Translating energy balance research from the bench to the clinic to the community: Parallel animal-human studies in cancer.

Advances in energy balance and cancer research to date have largely occurred in siloed work in rodents or patients. However, substantial benefit can be derived from parallel studies in which animal models inform the design of clinical and population studies or in which clinical observations become the basis for animal studies. The conference Translating Energy Balance from Bench to Communities: Application of Parallel Animal-Human Studies in Cancer, held in July 2021, convened investigators from basic, translational/clinical, and population science research to share knowledge, examples of successful parallel studies, and strong research to move the field of energy balance and cancer toward practice changes. This review summarizes key topics discussed to advance research on the role of energy balance, including physical activity, body composition, and dietary intake, on cancer development, cancer outcomes, and healthy survivorship.

The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NFκB signaling, and inhibits mammary tumor growth.

PURPOSE: Exposure to the polyphenolic plant lignan secoisolariciresinol diglucoside (SDG) and its metabolite enterolactone (ENL) has been associated with reduced breast cancer progression, particularly for estrogen receptor alpha (ERα)-negative disease, and decreased preclinical mammary tumor growth. However, while preclinical studies have established that SDG and ENL affect measures of progression in models of triple-negative breast cancer (TNBC, a subset of ERα-negative disease), the molecular mechanisms underlying these effects remain unclear. METHODS: C57BL/6 mice were fed a control diet (control, 10% kcal from fat) or control diet + SDG (SDG, 100 mg/kg diet) for 8 weeks, then orthotopically injected with syngeneic E0771 mammary tumor cells (a model of TNBC); tumor growth was monitored for 3 weeks. The role of reduced NF-κB signaling in SDG's anti-tumor effects was explored in vitro via treatment with the bioactive SDG metabolite ENL. In addition to the murine E0771 cells, the in vitro studies utilized MDA-MB-231 and MCF-7 cells, two human cell lines which model the triple-negative and luminal A breast cancer subtypes, respectively. RESULTS: SDG supplementation in the mice significantly reduced tumor volume and expression of phospho-p65 and NF-κB target genes (P < 0.05). Markers of macrophage infiltration were decreased in the distal-to-tumor mammary fat pad of mice supplemented with SDG relative to control mice (P < 0.05). In vitro, ENL treatment inhibited viability, survival, and NF-κB activity and target gene expression in E0771, MDA-MB-231, and MCF-7 cells (P < 0.05). Overexpression of Rela attenuated ENL's inhibition of E0771 cell viability and survival. CONCLUSIONS: SDG reduces tumor growth in the E0771 model of TNBC, likely via a mechanism involving inhibition of NF-κB activity. SDG could serve as a practical and effective adjuvant treatment to reduce recurrence, but greater understanding of its effects is needed to inform the development of more targeted recommendations for its use.

Circulating adipose stromal cells as a response biomarker in phase II energy balance trials of obese breast cancer survivors and high-risk women.

PURPOSE: Circulating adipose stromal cells (CASC) are thought to be increased in obesity and facilitate angiogenesis, and tumor metastases. METHODS: CASC were identified from buffy coat peripheral blood mononuclear cells (PBMCs) by flow cytometry as CD34brightCD31- CD45- and CASC frequency was compared to adiposity measures in 33 women at increased risk for breast cancer. Feasibility of CASC as a response biomarker for a diet and exercise intervention in ten breast cancer survivors was then explored. RESULTS: For 33 high-risk women, median CASC frequency was 9.7 per million PBMCs and trended positively with body mass index, fat mass index (FMI), and percent android fat. Correlation was significant when BMI was dichotomized at > versus < 35 kg/m2 (p = 0.02). For ten breast cancer survivors with a median BMI of 37 kg/m2, median CASC frequency was 16.4 per million PBMCs. In univariate analyses, change in BMI, total fat and visceral fat were significantly correlated with change in CASC frequency. On multivariate analysis, change in visceral adipose had the strongest association with change in CASC frequency (p < 0.00078). CONCLUSIONS: The association between the reduction in visceral adipose tissue and the decrease in frequency of circulating adipose stromal cells suggests that the latter might be a useful biomarker in clinical trials of obese breast cancer survivors undergoing a weight loss intervention.

Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.

BACKGROUND: Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS: We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS: At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS: Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).

Cognitive functioning and quality of life following chemotherapy in pre- and peri-menopausal women with breast cancer.

PURPOSE: The purpose of the study was to prospectively examine changes in subjective and objective cognitive functions and quality of life (QOL) for pre- and peri-menopausal women receiving chemotherapy for breast cancer and to explore potential predictors of cognitive changes. METHODS: Participants were assessed as follows: prior to chemotherapy (T1), after cycle 3 (T2), within 2-3 weeks of completing adjuvant chemotherapy (T3) (N = 20), and 8+ years later (T4; n = 18). Objective cognitive function was measured with the High Sensitivity Cognitive Screen (T1, T3, T4). Subjective measures for cognitive function, depressive symptoms, fatigue, and mental and physical QOL were assessed at all time points. Estradiol levels were measured at T1, T2, and T3. The Functional Assessment of Cancer Therapy-Cognition and the MD Anderson Cancer Symptom Inventory item for neuropathy were administered at T4. RESULTS: No significant changes in objective cognitive function were found. However, participants reported decreased cognitive function over the course of treatment accompanied by depressive symptoms and fatigue. Depression and fatigue returned to near-baseline levels at T4, but over half of the participants continued to report mild to moderate depression. Estradiol levels were not associated with cognitive function. Neuropathy and higher body mass index (BMI) were associated with persistent cognitive complaints at T4 (adjusted R 2 = 0.712, p = 0.001). Higher QOL was correlated with better subjective cognitive function (r = 0.705, p = 0.002) and lower body mass index (r = - 0.502, p = 0.017) at T4. CONCLUSIONS: Further investigation of BMI, neuropathy, and depressive symptoms as predictors of persistent cognitive dysfunction following chemotherapy for breast cancer is warranted.

Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial.

PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000 IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer. METHODS: Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40 ng/ml were eligible. All subjects received standard daily supplement of 1200 mg calcium and 600 IU vitamin D3 and were randomized to 30,000 IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24 weeks. The primary endpoint was incidence of an AIMSS event. RESULTS: Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 weeks, and 31 at 24 weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p = 0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p = 0.024). CONCLUSIONS: Although 30,000 IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS.

Breast Cancer Genetic and Molecular Subtype Impacts Response to Omega-3 Fatty Acid Ethyl Esters.

Epidemiological studies have correlated frequent omega-3 (n-3) fatty acid consumption with a lower risk for breast cancer; however, recent prospective studies have been less conclusive. Efforts in the preventive setting have focused on the use of n-3 fatty acids, and the pharmaceutical ethyl esters (EE) of these natural compounds, for high-risk patient populations. Limited understanding of specific mechanisms by which these agents function has hampered identification of the cancer subtype(s) that would gain the greatest therapeutic benefit. In this study, we investigated the in vitro effects of n-3 EEs in four distinct breast cancer subtypes and explored how they affect not only breast cancer cell survival but also modulate the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma signaling pathways. Similar to the high variance in response observed in human studies, we found that the effectiveness of n-3 EEs depends on the molecular characteristics of the MCF-7, CAMA-1, MDA-MB-231, and SKBR3 breast cancer cell lines and is closely associated with the suppression of NF-κB. These data strongly suggest that the use of n-3 fatty acids and their pharmaceutical ether esters in the prevention and therapeutic setting should be guided by specific tumor characteristics.

Dietary Associations with a Breast Cancer Risk Biomarker Depend on Menopause Status.

