Publications by authors named "Tara Sanft"

56 Publications

Randomized trial of weight loss on circulating ghrelin levels among breast cancer survivors.

NPJ Breast Cancer 2021 May 11;7(1):49. Epub 2021 May 11.

Yale University School of Public Health, New Haven, CT, USA.

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/m. 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/m. 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 < 0.001) and inversely correlated with weight (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.
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http://dx.doi.org/10.1038/s41523-021-00260-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113314PMC
May 2021

Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/HER2- advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1).

Clin Cancer Res 2021 Mar 15. Epub 2021 Mar 15.

Breast Medical Oncolohy, The University of Texas MD Anderson Cancer Center.

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 ETrefractory HR+/HER2- ABC after progression on a CDK4/6i.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2114DOI Listing
March 2021

Examining the effect of obesity-associated gene variants on breast cancer survivors in a randomized weight loss intervention.

Breast Cancer Res Treat 2021 Jun 6;187(2):487-497. Epub 2021 Mar 6.

Yale School of Public Health, MPH, 55 Church Street, Suite 801, New Haven, CT, 06510, USA.

Purpose: 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.

Methods: 151 breast cancer survivors with a body mass index ≥ 25 kg/m 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.

Results: Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p < 0.001), regardless of genotype. Changes in weight and percent body fat did not differ significantly between carriers of the FTO rs9939609, MC4R rs6567160, BDNF rs11030104, and CREB1 rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each single-nucleotide polymorphisms).

Conclusions: 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).
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http://dx.doi.org/10.1007/s10549-021-06151-5DOI Listing
June 2021

Association of relative dose intensity with BMI and pathologic complete response in patients treated with neoadjuvant chemotherapy for breast cancer.

Breast Cancer Res Treat 2021 Feb 30;186(1):191-197. Epub 2020 Oct 30.

Yale Cancer Center, New Haven, CT, USA.

Purpose: 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.

Methods: 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.

Results: Our cohort (n = 237) had an average age of 53 years (SD 13) and mean BMI of 29.5 kg/m (SD 7.0). Fifty-eight patients (24%) received <85% RDI, and 61% of patients experienced at least one dose reduction or delay. BMI was not associated with RDI (p = 0.71), and RDI was not associated with pCR (p = 0.31); however, fewer dose delays was associated with pCR (p = 0.02). The most common reasons for dose reduction or delays were neuropathy, myelosuppression, and personal reasons.

Conclusions: Nearly one quarter of our cohort had RDI <85%. 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.
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http://dx.doi.org/10.1007/s10549-020-05994-8DOI Listing
February 2021

Education needed to improve antimicrobial use during end-of-life care of older adults with advanced cancer: A cross-sectional survey.

Palliat Med 2021 01 15;35(1):236-241. Epub 2020 Sep 15.

Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA.

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 ( = 54/67, 81%), viewed the initiation of additional intravenous antimicrobials as escalation of care ( = 44/67, 66%), and believed decision-making should involve patients or surrogates and providers ( = 64/67, 96%). Fifty-one percent ( = 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.
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http://dx.doi.org/10.1177/0269216320956811DOI Listing
January 2021

Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial.

Cancer Prev Res (Phila) 2020 12 28;13(12):1055-1062. Epub 2020 Aug 28.

Dana-Farber Cancer Institute, Boston, Massachusetts.

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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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718298PMC
December 2020

NCCN Guidelines Insights: Survivorship, Version 2.2020.

J Natl Compr Canc Netw 2020 08;18(8):1016-1023

Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

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.
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http://dx.doi.org/10.6004/jnccn.2020.0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785060PMC
August 2020

Skin carotenoids are inversely associated with adiposity in breast cancer survivors.

Nutr Res 2020 07 24;79:77-86. Epub 2020 May 24.

Yale School of Public Health, 60 College St, New Haven, CT 06511; Yale Cancer Center, PO Box 208028, New Haven, CT 06519. Electronic address:

Carotenoids are antioxidants which may mitigate some of the adverse effects of obesity, a condition associated with poor outcomes in breast cancer patients. We hypothesized that baseline skin carotenoids would be inversely associated with adiposity in breast cancer survivors and would increase with weight loss. Skin carotenoid score (SCS) was assessed by resonance Raman spectroscopy in breast cancer survivors (body mass index ≥25 kg/m) enrolled in a 6-month randomized controlled weight loss trial (n = 47). Measurements included total body fat using dual-energy X-ray absorptiometry, height, weight, waist and hip circumference, dietary intake, and serum biomarkers. Associations between SCS, adiposity measures, and serum biomarkers were assessed at baseline, as was the change in SCS from baseline to 6 months, in the intervention and usual care groups. At baseline, SCS was inversely correlated with all adiposity measures (P ≤ .05). In multivariate analyses, baseline percent body fat had the strongest association with baseline SCS (partial R= 0.20). Baseline SCS was significantly inversely associated with log C-reactive protein levels (regression coefficient β ± SE: -0.051± 0.019; P = .011) and log leptin (β ± SE: -0.019± 0.009; P = .046), but the associations were no longer significant after adjustment for adiposity. Over the 6-month study, the intervention group had a 17.6% increase in SCS compared to a 1.5% decrease in the usual care group (P = .28). In our study of overweight and obese breast cancer survivors, dual-energy X-ray absorptiometry-measured body fat explained a large portion of the variation in skin carotenoids at baseline, suggesting a stronger association than that previously seen in studies using less accurate measures of adiposity.
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http://dx.doi.org/10.1016/j.nutres.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409553PMC
July 2020

