A review of the impact of energy balance on triple-negative breast cancer.

Cancer cells cannot proliferate without sufficient energy to generate biomass for rapid cell division, as well as to fuel their functions at baseline. For this reason, many recent observational and interventional studies have focused on increasing energy expenditure and/or reducing energy intake during and after cancer treatment. The impact of variance in diet composition and in exercise on cancer outcomes has been detailed extensively elsewhere and is not the primary focus of this review. Instead, in this translational, narrative review we examine studies of how energy balance impacts anticancer immune activation and outcomes in triple-negative breast cancer (TNBC). We discuss preclinical, clinical observational, and the few clinical interventional studies on energy balance in TNBC. We advocate for the implementation of clinical studies to examine how optimizing energy balance-through changes in diet and/or exercise-may optimize the response to immunotherapy in people with TNBC. It is our conviction that by taking a holistic approach that includes energy balance as a key factor to be considered during and after treatment, cancer care may be optimized, and the detrimental effects of cancer treatment and recovery on overall health may be minimized.

Utilization of cancer survivorship services during the COVID-19 pandemic in a tertiary referral center.

BACKGROUND: All Commission on Cancer-accredited comprehensive cancer centers offer survivorship programs (SPs) to women upon completion of treatment. These SPs can include clinical and non-clinical programming such as physical rehabilitation, emotional and psychosocial support, nutrition, and exercise programming. Concern about the availability and access to these programs during the COVID-19 pandemic has been described in recent literature. We sought to identify the impact of the COVID-19 pandemic on participation in these supportive services for breast cancer patients within a single institution. METHODS: The Ohio State University tertiary care center offers clinical and non-clinical breast cancer support services. Descriptive statistics were utilized to summarize referral and patient participation data from January 2019 through July 2021. Data from calendar year 2019 was used as a normative comparison for pre-COVID-19. In-person and telehealth use was tracked longitudinally. RESULTS: During the lockdown due to the COVID-19 pandemic (March through May 2020), provider referrals to SPs declined by 10%, while the overall total for the calendar year modestly increased from 1195 in 2019 to 1210 in 2020, representing a 1.3% increase. Psycho-oncology referrals increased from 280 to 318 (13.5%). The most significant change of participation rates in non-clinical SPs during the pandemic was utilization of exercise content, which increased by 220% from 2019 to 2020. The total proportion of breast cancer participants choosing an exercise program increased from 16.8% in 2019 to 42.2% in 2021, making it the most selected program area overall. Previously, nutrition was the most selected program area as it comprised 42.5% of overall utilization in 2019. CONCLUSION: The pandemic's potential to place barriers to participation in SPs is a legitimate concern. We found a modest decline in provider referrals to clinical services during the lockdown period, while patient-directed participation increased with more survivors engaging in exercise-based programs. Transitioning to virtual platforms served to maintain access for patients. IMPLICATIONS FOR CANCER SURVIVORS: As we grapple with the COVID-19 pandemic, patients with cancer deserve increased attention due to the expected stressors associated with the diagnosis. Those in the survivorship stage utilize services for psychosocial support, and the observed increase in utilization of SPs suggests an elevated need for connectivity. To meet this need, telehealth platforms have been expanded to allow for continued participation. It remains to be seen whether this will be sustained post-COVID-19 or whether reduced human contact will create new needs for programming.

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series.

Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

Erythrocyte Long-Chain ω-3 Fatty Acids Are Positively Associated with Lean Mass and Grip Strength in Women with Recent Diagnoses of Breast Cancer.

