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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.

Background: Older adults with advanced cancer are exposed to antibiotics but estimates of adverse drug events associated with antibiotic therapy are lacking. Aim: Evaluate the association of antibiotic therapy with adverse drug events in older adults with advanced cancer. Design: Cohort study where the exposure was the ratio of days of therapy of an oral or intravenous antibiotic per patient-day and the outcome was an adverse drug event, defined as cardiotoxicity, hepatotoxicity, nephrotoxicity, Clostridioides difficile infection, or new detection of a multidrug-resistant organism. Setting/participants: Patients aged ⩾65 years with solid tumors from a tertiary care center who received palliative chemotherapy ( n = 914). Results: Mean age was 75 ± 6.6 years, and 52% were female. Common tumors were lung (31%, n = 284) and gastrointestinal (26%, n = 234). Mean time from first course of palliative chemotherapy to index admission was 128 days. Five-hundred thirty (58%) patients were exposed to antibiotics during the index admission; of these, 27% ( n = 143) met standardized criteria for infection. Patients were commonly exposed to cephalosporins (33%, n = 298) and vancomycin (30%, n = 276). Among patients exposed to antibiotics, 35% ( n = 183/530) developed an adverse drug event. In multivariable testing, antibiotic therapy was associated with development of an adverse drug event (>0 to Conclusion: Antibiotic therapy was independently associated with adverse drug events in hospitalized older adults with advanced cancer. These findings may inform antibiotic decision-making among palliative care providers.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals who work with survivors to ensure that the survivors’ complex and varied needs are addressed. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for the consequences of adult-onset cancer and its treatment; recommendations to help promote physical activity, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes updates to the NCCN Guidelines pertaining to preventive health for cancer survivors, including recommendations about alcohol consumption and vaccinations.

Young women with breast cancer (YWBC) report physical and psychological symptom distress after therapy but little is known about their sleep health. The purpose of this study was to identify sociodemographic, clinical, and psychosocial factors associated with sleep health and assess the potential role of appraisal of illness and coping on sleep health. An adapted cognitive appraisal and coping conceptual framework guided the study. We used a cross-sectional design with 159 women who were diagnosed with stage I-III breast cancer ≤50 years old. Sleep health was measured by the Pittsburgh Sleep Quality Index (PSQI). The mean age was 43.6 years (SD = 6.8), the majority of whom were non-Hispanic White (84%) and completed chemotherapy or radiotherapy (70%). More than half of participants (55%) reported poor sleep health (PSQI 8), and those with worse family functioning and from a racial/ethnic minority group were significantly more likely to have poor sleep health. Cognitive appraisal had a minimal mediation effect for anxiety on sleep health, and coping did not mediate the effect of any psychosocial variables on sleep health. Poor sleep health is a significant clinical problem in YWBC. Further research is needed to explore sleep health disparities among diverse cancer survivors and to examine sleep health in the context of family. Sleep assessment, management, and appropriate referrals to sleep providers should be part of routine survivorship care.

A cancer diagnosis thrusts patients and caregivers into a foreign world of health care with systems, protocols, and norms that can leave little room for individual needs and circumstances. Quality and efficacious oncology care requires clinicians to partner with patients and caregivers to understand and incorporate their needs, values, and priorities into information sharing, decision making, and care provision. This partnership is necessary for effective patient- and family-centered care and access to individualized and equitable information, treatment, and research participation. Partnering with patients and families also requires oncology clinicians to see that our personal values, preconceived ideas, and established systems exclude certain populations and potentially lead to poorer care for all patients. Furthermore, inequitable access to participation in research and clinical trials can contribute to an unequal burden of cancer morbidity and mortality. Leveraging the expertise of the authorship team with transgender, Hispanic, and pediatric populations, this chapter provides insights and suggestions for oncology care that are applicable across patient populations to mitigate stigma and discrimination and improve the quality of care for all patients.

