, and 64.9% of women met the 150 min/week goal. Women attended 22.8 ±3.6 (92%) counseling sessions. No cancer recurrence during the study (OR = 9.15, 95% Cl: 1.09–44.02) and greater session attendance (OR = 1.21, 95% Cl: 1.02–1.43) were related to meeting the exercise goal. Greater session attendance (P

Weight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status.The authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self-reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis.The cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self-perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self-perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment-related menopause were not associated with weight change.One third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment-related associations were not observed. Age-appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high-risk population.

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [−30.2%; 95% confidence interval (CI), −50.3, −1.0] and IL6 (−30.9%; 95% CI, −47.3, −9.5) but did not change sTNFαR2 (1.0%; 95% CI, −10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (−13.9%; 95% CI, −40.0, 23.4), sTNFαR2 (−10.4%; 95% CI, −21.3, 2.0), or IL6 (−22.9%; 95% CI, −42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (−13.1%; 95% CI, −22.9, −1.0) and IL6 (−38.7%; 95% CI, −52.3, −18.9) but did not change hs-CRP (−20.5%; 95% CI, −44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.

Supplementary Tables 1 and 2

Supplementary Figure 3 - Expression of VEGFR-1 and IL-1ß in TAMs in PAN02 tumors.

Effects of VEGFR-1 signaling ablation on E0771 tumor growth, vascular and immune environment in lean and obese mice.

Supplementary Figure 5 - Effects of VEGFR-1 signaling ablation on PAN02 tumor progression in body-weight matched mice.

Supplementary Figure 10 - Additional measurements of PlGF and VEGF-B; Supplementary Figure 11 - Additional effects of PlGF deletion on obesity-induced tumor progression and systemic metabolism.

Effects of VEGFR-1 signaling ablation on glucose/insulin tolerance and insulin production by the pancreas during obesity.

Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity.Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples.Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity.Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993–3004. ©2016 AACR.

Supplementary Figure 1 - A) Vessel density in PAN02 tumors from lean and obese mice, and effect of VEGFR-1-TK-deletion on tumor vessel density and hypoxia markers in obese mice. Supplementary Figure 2 - Gene expression of M1 / M2 markers in TAMs isolated from PAN02 tumors in lean and obese mice.

Supplementary Figure 7 - Effects of VEGFR-1 signaling ablation on IGF-1R/IR signaling pathways in PAN02 and E0771 tumors implanted in obese mice; Supplementary Figure 8 - Additional effects of VEGFR-1 signaling ablation and metformin on tumor metabolism and vessel density in obese mice.

Effects of VEGFR-1 signaling ablation on body weight gain, immune cell infiltration and vasculature in adipose tissues during obesity.

Supplemental Figure 1: Study Schema Supplemental Table 1: Tissue Insulin Receptor Staining

Supplementary Table 1: Protein quantification of cytokines in tumors and plasma of WT and Flt1TK-/- obese using ELISA; Supplementary Table 2: Quantification of the expression of IL-1ÃŽÃ,² and VEGFR-1 in TAMs from PAN02 tumors by mmunofluorescence.

Purpose:Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.Experimental Design:Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind–body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.Results:Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08).Conclusions:A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.See related commentary by Koelwyn and Jones, p. 5179

Supplementary Methods

The American Society of Clinical Oncology (ASCO) surveyed cancer patients to assess practice patterns related to weight, diet, and exercise as a part of cancer care.An online survey was distributed between March and June 2020 through ASCO channels and patient advocacy organizations. Direct email communication was sent to more than 25,000 contacts, and information about the survey was posted on Cancer.Net. Eligibility criteria included being aged at least 18 years, living in the United States, and having been diagnosed with cancer. Logistic regression was used to determine factors associated with recommendation and referral patterns.In total, 2419 individuals responded to the survey. Most respondents were female (60.1%), 61.1% had an early-stage malignancy, and 48.4% were currently receiving treatment. Breast cancer was the most common cancer (35.7%). The majority of respondents consumed ≤2 servings of fruits and vegetables/d (50.5%) and exercised ≤2 times/wk (50.1%). Exercise was addressed at most or some oncology visits in 56.8% of respondents, diet in 50.1%, and weight in 28.0%. Respondents whose oncology provider provided diet and/or exercise recommendations were more likely to report changes in these behaviors vs. those whose oncology provider did not (exercise: 79.6% vs 69.0%, P.001; diet 81.1% vs 71.3%, P.001; weight 81.0% vs 73.3%, P = .003).In a national survey of oncology patients, slightly more than one-half reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as a part of oncology care.

