Early Implementation of Exercise to Facilitate Recovery After Breast Cancer Surgery: A Randomized Clinical Trial.

Importance: Recovery of shoulder function following breast cancer surgery is crucial for physical functioning and quality of life. While early implementation of shoulder rehabilitation exercises may enhance recovery, the optimal timing and exercise program remain unclear. Objective: To investigate whether an early exercise intervention, initiated 1 day postsurgery and continued for 1 month through subsequent visits, could improve shoulder range of motion (ROM) and strength in patients with breast cancer. Design, Setting, and Participants: A parallel-group, 2-arm randomized clinical trial was conducted between June 2020 and October 2021 at the Breast Cancer Center in Seoul, South Korea. Fifty-six patients (of 119 screened) with early-stage breast cancer who were scheduled for partial or total mastectomy were randomized into a tailored resistance exercise group (n = 28) or a usual care group (n = 28). Data were analyzed from November 2021 to June 2022. Interventions: The exercise intervention commenced 1 day postsurgery and consisted of 4 supervised exercise education sessions corresponding with surgeon visits and daily home-based exercises for the first postoperative month. Tailored programs, including stretching and strength exercises, were adjusted based on individual shoulder function recovery status. Main Outcomes and Measures: Primary end points were shoulder ROM and strength at 1 and 6 months postsurgery. Physical activity, body composition, and quality of life were assessed at 6 months. Results: Of 56 patients randomized (mean [SD] age, 50.3 [6.6] years), 54 completed the trial (96%), with 100% and 97% compliance to supervised and home-based exercise sessions, respectively. At 1 month postsurgery, 19 (67.9%) in the exercise group had fully recovered shoulder strength compared to 1 (3.6%) in the usual care group (P < .001). At 6 months, 22 (78.6%) in the exercise group had fully recovered shoulder ROM and 24 (85.7%) had fully recovered strength compared to 6 (21.4%) and 5 (17.9%), respectively, in the usual care group (P < .001). The exercise group exhibited less loss in muscle mass and improved physical activity and quality of life compared to the usual care group. Conclusion and Relevance: In this trial, 1-month tailored exercise program, initiated immediately after breast cancer surgery and supplemented with supervised sessions coinciding with surgeon visits, significantly improved shoulder function in patients with breast cancer. Trial Registration: WHO International Clinical Trials Registry identifier: KCT0006997.

Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi-centre factorial randomized trial.

BACKGROUND: Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. METHODS: This hypothesis-generating analysis used biospecimens collected from a multi-centre 2 × 2 factorial randomized design of 116 patients with stage I-III breast and colorectal cancer who were randomized to 12 weeks of (1) aerobic exercise (moderate intensity titrated to 220 min/week); (2) metformin (850 mg daily for 2 weeks and then titrated to 850 mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log-transformed, and main effects analyses were conducted using linear mixed-effects regression models. The type I error rate was controlled with the Holm sequential testing procedure. RESULTS: Randomization to exercise increased leukaemia inhibitory factor (1.26 pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P = 0.001) and interleukin-15 (2.23 pg/mL, 95% CI: 0.87, 3.60; adjusted P = 0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (-2.69 pg/mL, 95% CI: -4.31, -1.07; adjusted P = 0.014) and interleukin-15 (-1.74 pg/mL, 95% CI: -2.79, -0.69; adjusted P = 0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons. CONCLUSIONS: This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis-generating observation warrants further basic, translational and clinical investigation and replication.

Management of Fatigue in Adult Survivors of Cancer: ASCO-Society for Integrative Oncology Guideline Update.