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

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Raw ctDNA data

Purpose:Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i.Patients and Methods:This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.Results:Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.Conclusions:Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Supplemental Figure 1. ER, PI3K/mTOR, and CDK4/6 Pathways in HR+ Breast Cancer Supplemental Figure 2. Median Ctrough From Cycle 1 Day 15 in Cohorts A and B. Supplemental Figure 3. Time to Progression or Time on Study Treatment Supplemental Figure 4. Baseline ctDNA Mutations and Time to Disease Progression or Death

Background: Hormone receptor-positive (HR+) is the most common molecular subtype of breast cancer accounting for approximately 2 out of every 3 patients. Adjuvant anti-estrogen therapy is the cornerstone of systemic therapy, underscoring the critical role of endocrine treatment which affects the majority of women with breast cancer. Furthering efforts to better understand endocrine response and resistance and implementing genomic tools to help individualize patient selection for endocrine therapy are of ongoing importance to improve outcomes. Breast Cancer Index (BCI) is a gene expression signature composed of the Molecular Grade Index (MGI) and HOXB13/IL17BR (H/I) that predicts the likelihood of extended endocrine benefit and quantifies the risk of both late (5-10 years) and overall (0-10 years) distant recurrence. BCI has recently been incorporated into the NCCN clinical practice guideline as a biomarker for prediction of benefit from extended endocrine therapy in patients with early-stage, HR+ breast cancer. The objective of the BCI Registry Study is to collect real-world evidence at a national level aimed at advancing patient care and optimizing duration of endocrine treatment and will be conducted in two phases. First, long-term patient outcomes and the impact of BCI on decision-making based on physician and patient reported outcomes as well as medication adherence to extended endocrine therapy will be assessed. Secondly, individual patient data on over 40 clinical variables will be collected and partnered with molecular profiling and genomic data for each patient to enable correlative analysis and novel biomarker research of endocrine sensitivity and resistance. Study Description: The BCI Registry Study is a prospective, multi-center, observational data registry and biospecimen repository for stage I-III HR+ breast cancer patients. The main objective of the Registry Study is prospective characterization of BCI predictive and prognostic performance. The primary endpoint is time to distant recurrence (TTDR), defined as the interval between the time of BCI testing and the first metastasis at distant organs. Secondary endpoints include time to any recurrences and medication adherence score over time. Eligibility criteria includes confirmed diagnosis of HR+ early-stage invasive breast carcinoma (ductal, lobular, or mixed ductal/lobular), either HER2 negative or positive and either node-negative or node-positive tumors with 1-3 positive lymph nodes (N1). Patients must have completed 4 to 7 years of primary adjuvant endocrine therapy and have pre-treatment tumor tissue available from a previous breast surgery or biopsy. Both physicians and patients will complete a pre- and post-test Decision Impact Questionnaire to assess the impact of BCI results on extended endocrine therapy decision-making. Patients who elect to complete 10 years of endocrine therapy will answer a Medication Adherence Questionnaire during annual follow-up visits. Follow-up of patients will end 10 years from initial breast cancer diagnosis. The Registry plans to enroll approximately 3,000 patients across approximately 40 study sites in the United States. Enrollment for the study began in Q2 2021, and 324 patients have been enrolled as of July 2021. For more information, please visit the ClinicalTrials.gov registration: NCT04875351. Citation Format: Joyce A O'Shaughnessy, Jenny R Fox, Carlos A Encarnación, Brandon O'Neal, Kai Treuner, Tara Sanft, Rachel C Jankowitz, Mark D Pegram, Catherine A Schnabel, Sami G Diab. The Breast Cancer Index registry study: A prospective multi-center observational study to evaluate patient outcome, clinical impact, and medication adherence in HR+ breast cancer patients considering treatment with extended endocrine therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-10-01.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals who work with survivors to ensure that the survivors' complex and varied needs are addressed. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for the consequences of adult-onset cancer and its treatment; recommendations to help promote physical activity, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes updates to the NCCN Guidelines pertaining to preventive health for cancer survivors, including recommendations about alcohol consumption and vaccinations.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor’s complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.