Adolescent and young adults (AYAs) with cancer experience significant psychological distress due to cancer treatment that can persist long after treatment. However, little is known regarding optimal interventions to support the psychosocial needs of AYAs with cancer.The overall objective of this single arm, longitudinal, pilot study was to determine the feasibility of implementing a mindfulness-based music therapy intervention to improve anxiety and stress in AYAs receiving cancer treatment.AYAs (15 - 39 years old) who were to receive cancer treatment for ≥ eight weeks were recruited from the pediatric, melanoma, sarcoma, breast, lymphoma, and leukemia oncology outpatient centers at Dana-Farber Cancer Institute. The music therapy intervention included four sessions of individual mindfulness-based music therapy in-person or using Zoom over twelve weeks. Prior to-and after the intervention period, participants completed the Patient-Reported Outcomes Measurement Information Anxiety 4a and Perceived Stress Scale. Changes in patient-reported outcomes are compared using Wilcoxon signed-rank tests.Over ∼14 months, 37 of 93 eligible AYAs were enrolled to the study (39.8% consent rate). Overall, 27 of 37 (73%) participants (Median age=32; 56.8% Female) completed at least two music therapy sessions and the baseline measures and end of study measures. Participation in the mindfulness-based music therapy sessions resulted in significant pre-to-posttest improvements in perceived stress (median change: -4.0, P = 0.013) and non-significant changes in anxiety (median change: -1.9, P = 0.20). Satisfaction and acceptability were highly rated.The delivery of a four-session mindfulness-based music therapy intervention to AYAs receiving chemotherapy was feasible and significantly improved perceived stress. These preliminary findings should be confirmed in a randomized controlled trial.ClinicalTrials.gov Identifier: NCT03709225.

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

The Breast Cancer Weight Loss (BWEL) trial, is a randomized, controlled trial designed to determine whether weight loss after breast cancer diagnosis can reduce the risk of cancer recurrence in women with overweight or obesity. BWEL will compare the efficacy of a telephone-based, weight loss intervention plus health education materials versus health education materials alone on invasive disease-free survival in 3181 women with stage II-III breast cancer and a body mass index (BMI) >27 kg/m(2). In this report, we provide a detailed description of the goals and methods of the lifestyle intervention and the evidence supporting the intervention used in the BWEL trial. The intervention’s primary goal for participants is to achieve and maintain a weight loss of ≥ 10% of baseline weight through increased physical activity and caloric restriction. The evidence supporting the diet, physical activity and behavioral components of this telephone-based weight loss intervention as well as strategies to promote participant engagement and retention are described. The intervention is provided through 42 sessions, delivered by trained health coaches, over a 2-year period. If the BWEL lifestyle intervention is successful in improving cancer outcomes, then weight loss will be incorporated into the care of thousands of breast cancer patients.

OBJECTIVE The Healthy Living and Eating After Cancer Trial demonstrated that a clinic-based weight loss program reduced body weight, as compared with a waitlist control group, over 15 weeks. Here we report the impact of the weight loss intervention on health-related quality-of-life outcomes at week 15, and maintenance of weight loss to week 30. METHODS This trial randomized cancer survivors of solid tumors and hematologic malignancies (breast cancer: 76.7%) to a 15-week group-based weight loss program (n = 30) or a waitlist control group (n = 30). Participants were not blinded to group assignment. Participants completed a variety of health-related quality-of-life outcome measures at baseline and week 15. From week 15 to week 30, participants initially randomized to the weight loss program were followed with no additional intervention, and participants initially randomized to the waitlist control group commenced the weight loss program. RESULTS Over the 15 weeks, the weight loss program improved physical functioning (6.2 ± 2.9; p = 0.02; d = 0.31) and reduced insomnia symptoms (-17.1 ± 7.4; p = 0.03; d = -0.30) as measured by the EORTC QLQ-C30, and sleep disturbance (-4.9 ± 1.6; p = 0.005; d = -0.40) as measured by PROMIS, compared to waitlist control. After a weight loss of 4.6 ± 3.9 kg, from week 15 to week 30, participants who were initially randomized to the weight loss program maintained their prior weight loss (+0.6 ± 3.5 kg) and participants who were initially randomized to the waitlist control group lost weight (-3.4 ± 2.9 kg; p