We investigated how timing influences the role of diet in breast cancer risk with a cross-sectional study of pre-malignant change in breast tissue. Women with an elevated risk of developing breast cancer (33 premenopausal and 32 postmenopausal) completed the National Cancer Institute's food frequency questionnaire and underwent random periareolar fine-needle aspiration for evaluation of cytologic atypia, an established risk biomarker. Fatty acid composition of breast adipose was measured in 32 (49%) subjects. We found that premenopausal and postmenopausal women had similar diets, but the associations between atypia and intake of total n-3 polyunsaturated fatty acids (PUFA) and soy differed by menopause status (both P interaction < 0.001). Total n-3 PUFA intake was inversely associated with atypia among premenopausal women (P < 0.0001), but not among postmenopausal women (P = 0.91); associations were similar for soy (P = 0.0003 and P = 0.48, respectively). This pattern of dietary interaction with menopause was mirrored in tissue fatty acids (P interaction < 0.05), wherein 1) higher levels of linolelaidic acid (an industrially-produced trans fat) and 2) lower levels of docosahexaenoic acid (the predominant long-chain n-3 PUFA) in breast adipose were associated with atypia in premenopausal (both P < 0.05) but not postmenopausal women (both P > 0.37). Dietary associations with breast cancer risk are stronger prior to menopause.

Incorporating Biomarkers in Studies of Chemoprevention.

Despite Food and Drug Administration approval of tamoxifen and raloxifene for breast cancer risk reduction and endorsement by multiple agencies, uptake of these drugs for primary prevention in the United States is only 4% for risk eligible women likely to benefit from their use. Side effects coupled with incomplete efficacy and lack of a survival advantage are the likely reasons. This disappointing uptake, after the considerable effort and expense of large Phase III cancer incidence trials required for approval, suggests that a new paradigm is required. Current prevention research is focused on (1) refining risk prediction, (2) exploring behavioral and natural product interventions, and (3) utilizing novel translational trial designs for efficacy. Risk biomarkers will play a central role in refining risk estimates from traditional models and selecting cohorts for prevention trials. Modifiable risk markers called surrogate endpoint or response biomarkers will continue to be used in Phase I and II prevention trials to determine optimal dose or exposure and likely effectiveness from an intervention. The majority of Phase II trials will continue to assess benign breast tissue for response and mechanism of action biomarkers. Co-trials are those in which human and animal cohorts receive the same effective dose and the same tissue biomarkers are assessed for modulation due to the intervention, but then additional animals are allowed to progress to cancer development. These collaborations linking biomarker modulation and cancer prevention may obviate the need for cancer incidence trials for non-prescription interventions.

Omega-3 fatty acids for breast cancer prevention and survivorship.

Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case-control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-κB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy-induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega-3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship.

Effects of Flaxseed Lignan Secoisolariciresinol Diglucosideon Preneoplastic Biomarkers of Cancer Progression in a Model of Simultaneous Breast and Ovarian Cancer Development.

Breast cancer prevention efforts are focused increasingly on potentially beneficial dietary modifications due to their ease of implementation and wide acceptance. Secoisolariciresinol diglucoside (SDG) is a lignan found in high concentration in flaxseed that may have selective estrogen receptor modulator-like effects resulting in antiestrogenic activity in a high estrogen environment. In parallel with a human phase II prevention trial, female ACI rats (n = 8-10/group) received 0, 10, or 100 ppm SDG in the feed. The 100 ppm SDG treatment produced similar blood lignan levels as those observed in our human pilot study. Mammary and ovarian cancer progression were induced using local ovarian DMBA treatment and subcutaneous sustained release 17ß-estradiol administered starting at 7 weeks of age. Mammary gland and ovarian tissues were collected at 3 mo after initiation of treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology, and dysplasia scores, as well as expression of selected genes involved in proliferation, estrogen signaling, and cell adhesion. Treatment with SDG normalized several biomarkers in mammary gland tissue (dysplasia, cell number, and expression of several genes) that had been altered by carcinogen. There is no indication that SDG promotes preneoplastic progression in the ovarian epithelium.

Impact of neoadjuvant chemotherapy on axillary nodal involvement in patients with clinically node negative triple negative breast cancer.