Establishing goals of care (GOC) is a crucial component of a patient's treatment plan. The need for better physician-patient communication in this area has been recognized for decades, yet several gaps remain. Challenges exist for both physician and patient. Physicians should pursue a patient-led approach, exercise cultural competency, and use various communication techniques to guide patients when establishing GOC.

New approaches to cancer survivorship care must address the rising number of survivors who need complex care; the need to personalize care to improve health equity; workforce shortages and clinician knowledge deficits about the long-term and late effects of cancer; the need to engage and coordinate oncology, primary care, and a large multidisciplinary team of subspecialists and programs to meet survivors’ needs; and the need to control costs and deliver better value. This review proposes eight core tenets of an evolved standard of care to meet these needs by starting at diagnosis and continuing throughout oncology and into follow-up to: (1) facilitate team medicine by connecting oncology, primary care, subspecialists and programs, researchers, and patients and caregivers; (2) educate patients and support them in self-management; (3) mitigate toxicities; (4) manage comorbidities; (5) promote healthy behaviors and wellness; (6) improve health equity; (7) provide clear personalized follow-up; and (8) provide ongoing opportunities for participation in research as the standard of care. Strategies to successfully implement this care are discussed from the perspectives of oncology, primary care, and health care administration.

Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Background: Obesity is a leading risk factor for breast cancer in post-menopausal women and is associated with greater risk of recurrence and cancer-specific mortality. There are over 3 million female breast cancer survivors in the United States, and nearly 65% are either overweight or obese. Lifestyle intervention studies have been shown to be effective in achieving clinically meaningful weight loss for breast cancer survivors with a BMI > 25 kg/m2. However, individual variability in body weight response to diet or exercise interventions has been previously reported among carriers of common obesity-genetic variants. Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB moderated the effects of an exercise and nutrition intervention on weight change among breast cancer survivors. Methods: A total of 151 breast cancer survivors with a body mass index (BMI) ≥ 25 kg/m2 at baseline were randomly assigned to a 6-month weight loss intervention (n=93) or usual care group (n=58). The weight loss intervention included eleven 30-min counseling sessions on improving nutrition and increasing physical activity. Height, weight and body composition (via dual energy X-ray absorptiometry) were measured at baseline and six months. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed using Taqman® SNP genotyping assays. Association analyses were performed in SAS version 9.4, separately for each SNP and assuming a dominant genetic model. Linear mixed models were used to analyze the main effects of genotype and the intervention on weight, BMI, and percent body fat changes at 6 months, with adjustment for age. Appropriate cross product terms were included in each regression model to analyze the potential interaction between genotype and treatment arm. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125. Results: The genetic distributions of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, CREB1 SNP rs17203016 did not differ significantly by treatment arm. Changes in weight, BMI, and percent body fat did not differ significantly between carriers of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, and CREB1 SNP rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each SNP and across all outcomes). Women in the intervention group achieved significantly greater weight loss than the usual care group (-4.8 kg vs -0.6 kg, p < 0.001) regardless of genotype. Conclusions: Common variants of known obesity-associated genes (FTO, MC4R, BDNF, and MC4R) did not modify the effect of the nutrition and exercise intervention on changes in body weight and body fat. Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may benefit from lifestyle changes similarly to women who are not genetically predisposed to obesity. Our findings may help guide the incorporation of lifestyle interventions and weight loss counseling into breast cancer survivorship care. Citation Format: ThaiHien Nguyen, Melinda L Irwin, Andrew T Dewan, Maura Harrigan, Brenda Cartmel, Tara Sanft, Lingeng Lu, Fangyong Li, Yasmmyn D Salinas. Assessing effect modification of obesity-associated genes variants in FTO, MC4R, BDNF, and CREB1 on weight loss among breast cancer survivors enrolled in the randomized lifestyle, exercise, and nutrition (LEAN) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-17.