Purpose To determine the feasibility of implementing a yoga intervention for cancer survivors with chronic CIPN pain, as well as the impact of the intervention on patient-reported outcomes. Methods Cancer survivors with chronic CIPN pain were recruited from the breast, gastrointestinal, and gynecological oncology centers at Dana-Farber Cancer Institute. Participants were randomized (2:1) to receive an 8-week yoga intervention or usual care. After 21/50 of participants were enrolled, the COVID-19 pandemic required the yoga intervention to be delivered virtually (i.e., Zoom). Pre- and post-intervention, participants self-reported CIPN and co-occurring symptom severity. Adherence to the intervention was defined as practicing ≥ 12 yoga sessions over the 8-week intervention period. Changes in patient-reported outcomes between groups were compared using Wilcoxon’s rank-sum tests. Results Participants (n = 28 yoga, n = 16 control) were mainly female (96%) and diagnosed with stage III/IV disease (66%). Overall, 19/28 (67.8%) of yoga group participants were adherent to the yoga protocol. Yoga group participants experienced significant within-group improvements in all patient-reported outcomes, including worst CIPN pain (median change = − 1.7, p 0.05) in changes in patient-reported outcomes between in-person (n = 6) or virtual (n = 15) yoga group participants. Conclusions Yoga is a feasible non-pharmacological modality for cancer survivors with CIPN, but more information is needed regarding its impact on CIPN and other symptoms. Trial registration ClinicalTrials.gov Identifier: NCT03824860 Implications for Cancer Survivors Oncology clinicians may consider referring cancer survivors to yoga for chronic CIPN pain, but yoga cannot be currently recommended as an efficacious treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11764-021-01081-z.

Background Timely detection of chemotherapy-induced peripheral neuropathy (CIPN) is critical to effectively tailor chemotherapy dose levels and offer supportive care. The purpose of this secondary analysis was to determine the reliability and validity of the two Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) numbness and tingling severity and interference items to screen for CIPN in patients receiving taxanes, platinums, or proteasome inhibitors. Methods Participants (N = 142) completed the two PRO-CTCAE items, a 0–10 numerical rating scale of worst CIPN pain intensity, and the Quality of Life Questionnaire–CIPN20 (QLQ-CIPN20) prior to three clinical visits (T1, T2, T3) during neurotoxic chemotherapy. Participants completed the two PRO-CTCAE items again following the T3 clinical visit (T4). In addition, study staff administered the modified Total Neuropathy Score–Clinical Version (TNSc©) at T3. We examined floor (i.e., no CIPN severity or interference) and ceiling effects, test–retest reliability, concurrent validity, longitudinal validity, construct validity of the response categories, and sensitivity and specificity of the two PRO-CTCAE items. Results At T3, 29% of participants had PRO-CTCAE severity scores at the floor; 60.1% of participants reported interference item scores at the floor. Agreements between scores reported at T3 and T4 for PRO-CTCAE severity (ICC = 0.79) and interference (ICC = 0.73) were moderate to strong. The PRO-CTCAE severity and interference items correlated moderately-strongly with QLQ-CIPN20 sensory (Spearman’s ρ-range = 0.53–0.72) and motor (Spearman’s ρ-range = 0.50–0.58) subscale scores. The Cohen’s d from T1 to T3 for the PRO-CTCAE items were small (severity: d = 0.32, interference: d = 0.40) and comparable to the effect sizes for change observed with the QLQ-CIPN20. The PRO-CTCAE severity (0–3) and interference (0–2) response categories distinguished respondents with significantly different levels of QLQ-CIPN20 sensory and motor subscale scores (p 0) to detect probable sensory peripheral neuropathy were 95.83% and 65.22%, while the sensitivity and specificity of the PRO-CTCAE™ interference item (cutoff > 0) were 51.39% and 73.91%. Conclusion Preliminary evidence supports the reliability and validity of the PRO-CTCAE numbness and tingling items for CIPN screening, although there may be floor effects and limitations in the capacity of the PRO-CTCAE items to identify the full range of CIPN sensory and motor features beyond numbness and tingling. Trial Registration ClinicalTrials.Gov, NCT03514680. Registered 21 April 2018. https://clinicaltrials.gov/ct2/show/NCT03514680

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.

Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy. Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.