BACKGROUND: Sarcopenia may hasten the risk of mortality in women with breast cancer. Long-chain omega-3 (n-3) polyunsaturated fatty acids (LCn-3PUFAs) may favor muscle mass which, in turn, could enhance resilience of cancer patients toward cancer treatment. OBJECTIVES: The objective of this study was to measure the relation of erythrocyte LCn-3PUFA concentrations with lean mass, grip strength, and postprandial energy metabolism in women with newly diagnosed breast cancer. METHODS: This cross-sectional analysis evaluated women (n = 150) ages 65 y and younger who were recently diagnosed with breast cancer (stages I-III). Erythrocyte LCn-3PUFA composition was measured using GC. Body composition was measured by DXA. Grip strength was assessed at the same visit. Postprandial energy metabolism was measured for 7.5 h after the consumption of a high-calorie, high-saturated-fat test meal using indirect calorimetry. Associations of fatty acids with outcomes were analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: The ω-3 index, a measurement of LCn-3PUFA status, was positively associated with appendicular lean mass (ALM)/BMI (ß = 0.015, P = 0.01) and grip strength (ß = 0.757, P = 0.04) after adjusting data for age and cancer stage. However, when cardiorespiratory fitness was also included in the analyses, these relations were no longer significant (P > 0.08). After a test meal, a higher ω-3 index was associated with a less steep rise in fat oxidation (P = 0.02) and a steeper decline in glucose (P = 0.01) when adjusting for age, BMI, cancer stage, and cardiorespiratory fitness. CONCLUSIONS: The ω-3 index was positively associated with ALM/BMI and grip strength in women newly diagnosed with breast cancer and was associated with altered postprandial substrate metabolism. These findings warrant further studies to determine whether enriching the diet with LCn-3PUFAs during and after cancer treatments is causally linked with better muscle health and metabolic outcomes in breast cancer survivors.

Impaired Postural Control and Altered Sensory Organization During Quiet Stance Following Neurotoxic Chemotherapy: A Preliminary Study.

Individuals diagnosed with chemotherapy-induced peripheral neuropathy (CIPN) demonstrate impaired balance and carry an increased risk of falling. However, prior investigations of postural instability have only compared these individuals against healthy controls, limiting the understanding of impairments associated with CIPN. Therefore, the purpose of this study was to better isolate postural control impairments that are associated with CIPN. Twenty cancer survivors previously diagnosed with breast or colorectal cancer participated. Participants were separated into 3 groups: no prior chemotherapy exposure (CON, n = 6), and recent treatment with taxane- or oxaliplatin-based chemotherapy with no/mild symptoms of CIPN (-CIPN, n = 8) or moderate/severe symptoms of CIPN (+CIPN, n = 6). Postural control was assessed by measuring center of pressure during standing balance conditions that systematically interfered with somatosensory, visual, and/or vestibular information. The presence of CIPN sensory symptoms was associated with impaired postural control, particularly during eyes-closed balance conditions ( P < .05). Additionally, medial-lateral postural instability was more pronounced in the +CIPN group compared with the -CIPN group and CON participants ( P < .05). Greater postural instability during eyes-closed balance in individuals with CIPN is consistent with impaired peripheral sensation. Balance impairments in cancer survivors with CIPN demonstrate the unique challenges in this population and motivate the need for targeted efforts to mitigate postural control deficits that have previously been associated with fall risk.

Low Sucrose, Omega-3 Enriched Diet Has Region-Specific Effects on Neuroinflammation and Synaptic Function Markers in a Mouse Model of Doxorubicin-Based Chemotherapy.

Chemotherapeutic agents such as doxorubicin may negatively affect long-term brain functioning in cancer survivors; neuroinflammation may play a causal role. Dietary approaches that reduce inflammation, such as lowering sucrose and increasing eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA), may attenuate chemotherapy-induced neuroinflammation and synaptic damage, thereby improving quality of life. Ovariectomized, C57BL/6 mice were assigned to a chemotherapy (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide) or vehicle two-injection regimen, with injections two and four weeks after starting diets. In Study 1, mice received low sucrose diets with EPA + DHA or No EPA + DHA for four to six weeks; tissues were collected four, seven, or 14 days after the second injection. Compared to vehicle, chemotherapy increased pro-inflammatory cytokine IL-1ß at day seven in the cortex and hippocampus, and reduced gene expression of synaptic marker Shank 3 at all timepoints in cortex, while EPA + DHA increased expression of Shank 3. In Study 2, high or low sucrose/EPA + DHA or No EPA + DHA diets were fed for five weeks; tissues were collected ten days after the second injection. Among chemotherapy-treated mice, brain DHA was higher with low sucrose feeding. Furthermore, low sucrose increased gene expression of Shank 1, while EPA + DHA increased expression of Shank 3 and reduced protein concentrations of pro-inflammatory markers IL-5, IL-6 and KC/GRO in the cortex, but not the hippocampus. Low sucrose, EPA + DHA diets may attenuate neuroinflammation and synaptic damage induced by doxorubicin-based chemotherapy in specific brain regions.

Dietary Long-Chain n-3 Fatty Acid Intake and Arthritis Risk in the Women's Health Initiative.