PURPOSE: To update the ASCO guideline on the management of cancer-related fatigue (CRF) in adult survivors of cancer. METHODS: A multidisciplinary panel of medical oncology, geriatric oncology, internal medicine, psychology, psychiatry, exercise oncology, integrative medicine, behavioral oncology, nursing, and advocacy experts was convened. Guideline development involved a systematic literature review of randomized controlled trials (RCTs) published in 2013-2023. RESULTS: The evidence base consisted of 113 RCTs. Exercise, cognitive behavioral therapy (CBT), and mindfulness-based programs led to improvements in CRF both during and after the completion of cancer treatment. Tai chi, qigong, and American ginseng showed benefits during treatment, whereas yoga, acupressure, and moxibustion helped to manage CRF after completion of treatment. Use of other dietary supplements did not improve CRF during or after cancer treatment. In patients at the end of life, CBT and corticosteroids showed benefits. Certainty and quality of evidence were low to moderate for CRF management interventions. RECOMMENDATIONS: Clinicians should recommend exercise, CBT, mindfulness-based programs, and tai chi or qigong to reduce the severity of fatigue during cancer treatment. Psychoeducation and American ginseng may be recommended in adults undergoing cancer treatment. For survivors after completion of treatment, clinicians should recommend exercise, CBT, and mindfulness-based programs; in particular, CBT and mindfulness-based programs have shown efficacy for managing moderate to severe fatigue after treatment. Yoga, acupressure, and moxibustion may also be recommended. Patients at the end of life may be offered CBT and corticosteroids. Clinicians should not recommend L-carnitine, antidepressants, wakefulness agents, or routinely recommend psychostimulants to manage symptoms of CRF. There is insufficient evidence to make recommendations for or against other psychosocial, integrative, or pharmacological interventions for the management of fatigue.Additional information is available at www.asco.org/survivorship-guidelines.

Prevalence and Cancer-Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022.

PURPOSE: To examine the prevalence and cancer-specific patterns of functional disabilities among US cancer survivors. METHODS: Data from 47,768 cancer survivors and 2,432,754 noncancer adults age 18 years and older from the 2017 to 2022 Behavioral Risk Factor Surveillance System were analyzed. Functional disabilities assessed included mobility disability (ie, serious difficulty walking or climbing stairs) and self-care disability (ie, self-reported difficulty dressing or bathing). Multivariable logistic regression models were used to assess the associations between functional disabilities and sociodemographic, lifestyle, and health-related factors. RESULTS: Cancer survivors tended to be older and non-Hispanic White than noncancer adults. The prevalence of mobility disability (27.9% v 13.4%) and self-care disability (7.4% v 3.8%) were higher among cancer survivors compared with noncancer adults. After multivariable adjustments, cancer survivors were more likely to report mobility (odds ratio [OR], 1.21 [95% CI, 1.16 to 1.26]) and self-care (OR, 1.19 [95% CI, 1.10 to 1.29]) disability than noncancer adults. The prevalence of mobility (34.9% v 26.3%) and self-care disability (9.8% v 6.7%) was higher in cancer survivors who were receiving active cancer treatment than in those who had completed cancer treatment. Higher prevalence of mobility and self-care disabilities was observed in cancer survivors who were racial/ethnic minorities and with higher BMI, low physical activity, lower levels of education and/or income, comorbidities, and those experiencing cancer/treatment-related pain. Patterns of mobility and self-care disabilities varied across cancer types. CONCLUSION: Over a quarter of US cancer survivors reported mobility disability, and nearly 10% reported self-care disability, with patterns varying across cancer types and treatment status. Racial/ethnic minorities, along with underserved groups and individuals with unhealthy lifestyles or comorbidities, were notably more affected by functional disabilities, underscoring the need for targeted disability prevention efforts.

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

BACKGROUND: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy. OBJECTIVE: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM). METHODS: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast. RESULTS: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025. CONCLUSIONS: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51368.

Improving lifestyle behaviors during chemotherapy for breast cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis (LEANer) Trial.

BACKGROUND: Little is known about improving physical activity (PA) and diet during and after chemotherapy for breast cancer. This secondary analysis examines changes in PA and diet quality during a yearlong intervention for patients with breast cancer undergoing chemotherapy and evaluates factors associated with these changes. METHODS: Newly diagnosed patients with breast cancer (N = 173) undergoing chemotherapy were randomized to a year-long nutrition and exercise intervention (n = 87) or usual care (UC, n = 86). Mixed models compared 1-year changes in PA and diet quality via the Healthy Eating Index (HEI)-2015 by study arm. Among the intervention group, baseline factors associated with change in PA and diet were assessed with multivariable linear and logistic regression. RESULTS: At 1 year, compared with UC, the intervention arm increased PA more (mean difference = 136.1 minutes/week; 95% CI, 90.2-182.0), participated in more strength training (56% vs. 15%; p < .001), and had suggestive improvements in HEI-2015 (mean difference = 2.5; 95% CI, -0.3 to 5.3; p = .08). In the intervention arm, lower fatigue was associated with improved PA (p = .04) and higher education was associated with improved HEI-2015 (p = .001) at 1 year. Higher HEI-2015 (p = .04) and married/living with someone (p = .05) were associated with higher odds of participating in strength training at 1 year. CONCLUSIONS: This year-long lifestyle intervention for patients with breast cancer undergoing chemotherapy resulted in increases in PA and suggestive improvements in diet quality. Behavior change was associated with baseline fatigue, diet quality, education, and married/living with someone. Addressing these factors in interventions may improve uptake of lifestyle behaviors in trials during and after chemotherapy.