BACKGROUND: We evaluated the impact of Neoadjuvant Chemotherapy (NAC) versus primary surgery (PS) on axillary disease burden/surgery in clinically node negative Triple Negative Breast Cancer (TNBC). METHODS: Two hundred forty-three Stage I-III TNBC patients have enrolled on an IRB approved multisite prospective registry. Clinical and treatment information was collected. RESULTS: One hundred fifty-five patients with clinically node negative TNBC were identified. 47%, 49%, and 4% of patients had T1, T2, and T3 disease, respectively. Patients underwent PS (103/155, 66%) or NAC (52/155, 34%) at the discretion of treating physicians. 17% of PS and 0% of NAC patients were node positive at surgery (P=0.006). For T2 disease, 32% of PS and 0% of NAC patients were node positive at surgery (P=0.001). NAC patients had a lower chance of positive SLNB (0% vs. 12%, P=0.004) and undergoing ALND (2% vs. 22%, P=0.001) than PS patients. CONCLUSION: In this clinically node negative TNBC cohort, all NAC-treated patients were node negative at surgery, whereas 17% of PS patients had involved axillary nodes. NAC should be considered for clinically node negative TNBC to reduce the extent of axillary surgery even if breast conservation is not planned.

Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors.

As recurrence free survival following a breast cancer diagnosis continues to improve, cardiovascular morbidity and mortality will assume greater importance in the breast cancer survivorship research agenda particularly for women receiving potentially cardiotoxic therapy. Development of (1) tools to readily identify pre-diagnostic risk factors for cardiac dysfunction, (2) well-tolerated prophylactic treatments to reduce the risk of cardiac injury, and (3) sensitive and affordable monitoring techniques which can identify subclinical toxicity prior to a drop in left ventricular ejection fraction are or should be focus areas of cardio-oncology research. Since weight as well as cardiorespiratory fitness generally decline after a breast cancer diagnosis, behavioral approaches which can improve energy balance and fitness are important to optimize cardiovascular health in all breast cancer survivors not just those undergoing cardiotoxic therapy. These goals are likely best achieved by partnerships between cardiologists, oncologists and internists such as those initiated with the formation of the International CardiOncology Society (ICOS) and the NCI Community Cardiotoxicity Task Force.

Risk Reduction from Weight Management and Physical Activity Interventions.

Obesity and low levels of physical activity are associated with a higher risk of breast cancer recurrence and mortality. Currently, over 65% of breast cancer survivors are overweight or obese, and fewer than 30% engage in recommended levels of physical activity. The reason for low adherence to lifestyle guidelines is likely multifactorial. Given the continuing trend of increased obesity and physical inactivity in the United States, worldwide and in breast cancer survivors, more research showing the direct effect of weight loss and/or exercise on breast cancer recurrence and mortality is needed. Many exercise interventions have examined the impact of increasing exercise on changes in quality of life, with most studies showing a favorable effect of exercise on quality of life. Smaller Phase II randomized trials using biomarkers as surrogate endpoints is likely appropriate to answer questions regarding mechanisms of action, exercise type, volume, and intensity, yet a definitive trial of weight loss and exercise on disease-free survival is critical for moving the field forward. Research is also necessary on how to disseminate lifestyle interventions into the clinic and community that lead to clinically meaningful weight losses of at least 5% that are maintained over time, and favorable sustained changes in physical activity levels. Changes in referrals, access, and reimbursement of lifestyle programs may lead to favorable changes in the prevalence of obesity and physical activity in breast cancer survivors and in turn rates of breast cancer recurrence and mortality.

Exemestane for breast-cancer prevention in postmenopausal women.

BACKGROUND: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS: In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS: A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing.

NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I-IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African-American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51-60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC.

Overcoming challenges in conducting early phase breast cancer prevention trials: Bazedoxifene and conjugated estrogens vs waitlist control.