BACKGROUND: The prevalence of arthritis in the United States is substantial and on the rise. Long-chain n-3 polyunsaturated fatty acids, which have anti-inflammatory properties, have been shown to provide therapeutic benefit to arthritis patients; however, to date few have examined these associations with arthritis risk. OBJECTIVE: The study objective was to examine the associations of long-chain n-3 polyunsaturated fatty acids intake with osteoarthritis (OA) and rheumatoid arthritis (RA) risk among postmenopausal women. DESIGN: This was a prospective cohort study. PARTICIPANTS: The sample for this analysis consisted of 80,551 postmenopausal women, aged 55 to 79 years and with no history of arthritis, recruited into the Women's Health Initiative Observational Study and Clinical Trials cohort between 1993 and 1998. Women completed a 120-item food frequency questionnaire at baseline. MAIN OUTCOME MEASURES: After a median follow-up of 8 years, 22,306 incident OA and 3,348 RA cases were identified. STATISTICAL ANALYSES PERFORMED: Adjusted Cox regression models were used to estimate hazard ratios and 95% CI for the associations between dietary LCn-3PUFA intake and OA and RA risk. RESULTS: Individual and total long-chain n-3 polyunsaturated fatty acids (Quintile 5 vs Quintile 1: hazard ratio 1.04, 95% CI 0.99 to 1.09 for OA; hazard ratio 1.01, 95% CI 0.90 to 1.13 for RA) were not associated with OA and RA risk. Further, no associations were observed between n-6 polyunsaturated fatty acids intake and either arthritis outcome. CONCLUSIONS: This study is the first to examine associations of long-chain n-3 polyunsaturated fatty acids intake with OA risk and the largest to examine associations with RA risk. Despite their therapeutic potential, the study provides no evidence of benefit of these nutrients in relation to arthritis risk.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PURPOSE: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. METHODS: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. RESULTS: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. CONCLUSION: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer.

PURPOSE: Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss. Receptor Activator of Nuclear Factor Kappa-B (RANK)-RANK ligand (RANK-L) signaling balances bone resorption and formation. Osteoprotegerin (OPG) acts as a decoy receptor for RANK, interrupting osteoclast activation and bone resorption. This study examined the relationship between OPG and bone loss in women with CIOF. METHODS: Premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated at chemotherapy initiation, 6 and 12 months. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), follicle stimulating hormone (FSH), ionized calcium, osteocalcin, and OPG were serially measured. CIOF was defined as a negative pregnancy test, FSH levels >30 MIU/mL, and ≥3 months of amenorrhea. RESULTS: Forty women were enrolled; 31 (77.5%) met CIOF criteria. BMD significantly decreased (p < 0.001) in the CIOF group at both time points: LS BMD decreased from a median of 0.993 g/cm(2) to 0.976 g/cm(2) and 0.937 g/cm(2) at 6 and 12 months, respectively. OPG was significantly elevated at 6 months (median increase 0.30 pmol/L, p = 0.015) and then decreased at 12 months to levels still above baseline (median difference 0.2 pmol/L, p = 0.70). CONCLUSIONS: In what was likely a compensatory response to rapid bone loss, CIOF patients' OPG levels increased at 6 months and then decreased at 12 months to values greater than baseline assessments. This phenomenon is described in other diseases, but never before in CIOF.

Bone health in adult cancer survivorship.

Optimizing health outcomes, including prevention of osteoporotic fractures, is essential for promoting the well-being of the growing number of cancer survivors. Medical providers who participate in the care of cancer survivors should be aware that various cancer treatments may cause bone loss, which can increase the risk of subsequent of osteoporosis. Healthy bone remodeling is a balanced and dynamic equation between new bone formation and bone resorption. Aging, natural menopause, and cancer treatments such as surgical oophorectomy, gonadotropin-releasing hormone agonists, chemotherapy-induced ovarian failure, androgen deprivation therapy, and aromatase inhibitors can all promote bone loss. The WHO Fracture Assessment Tool can be used as a clinical aid to assess an individual's osteoporotic fracture risk, with or without bone mineral density measurements obtained from dual-energy x-ray absorptiometry. Preventative strategies include adequate calcium and vitamin D supplementation and modifying risk factors such as alcohol intake, tobacco use, and lack of exercise. Bisphosphonate therapy and rank-ligand monoclonal antibody therapy are the most commonly used agents for management of bone loss resulting from cancer treatment. This review will summarize the mechanisms by which cancer treatments cause bone loss as well provide screening and treatment recommendations for the management of bone loss.