A qualitative analysis of algorithm-based decision support usability testing for symptom management across the trajectory of cancer care: one size does not fit all.

BACKGROUND: Adults with cancer experience symptoms that change across the disease trajectory. Due to the distress and cost associated with uncontrolled symptoms, improving symptom management is an important component of quality cancer care. Clinical decision support (CDS) is a promising strategy to integrate clinical practice guideline (CPG)-based symptom management recommendations at the point of care. METHODS: The objectives of this project were to develop and evaluate the usability of two symptom management algorithms (constipation and fatigue) across the trajectory of cancer care in patients with active disease treated in comprehensive or community cancer care settings to surveillance of cancer survivors in primary care practices. A modified ADAPTE process was used to develop algorithms based on national CPGs. Usability testing involved semi-structured interviews with clinicians from varied care settings, including comprehensive and community cancer centers, and primary care. The transcripts were analyzed with MAXQDA using Braun and Clarke's thematic analysis method. A cross tabs analysis was also performed to assess the prevalence of themes and subthemes by cancer care setting. RESULTS: A total of 17 clinicians (physicians, nurse practitioners, and physician assistants) were interviewed for usability testing. Three main themes emerged: (1) Algorithms as useful, (2) Symptom management differences, and (3) Different target end-users. The cross-tabs analysis demonstrated differences among care trajectories and settings that originated in the Symptom management differences theme. The sub-themes of "Differences between diseases" and "Differences between care trajectories" originated from participants working in a comprehensive cancer center, which tends to be disease-specific locations for patients on active treatment. Meanwhile, participants from primary care identified the sub-theme of "Differences in settings," indicating that symptom management strategies are care setting specific. CONCLUSIONS: While CDS can help promote evidence-based symptom management, systems providing care recommendations need to be specifically developed to fit patient characteristics and clinical context. Findings suggest that one set of algorithms will not be applicable throughout the entire cancer trajectory. Unique CDS for symptom management will be needed for patients who are cancer survivors being followed in primary care settings.

Association of N-terminal pro-brain natriuretic peptide with survival among US cancer survivors.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a cardiac biomarker associated with the risk of heart failure and death in the general population, but it has not been explored in cancer survivors. METHODS: Using a US nationally representative sample of adults 20 years of age and older from the National Health and Nutrition Examination Survey from 1999 to 2004, this study compared NT-proBNP levels between adults without cancer (n = 12 574) and adult cancer survivors (n = 787). It examined the association of NT-proBNP with all-cause and cause-specific mortality among cancer survivors. RESULTS: Cancer survivors had higher NT-proBNP levels than adults without cancer (median [interquartile range] = 125.4 pg/mL [52.4-286.0] vs 43.2 pg/mL [20.3-95.0]). In particular, survivors of breast, prostate, and colorectal cancers had higher NT-proBNP levels than adults without cancer (multivariable-adjusted P < .05). In total, 471 survivors died (141 from cancer; 95 from cardiac disease) during a median follow-up period of 13.4 years (9393 person-years). Among cancer survivors, higher NT-proBNP levels were statistically associated with increased risks of all-cause death (hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.18 to 1.46) and cardiac death (HR = 1.55, 95% CI = 1.21 to 2.00) but not with death from cancer (HR = 1.10, 95% CI = 0.92 to 1.32]). Higher NT-proBNP levels were associated with elevated overall mortality in survivors of prostate cancer (HR = 1.49, 95% CI = 1.22 to 1.81) and colorectal cancer (HR = 1.78, 95% CI = 1.00 to 3.16) (P = .169 for interaction). Nonlinear dose-response relationships were observed between NT-proBNP and mortality, with statistically significant relationships emerging above 125 pg/mL. CONCLUSIONS: Cancer survivors had higher NT-proBNP levels than adults without cancer, and elevated NT-proBNP levels were associated with higher risks of all-cause and cardiac mortality in cancer survivors.