Previous work found that lower BMI is associated with a pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer. Relative dose intensity (RDI) of chemotherapy is an important marker of treatment tolerability. We hypothesized that patients with low BMI would have higher RDI than patients with high BMI, explaining the mechanism for the association between BMI and pCR. We conducted a retrospective study of women treated with neoadjuvant chemotherapy for stage I-III breast cancer at Yale New Haven Hospital-Smilow Cancer Hospital. We reviewed medical records to determine tumor characteristics, chemotherapy doses, and reasons for dose reductions or delays. The treatment RDI was calculated using published methods. Chi-squared analyses were conducted to determine the associations between RDI and BMI and between RDI and pCR. Our cohort (n = 237) had an average age of 53 years (SD 13) and mean BMI of 29.5 kg/m2 (SD 7.0). Fifty-eight patients (24%) received

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors’ needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.

Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

Background: While the side effects of anthracycline and taxane based chemotherapy are well characterized, introduction of experimental agents and immunotherapy in the neoadjuvant and adjuvant setting may significantly alter the toxicity profiles of these regimens, resulting in short and long-term changes in patient quality of life (QOL). Trial Design: I-SPY 2 is a phase 2 trial investigating novel targeted therapies and immunotherapy in combination with standard chemotherapy in the neoadjuvant setting for Mammaprint high-risk stage 2 and 3 breast cancers. A QOL sub-study was introduced into the I-SPY 2 trial platform in 2012. All patients who consent to screen for the I-SPY 2 trial receive a baseline QOL questionnaire. Patients who consent to the treatment phase of I-SPY 2 also complete questionnaires on the first day of treatment, mid-way through neoadjuvant treatment, prior to surgery, and then 1, 6, 12 and 24 months post-surgery. Instruments have included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ C30 and BR23, as well as NCI Patient-Reported Outcomes Measurement Information System (PROMIS) measures, the National Comprehensive Cancer Network (NCCN) Distress Thermometer, and a Fear of Recurrence (FOR) instrument. We are currently implementing an electronic platform for survey collection and modifying the survey instruments to incorporate 31 items from the Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system along with previously included PROMIS items in domains of physical, psychological, cognitive, and sexual function, the Distress Thermometer, and the FOR instrument. During neoadjuvant treatment, patients will also complete weekly abbreviated surveys containing PRO-CTCAE items only. We are using the data from these measures to generate a Clinical Benefit Index (CBI), a single composite score that integrates a PROMIS Preference (PROPr) score with a clinical efficacy assessment (residual cancer burden- RCB index) to provide new insight into the overall impact that therapeutic agents in I-SPY2 have on cancer recurrence risk, general health, and QOL. Specific Aims: The primary objective of the QOL study is to evaluate the short- and long-term impact on QOL of novel agents added to standard treatment in high-risk breast cancer patients receiving neoadjuvant therapy. Factors including patient age, hormone receptor and HER2 status, and response to treatment by residual cancer burden will be evaluated to understand their impact on a patients’ QOL trajectory over time. A secondary objective is to compare patient reported toxicities (using PRO-CTCAE measures) with clinician-reported adverse events. Accrual: The I-SPY 2 trial has registered 2729 patients to date and there are 18 sites open across the US. Since the initiation of the QOL study, at least one QOL survey has been collected from 1066 patients. Given the adaptive design, enrollment for each agent varies based on patient outcomes, but collection of PRO measures on all patients will continue as new agents enter the trial. Clinical trial information: NCT01042379. Citation Format: Hila Ghersin, Aheli Chattopadhyay, Anne Blaes, Tara Sanft, Dawn Hershman, Amrita Basu, Ruby Singhrao, Susie Brain, Diane Heditsian, Hope S Rugo, Laura Esserman, Michelle Melisko. Introducing an electronic platform to collect patient reported outcomes in the I-SPY 2 trial, a neoadjuvant clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-19-02.

Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-02.

Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility ( Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-02.

Background: A growing number of lifestyle interventions are being developed to promote weight loss and adoption of a healthy lifestyle among breast cancer (BC) survivors. However, Black and Latina BC survivors remains underrepresented. We performed a scoping review to examine the available peer-reviewed literature to describe the content, design, methods, and primary outcomes of current diet and/or physical activity (PA) interventions designed specifically for Black and Latina BC survivors. Methods: PubMed, EMBASE, CINAHL, MEDLINE and Clinicaltrials.gov databases were queried up to May 14, 2022, using an inclusion criterion that consisted of four overarching concepts: 1) female breast cancer, 2) diet and/or PA intervention, 3) self-reported race, ethnicity as Black/African American and/or Hispanic/Latina and 4) randomized study design. Results: Our search yielded 1,436 trials, of which 22 trials met inclusion criteria for this review. We identified 6 efficacy trials, 12 pilot trials, and 5 currently ongoing studies. Nine trials were conducted among Latina BC survivors (4 diet, 5 PA, and 2 diet and PA interventions), 6 trials were among Black BC survivors (2 PA and 1 diet and PA interventions) and 7 were conducted among both groups (5 PA and 2 diet and PA interventions). Only 8 out of 22 trials incorporated intervention content on both diet and PA behaviors, of which, 3 incorporated a culturally focused approach for Latinas BC survivors and 1 for Black BC survivors (i.e., traditional/cultural foods, music, education materials in Spanish, bicultural health coaches, connections to spirituality). Among the 8 trials targeting both diet and PA, all of them were pilot studies and only 3 were found to have favorable impact on healthy diet and exercise behaviors. Out of 4 trials with one-year outcomes, 3 (1 diet, 1 PA and 1 diet and PA intervention) showed a change in behavior sustained at this time point with only 1 being an efficacy trial for PA. Electronic/mobile components (e.g., websites, mobile applications, emails) were incorporated in 6 trials (3 among Black BC survivors , 2 among Latina BC survivors , and 2 among both groups) and just 1 trial conducted among Latina BC survivors involved informal caregivers (i.e., family or friends). Lastly, most trials in this review were conducted in the Northeast (n=7, NY, NC, DC, NJ) and Texas (n=4), limiting generalizability of findings to Black and Latina BC survivors residing in other states and settings. Conclusions: There is a growing number of lifestyle interventions among BC survivors, yet few are designed and culturally tailored to the unique needs of Black and Latina BC survivors. There is an unmet need for dietary and PA randomized clinical interventions for Black and Latina BC survivors as well as randomized rials that incorporate technology and informal sources of support (e.g., caregivers, family, etc.)—factors that are critical to increase access, adoption, and maintenance of healthful lifestyles among cancer survivors. Citation Format: Yaideliz M. Romero-Ramos, Melinda Irwin, Ana I. Velazquez, Leah M. Ferruci, Tara Sanft, Brenda Cartmel, Margaret S. Pichardo. A scoping review of diet and physical activity interventions in Latina and Black breast cancer survivors [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C104.

Is it okay to cry with your patients? This narrative tells a story to help answer this complicated question.

The use of dietary supplements is common in the general population and even more prevalent among cancer survivors. The World Cancer Research Fund/American Institute for Cancer Research specifies that dietary supplements should not be used for cancer prevention. Several dietary supplements have potential pharmacokinetic and pharmacodynamic interactions that may change their clinical efficacy or potentiate adverse effects of the adjuvant endocrine therapy prescribed for breast cancer treatment. This analysis examined the prevalence of self-reported dietary supplement use and the potential interactions with tamoxifen and aromatase inhibitors (AIs) among breast cancer survivors enrolled in three randomized controlled trials of lifestyle interventions conducted between 2010 and 2017. The potential interactions with tamoxifen and AIs were identified using the Natural Medicine Database. Among 475 breast cancer survivors (2.9 (mean) or 2.5 (standard deviation) years from diagnosis), 393 (83%) reported using dietary supplements. A total of 108 different types of dietary supplements were reported and 36 potential adverse interactions with tamoxifen or AIs were identified. Among the 353 women taking tamoxifen or AIs, 38% were taking dietary supplements with a potential risk of interactions. We observed a high prevalence of dietary supplement use among breast cancer survivors and the potential for adverse interactions between the prescribed endocrine therapy and dietary supplements was common.