BACKGROUND: The combination of bazedoxifene 20 mg (BZA) and conjugated estrogens 0.45 mg (CE) marketed as Duavee® is approved for vasomotor symptom relief and osteoporosis prevention. Our pilot study suggested it had potential breast cancer risk reduction, and we proposed a multisite Phase IIB primary prevention trial assessing change in breast imaging and tissue risk biomarkers. By the time funding was acquired in February 2021, Duavee® was unavailable with an uncertain return date. A redesign was needed to salvage the study. METHODS: The basic trial design was minimally altered. Women age 45-64 at elevated risk for breast cancer with vasomotor symptoms and no menses for at least 2 months have mammography, phlebotomy, and benign breast tissue sampling before and after 6 months of intervention. However, instead of Duavee® (single pill) vs placebo, women are randomized to 6 months of BZA + CE vs Waitlist. Those initially randomized to Waitlist can receive BZA + CE after 6 months. The primary endpoint is between arm difference in change in a fully automated measure of mammographic density with blood and tissue-based secondary endpoints. OUTCOMES: Accrual initiation was delayed due to contractual difficulties surrounding BZA importation during COVID-19 and deploying a fully automated method (Volpara®) to assess the primary endpoint. To accommodate this delay, a mid-grant no cost extension along with amended eligibility requirements were employed. 61/120 participants needed were entered in the initial 27 months of accrual and 37 months of funding. Despite a late start, accrual is likely to be completed within the funding period.

Favorable modulation of benign breast tissue and serum risk biomarkers is associated with > 10 % weight loss in postmenopausal women.

We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m(2) and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women.

A prospective model of care for breast cancer rehabilitation: bone health and arthralgias.

Musculoskeletal health can be compromised by breast cancer treatment. In particular, bone loss and arthralgias are prevalent side effects experienced by women treated with chemotherapy and/or adjuvant endocrine therapy. Bone loss leads to osteoporosis and related fractures, while arthralgias threaten quality of life and compliance to treatment. Because the processes that lead to these musculoskeletal problems are initiated when treatment begins, early identification of women who may be at higher risk of developing problems, routine monitoring of bone density and pain at certain stages of treatment, and prudent application of therapeutic interventions are key to preventing and/or minimizing musculoskeletal sequelae. Exercise may be a particularly suitable intervention strategy because of its potential to address a number of impairments; it may slow bone loss, appears to reduce joint pain in noncancer conditions, and improves other breast cancer outcomes. Research efforts continue in the areas of etiology, measurement, and treatment of bone loss and arthralgias. The purpose of this review is to provide an overview of the current knowledge on the management and treatment of bone loss and arthralgias in breast cancer survivors and to present a framework for rehabilitation care to preserve musculoskeletal health in women treated for breast cancer.

A prospective surveillance model for rehabilitation for women with breast cancer.

BACKGROUND: The current model of care for individuals with breast cancer focuses on treatment of the disease, followed by ongoing surveillance to detect recurrence. This approach lacks attention to patients' physical and functional well-being. Breast cancer treatment sequelae can lead to physical impairments and functional limitations. Common impairments include pain, fatigue, upper-extremity dysfunction, lymphedema, weakness, joint arthralgia, neuropathy, weight gain, cardiovascular effects, and osteoporosis. Evidence supports prospective surveillance for early identification and treatment as a means to prevent or mitigate many of these concerns. This article proposes a prospective surveillance model for physical rehabilitation and exercise that can be integrated with disease treatment to create a more comprehensive approach to survivorship health care. The goals of the model are to promote surveillance for common physical impairments and functional limitations associated with breast cancer treatment; to provide education to facilitate early identification of impairments; to introduce rehabilitation and exercise intervention when physical impairments are identified; and to promote and support physical activity and exercise behaviors through the trajectory of disease treatment and survivorship. METHODS: The model is the result of a multidisciplinary meeting of research and clinical experts in breast cancer survivorship and representatives of relevant professional and advocacy organizations. RESULTS/CONCLUSIONS: The proposed model identifies time points during breast cancer care for assessment of and education about physical impairments. Ultimately, implementation of the model may influence incidence and severity of breast cancer treatment-related physical impairments. As such, the model seeks to optimize function during and after treatment and positively influence a growing survivorship community.