Dietary and serum advanced glycation end-products and clinical outcomes in breast cancer.

One in five women with breast cancer will relapse despite ideal treatment. Body weight and physical activity are strongly associated with recurrence risk, thus lifestyle modification is an attractive strategy to improve prognosis. Trials of dietary modification in breast cancer are promising but the role of specific diets is unclear, as is whether high-quality diet without weight loss can impact prognosis. Advanced glycation end-products (AGEs) are compounds produced in the body during sugar metabolism. Exogenous AGEs, such as those found in food, combined with endogenous AGEs, make up the total body AGE load. AGEs deposit in tissues over time impacting cell signaling pathways and altering protein functions. AGEs can be measured or estimated in the diet and measured in blood through their metabolites. Studies demonstrate an association between AGEs and breast cancer risk and prognosis. Here, we review the clinical data on dietary and serum AGEs in breast cancer.

Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance.

BACKGROUND: We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. METHODS: Using Vessel Architectural Imaging (VAI), a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial- and venous-dominance, and vascular permeability were measured before and after treatment with pembrolizumab. RESULTS: BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend towards a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI. CONCLUSIONS: This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

Exploring anxiety as an influencing factor of the impact of exercise and mind-body prehabilitation on cognitive functioning among women undergoing breast cancer surgery.

OBJECTIVE: The purpose of this secondary analysis was to describe the prevalence of anxiety, depression, and perceived stress among women newly diagnosed with breast cancer and the impact of baseline and changes in anxiety on cognitive functioning following exercise and mind-body prehabilitation interventions. METHODS: The sample consisted of 49 women with newly diagnosed breast cancer (stages I-III) who planned to undergo breast cancer surgery at two academic cancer centers. Participants were randomized to receive an exercise or mind-body prehabilitation intervention between the time of diagnosis and breast cancer surgery. Participants completed self-report measures of anxiety, depression (HADS), perceived stress, and cognitive functioning (EORTC-QLQ-C30) at study enrollment and prior to surgery (post-intervention). The relationships between change in cognitive functioning and change in anxiety among all participants were estimated using linear regression modeling. RESULTS: A significant proportion of women with newly diagnosed breast cancer had clinically significant anxiety (34.0%). Greater anxiety was moderately associated with worse cognitive functioning (r = -0.33) at baseline. Linear modeling found that changes in cognitive functioning and anxiety were inversely related: Each one-unit decrease in anxiety was associated with a two-unit improvement in cognitive function (p = .06). CONCLUSIONS: Anxiety was common in women with newly diagnosed breast cancer and was related to worse cognitive functioning. Assessment of anxiety at the time of diagnosis may allow for earlier anxiety management and subsequent improvement in cognitive functioning.

Well-Being Parameters and Intention to Leave Current Institution Among Academic Physicians.