Lifestyle interventions among breast cancer survivors with obesity have demonstrated successful short-term weight loss, but data on long-term weight maintenance are limited. We evaluated long-term weight loss maintenance in 100 breast cancer survivors with overweight/obesity in the efficacious six-month Lifestyle, Exercise, and Nutrition (LEAN) Study (intervention = 67, usual care = 33). Measured baseline and six-month weights were available for 92 women. Long-term weight data were obtained from electronic health records. We assessed weight trajectories between study completion (2012–2013) and July 2019 using growth curve analyses. Over up to eight years (mean = 5.9, SD = 1.9) of post-intervention follow-up, both the intervention (n = 60) and usual care (n = 32) groups declined in body weight. Controlling for body weight at study completion, the yearly weight loss rate in the intervention and usual care groups was –0.20 kg (−0.2%/year) (95% CI: 0.06, 0.33, p = 0.004) and −0.32 kg (−0.4%/year) (95% CI: 0.12, 0.53, p = 0.002), respectively, mean weight change did not differ between groups (p = 0.31). It was encouraging that both groups maintained their original intervention period weight loss (6% intervention, 2% usual care) and had modest weight loss during long-term follow-up. Breast cancer survivors in the LEAN Study, regardless of randomization, avoided long-term weight gain following study completion.

Introduction Poor sleep health adversely affects quality of life and prognosis in cancer survivors, yet there is limited evidence on sleep health in young women with breast cancer (YWBC). The purpose of this study was to identify sociodemographic, clinical, and psychosocial factors associated with sleep health. Methods We conducted a cross-sectional study. Eligible participants were women diagnosed with stage I-III breast cancer ≤ 50 years of age and within 5 years from primary cancer treatment. Sociodemographic, clinical, and psychosocial data were collected through an online survey. Sleep health and psychosocial data were assessed by the Pittsburgh Sleep Quality Index (PSQI), PROMIS depression and anxiety, and the McMaster Family Device General Functioning subscale. Data were analyzed with logistic regression. A PSQI cut-off score of >8 was used to define poor sleep health based on the study data and the cancer sleep literature. Results The sample included 159 YWBC with a mean age of 43.6 years (SD=6.8), the majority of whom were non-Hispanic White (84%) and completed chemotherapy or radiotherapy (>70%). Half of the participants were premenopausal at diagnosis and became peri- or postmenopausal after treatment. The mean global PSQI was 9.3 (SD=3.6) and 55% reported poor sleep health. About half of the participants slept 15 minutes falling asleep, and 58% reported taking medication to sleep. Non-White underrepresented groups (OR=7.56, p Conclusion The findings suggest that poor sleep health is a significant clinical problem in YWBC. Sleep assessment, education, and appropriate referrals should be part of routine survivorship care. Social determinants of health such as race and ethnicity and family functioning warrant further investigation related to sleep health. Future studies are needed to confirm the relationships of sociodemographic and clinical factors, psychological symptoms, and family functioning with sleep health. Support (If Any) The Global Korean Nursing Foundation.