Importance: Physician turnover interrupts care delivery and creates health care system financial burden. Objective: To describe the prevalence of burnout, professional fulfillment, and intention to leave (ITL) among physicians at academic-affiliated health care systems and identify institutional and individual factors associated with ITL. Design, Setting, and Participants: This cross-sectional study administered a survey to 37 511 attending-level medical specialists at 15 academic medical institutions participating in the Healthcare Professional Well-Being Academic Consortium. Data were collected from October 2019 to July 2021. Statistical analysis was performed from May 2022 to March 2023. Exposures: Hypothesized institutional and individual determinants of occupational well-being. Main Outcomes and Measures: The main outcome was ITL, defined as having at least a moderate intention (a score of 2 on a 0-4 scale) to leave one's institution within the next 2 years. Additional outcomes included burnout and professional fulfillment, defined using published Professional Fulfillment Index cut points. Results: Of 18 719 academic physician survey respondents (8381 [44.8%] male; 2388 [12.8%] Asian, 10 599 [56.6%] White, 1039 [5.6%] other race, 4693 [25.1%] unknown race; 294 [1.6%] Hispanic or Latina/Latino/Latinx), 6903 of 18 217 (37.9%) met criteria for burnout and 7301 of 18 571 (39.3%) for professional fulfillment; 5177 of 15 890 (32.6%) reported moderate or greater ITL. Burnout, professional fulfillment, and ITL varied across specialties. After adjusting for demographics, each 1-point increase (range 0-10) in burnout was directly associated with ITL (odds ratio [OR], 1.52 [95% CI, 1.49-1.55])c, and each 1-point increase in professional fulfillment was inversely associated with ITL (OR, 0.64 [95% CI, 0.63-0.65]). After adjusting for demographics, burnout, and professional fulfillment, each 1-point increase (range 0-10) in supportive leadership behaviors (OR, 0.83 [95% CI, 0.82-0.84]), peer support (OR, 0.93 [95% CI, 0.91-0.95]), personal-organizational values alignment (OR, 0.81 [95% CI, 0.80-0.82]), perceived gratitude (OR, 0.95 [95% CI, 0.92-0.97]), COVID-19 organizational support (OR, 0.88 [95% CI, 0.85-0.91]), and electronic health record helpfulness (OR, 0.95 [95% CI, 0.93-0.97]) were inversely associated with ITL, whereas each 1-point increase (range 0-10) in depression (OR, 1.08 [95% CI, 1.05-1.10]) and negative impact of work on personal relationships (OR, 1.09 [1.07-1.11]) were directly associated with ITL. Conclusions and Relevance: In this cross-sectional study of academic physicians, 32.6% indicated moderate or higher ITL within 2 years. Burnout, lack of professional fulfillment, and other well-being factors were associated with ITL, suggesting the need for a comprehensive approach to reduce physician turnover.

Fertility concerns and treatment decision-making among national sample of young women with breast cancer.

BACKGROUND: Diagnosis of breast cancer in young women has been shown to affect their decision-making with regard to fertility and family planning. Limited data are available from populations across the U.S. regarding this issue; thus, we sought to describe fertility concerns and efforts to preserve fertility in a national clinical trial population of young breast cancer patients. METHODS: The young and strong study was a cluster-randomized controlled trial testing an intervention program for young women with breast cancer. Patients were surveyed within 3 months after diagnosis and at 3, 6, and 12 months after. Surveys asked about sociodemographics, psychosocial domains, fertility concerns, and fertility preservation strategies. Univariable and multivariable models were used to investigate sociodemographic, clinical, and psychosocial predictors of fertility concerns. RESULTS: Of 467 women from 54 clinical sites across the U.S. (14 academic, 40 community), 419 were evaluable regarding fertility concerns. Median age was 40 years (range 22-45), 11% were Black, 6% Hispanic, and 75% had children. Tumor stage was I (35%), II (51%), or III (14%); 82% received chemotherapy. At time of the treatment decision, 133 (32%) participants had fertility concerns, among whom 47% indicated this affected their treatment decisions. Sixty percent of participants reported having discussed fertility with their physician. Twenty percent of those with fertility concerns used fertility preservation strategies. History of difficulty becoming pregnant and younger age were associated with higher odds of fertility concerns in multivariable modeling. CONCLUSION: Many young women with newly diagnosed breast cancer are concerned about fertility in a way that impacts their treatment decisions. Concerns were discussed, but few used fertility preservation strategies. These findings have implications for counseling young patients.

Randomized Trial of Exercise and Nutrition on Chemotherapy Completion and Pathologic Complete Response in Women With Breast Cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis Study.

PURPOSE: Successful completion of chemotherapy is critical to improve breast cancer outcomes. Relative dose intensity (RDI), defined as the ratio of chemotherapy delivered to prescribed, is a measure of chemotherapy completion and is associated with cancer mortality. The effect of exercise and eating a healthy diet on RDI is unknown. We conducted a randomized trial of an exercise and nutrition intervention on RDI and pathologic complete response (pCR) in women diagnosed with breast cancer initiating chemotherapy. METHODS: One hundred seventy-three women with stage I-III breast cancer were randomly assigned to usual care (UC; n = 86) or a home-based exercise and nutrition intervention with counseling sessions delivered by oncology-certified registered dietitians (n = 87). Chemotherapy dose adjustments and delays and pCR were abstracted from electronic medical records. T-tests and chi-square tests were used to examine the effect of the intervention versus UC on RDI and pCR. RESULTS: Participants randomly assigned to intervention had greater improvements in exercise and diet quality compared with UC (P < .05). RDI was 92.9% ± 12.1% and 93.6% ± 11.1% for intervention and UC, respectively (P = .69); the proportion of patients in the intervention versus UC who achieved ≥85% RDI was 81% and 85%, respectively (P = .44). The proportion of patients who had at least one dose reduction and/or delay was 38% intervention and 36% UC (P = .80). Among 72 women who received neoadjuvant chemotherapy, women randomly assigned to intervention were more likely to have a pCR than those randomly assigned to UC (53% v 28%; P = .037). CONCLUSION: Although a diet and exercise intervention did not affect RDI, the intervention was associated with a higher pCR in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative and triple-negative breast cancer undergoing neoadjuvant chemotherapy.

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.

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy.

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

Effect of Exercise on Chemotherapy-Induced Peripheral Neuropathy Among Patients Treated for Ovarian Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among survivors of ovarian cancer. Currently, there is no effective treatment for CIPN. Objective: To evaluate the effect of a 6-month aerobic exercise intervention vs attention-control on CIPN among women treated for ovarian cancer in the Women's Activity and Lifestyle Study in Connecticut (WALC) to provide evidence to inform the guidelines and recommendations for prevention or treatment of CIPN. Design, Setting, and Participants: This prespecified secondary analysis evaluated the Women's Activity and Lifestyle Study in Connecticut (WALC), a multicentered, open-label, population-based, phase 3 randomized clinical trial of an aerobic exercise intervention vs attention control for CIPN in patients who were diagnosed with ovarian cancer. Only WALC participants who received chemotherapy were included in this analysis. Participants were randomized 1:1 to either a 6-month aerobic exercise intervention or to attention control. All analyses were conducted between September 2022 and January 2023. Interventions: The exercise intervention consisted of home-based moderate-intensity aerobic exercise facilitated by weekly telephone counseling from an American College of Sports Medicine/American Cancer Society-certified cancer exercise trainer. Attention control involved weekly health education telephone calls from a WALC staff member. Main Outcomes and Measure: Change in CIPN was the primary outcome in this secondary analysis. This outcome was represented by CIPN severity, which was self-measured by participants at baseline and 6 months using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, with a score range of 0 to 44. A mixed-effects model was used to assess the 6-month change in CIPN between the exercise intervention and attention control arms. Results: Of the 134 participants (all females; mean [SD] age, 57.5 [8.3] years) included in the analysis, 69 were in the exercise intervention arm and 65 were in the attention control arm. The mean (SD) time since diagnosis was 1.7 (1.0) years. The mean (SD) baseline CIPN scores were 8.1 (5.6) in the exercise intervention arm and 8.8 (7.9) in the attention control arm (P = .56). At 6 months, the self-reported CIPN score was reduced by 1.3 (95% CI, -2.3 to -0.2) points in the exercise intervention arm compared with an increase of 0.4 (95% CI, -0.8 to 1.5) points in the attention control arm. The between-group difference was -1.6 (95% CI, -3.1 to -0.2) points. The point estimate was larger among the 127 patients with CIPN symptoms at enrollment (-2.0; 95% CI, -3.6 to -0.5 points). Conclusions and Relevance: Findings of this secondary analysis of the WALC trial indicate that a 6-month aerobic exercise intervention vs attention control significantly improved self-reported CIPN among patients who were treated for ovarian cancer. While replication of the findings in other studies is warranted, incorporating referrals to exercise programs into standard oncology care could reduce CIPN symptoms and increase quality of life in patients with ovarian cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02107066.

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.

Randomized trial of exercise on cancer-related blood biomarkers and survival in women with ovarian cancer.

BACKGROUND: In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. METHODS: This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided. RESULTS: Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). CONCLUSIONS: Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.