Few trials have examined the effect of lifestyle behavioral interventions on tissue markers in patients with cancer. The purpose of this study was to examine the feasibility and impact of a 6-month weight loss intervention on breast tissue and serum biomarkers in women with breast cancer. Fifty-one women who completed breast cancer treatment and had a BMI ≥ 25.0 kg/m2 were randomized to a weight loss intervention or usual care. Breast tissue biopsies, fasting blood draw and body composition were collected at baseline and 6 months, with between-group changes examined using analysis of covariance method. Baseline and post-intervention biopsies were conducted in 49 and 42 women, respectively, with pre- and post-epithelial tissue available from 25 tissue samples. Average 6-month weight loss was 6.7% for the weight loss group and 2.0% increase for the usual care group (p p p

Purpose: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.

BACKGROUND The objective of this study was to evaluate the role of a 12-month exercise intervention on endocrine-related quality of life (QOL) and overall QOL among breast cancer survivors with aromatase inhibitor (AI)-induced arthralgia in the Hormones and Physical Exercise (HOPE) Study. METHODS This was a randomized controlled trial of 121 breast cancer survivors who were currently receiving AIs and experiencing at least mild arthralgia. QOL was assessed using the Functional Assessment of Cancer Therapy (FACT) questionnaires and the 36-Item Short Form Survey (SF-36) at baseline, 6 months, and 12 months. Participants were randomized to either a 1-year gym-based, supervised exercise intervention group (150 minutes of aerobic exercise and 2 strength-training sessions each week) or a usual care group. Effects of the intervention on QOL were assessed using mixed-model, repeated-measures analysis. RESULTS At 12 months, the exercise group had greater improvement in the overall QOL measures as well as the breast cancer-specific (scores, 2.2 vs 0.7; P = .02), endocrine-specific (scores, 5.6 vs 1.6; P

Obesity among breast cancer survivors is associated with increased risk for recurrence and mortality. The hormone ghrelin plays a role in initiating appetite and thus regulating body weight. This study aims to determine the effect of a lifestyle intervention on ghrelin levels in breast cancer survivors with a body mass index (BMI) ≥ 25 kg/m2. The Lifestyle, Exercise, and Nutrition (LEAN) study was a 6-month randomized trial, examining the effectiveness of a weight loss intervention versus usual care in 151 breast cancer survivors with BMI ≥ 25 kg/m2. Ghrelin was measured in fasting baseline and 6-month blood samples. Baseline associations between ghrelin, body composition, and blood biomarkers were examined. Six-month change in ghrelin was compared between study arms. Ghrelin measurements were available for 149 women. At baseline, ghrelin was correlated with age (r = 0.28, p r = −0.18, p = 0.03), lean body mass (r = −0.18, p = 0.02), and leptin (r = −0.18, p = 0.03). Over 6 months, ghrelin increased by 144 pg/mL (7.2%) in the intervention and decreased by 466 pg/mL (32.5%) in the usual care (p = 0.07). Among all women, greater weight loss was associated with an increase in ghrelin (p = 0.01). These findings indicate that weight loss, achieved through a lifestyle intervention, is associated with higher ghrelin levels in breast cancer survivors which may be informative for developing sustainable weight loss programming for this population. Future research should investigate the long term impacts of lifestyle interventions on ghrelin levels in the context of weight maintenance and weight regain.

Background The World Cancer Research Fund and the American Cancer Society provide nutrition and physical activity guidelines for cancer survivors. Many women with breast cancer do not follow these guidelines and delay efforts toward following them until active treatment is complete. However, adoption of these recommended lifestyle behaviors soon after diagnosis may prevent adverse treatment-related side effects and may improve adherence to treatment, resulting in improved breast cancer prognosis. The L ifestyle, E xercise, and N utrition Ear ly after Diagnosis (LEANer) study is testing the effect of a nutrition and physical activity intervention on chemotherapy completion rates. Methods 172 women with stage I-III breast cancer undergoing chemotherapy will be randomized 1:1 to a yearlong, 16 session, nutrition and exercise intervention or usual care control group. The intervention is delivered by registered dietitians specializing in oncology nutrition and exercise training. The intervention includes goal setting to meet nutrition and physical activity guidelines for cancer survivors. After each chemotherapy session, date and dose of each drug administered, and reason for dose-adjustments and/or dose-delays are abstracted from the electronic medical record or obtained from the treating oncologist. Chemotherapy completion rate is assessed as the average relative dose-intensity (RDI) for the originally planned regimen based on standard formulas. Secondary endpoints of endocrine therapy adherence, treatment-related side effects, and changes in inflammatory and metabolic biomarkers, body composition, and patient reported outcomes are assessed at four timepoints. Discussion If successful, this study has the potential to make healthy lifestyle interventions a standard component of breast cancer treatment.

Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB1 moderated the effects of a lifestyle intervention on weight change among breast cancer survivors. 151 breast cancer survivors with a body mass index ≥ 25 kg/m2 were randomly assigned to a 6-month weight loss intervention or usual care group. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed. Linear mixed models were used including the main effects of genotype (assuming a dominant genetic model), treatment arm on weight and percent body fat changes, and genotype by treatment interaction variable. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125. Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p 0.0125 for each single-nucleotide polymorphisms). Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may achieve significant and clinically meaningful weight loss through healthy eating and exercise. Clinical Trial Registration: NCT02863887 (Date of Registration: August 11, 2016); NCT02110641 (Date of Registration: April 10, 2014)

Background: Antimicrobial use during end-of-life care of older adults with advanced cancer is prevalent. Factors influencing the decision to prescribe antimicrobials during end-of-life care are not well defined. Aim: To evaluate factors influencing medicine subspecialists to prescribe intravenous and oral antimicrobials during end-of-life care of older adults with advanced cancer to guide an educational intervention. Design: 18-item single-center cross-sectional survey. Setting/participants: Inpatient medicine subspecialists in 2018. Results: Of 186 subspecialists surveyed, 67 (36%) responded. Most considered withholding antimicrobials at the time of clinical deterioration during hospitalization ( n = 54/67, 81%), viewed the initiation of additional intravenous antimicrobials as escalation of care ( n = 44/67, 66%), and believed decision-making should involve patients or surrogates and providers ( n = 64/67, 96%). Fifty-one percent ( n = 30/59) of respondents who conducted advance care planning did not discuss antimicrobials. Barriers to discussing end-of-life antimicrobials included the potential to overwhelm patients or families, challenges of withdrawing antimicrobials, and insufficient training. Conclusions: Although the initiation of additional intravenous antimicrobials was viewed as escalation of care, antimicrobials were not routinely discussed during advance care planning. Educational interventions that promote recognition of antimicrobial-associated adverse events, incorporate antimicrobial use into advance care plans, and offer communication simulation training around the role of antimicrobials during end-of-life care are warranted.

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

Previous work found that lower BMI is associated with a pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer. Relative dose intensity (RDI) of chemotherapy is an important marker of treatment tolerability. We hypothesized that patients with low BMI would have higher RDI than patients with high BMI, explaining the mechanism for the association between BMI and pCR.We conducted a retrospective study of women treated with neoadjuvant chemotherapy for stage I-III breast cancer at Yale New Haven Hospital-Smilow Cancer Hospital. We reviewed medical records to determine tumor characteristics, chemotherapy doses, and reasons for dose reductions or delays. The treatment RDI was calculated using published methods. Chi-squared analyses were conducted to determine the associations between RDI and BMI and between RDI and pCR.Our cohort (n = 237) had an average age of 53 years (SD 13) and mean BMI of 29.5 kg/mNearly one quarter of our cohort had RDI85%. Although RDI overall was not associated with pCR, having fewer dose delays was associated with pCR. Our results highlight a need for improved patient adherence to and tolerability of neoadjuvant chemotherapy to minimize treatment delays.

PURPOSE: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i which has recently demonstrated significant OS benefit in 2 phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. METHODS: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− BC. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. RESULTS: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% CI, 31.1%−51.6%), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. CONCLUSION: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.