Randomized Phase II Trial of Exercise, Metformin, or Both on Metabolic Biomarkers in Colorectal and Breast Cancer Survivors.

JNCI Cancer Spectr 2020 Feb 20;4(1):pkz096. Epub 2019 Nov 20.

See the Notes section for the full list of authors' affiliations.

Background: Observational data support inverse relationships between exercise or metformin use and disease outcomes in colorectal and breast cancer survivors, although the mechanisms underlying these associations are not well understood.

Methods: In a phase II trial, stage I-III colorectal and breast cancer survivors who completed standard therapy were randomly assigned to structured exercise or metformin or both or neither for 12 weeks. The primary outcome was change in fasting insulin levels; secondary outcomes included changes in other blood-based energetic biomarkers and anthropometric measurements. Analyses used linear mixed models.

Results: In total, 139 patients were randomly assigned; 91 (65%) completed follow-up assessments. Fasting insulin levels statistically significantly decreased in all three intervention arms (-2.47 μU/mL combination arm, -0.08 μU/mL exercise only, -1.16 μU/mL metformin only, + 2.79 μU/mL control arm). Compared with the control arm, all groups experienced statistically significant weight loss between baseline and 12 weeks (-1.8% combination arm, -0.22% exercise only, -1.0% metformin only, +1.55% control). The combination arm also experienced statistically significant improvements in the homeostatic model assessment for insulin resistance (-30.6% combination arm, +61.2% control) and leptin (-42.2% combination arm, -0.8% control), compared with the control arm. The interventions did not change insulin-like growth factor-1 or insulin-like growth factor binding protein-3 measurements as compared with the control arm. Tolerance to metformin limited compliance (approximately 50% of the participants took at least 75% of the planned dosages in both treatment arms).

Conclusions: The combination of exercise and metformin statistically significantly improved insulin and associated metabolic markers, as compared to the control arm, with potential greater effect than either exercise or metformin alone though power limited formal synergy testing. Larger efforts are warranted to determine if such a combined modality intervention can improve outcomes in colorectal and breast cancer survivors.
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http://dx.doi.org/10.1093/jncics/pkz096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025659PMC
February 2020

Musculoskeletal Effects of Antineoplastic Agents.

J Am Acad Orthop Surg 2019 Nov;27(22):834-839

From the Department of Oncology, Yale New Haven Hospital, Yale University (Dr. Sutton and Dr. Knobf), the Department of Orthopaedics and Rehabilitation, Yale New Haven Hospital, Yale University (Dr. Ibe), New Haven, CT, and the Department of Orthopaedic Surgery and Sports Medicine, Hospital for Special Surgery, Stamford, CT (Dr. Sanft).

Cancer remains a common disease with approximately 40% of Americans diagnosed with cancer in their lifetime. Medical advances in the field of oncology have led to an increased life expectancy and a decreased mortality rate. Antineoplastic agents such as taxanes and targeted therapies are indicated in the treatment of many cancers, and their use can be associated with various musculoskeletal complaints and adverse effects. Orthopaedic Surgeons are trained to identify primary bone tumors and metastasis to bones. It is also important for them to have an understanding of the profile of musculoskeletal adverse effects associated with the treatment of the more common neoplasms. This article reviews the current literature on the commonly used chemotherapeutic agents and their associated musculoskeletal effects.
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http://dx.doi.org/10.5435/JAAOS-D-17-00713DOI Listing
November 2019

NCCN Guidelines Insights: Survivorship, Version 2.2019.

J Natl Compr Canc Netw 2019 07;17(7):784-794

Robert H. Lurie Comprehensive Cancer Center of Northwestern University; and.

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.
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http://dx.doi.org/10.6004/jnccn.2019.0034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094216PMC
July 2019

Defining the patient experience in medical oncology.

Support Care Cancer 2020 Apr 8;28(4):1649-1658. Epub 2019 Jul 8.

Yale School of Medicine, Yale University, New Haven, CT, USA.

Purpose: Higher patient satisfaction is associated with improved health outcomes, treatment adherence, and quality of life. The goal of this study was to explore oncology patients' perceptions on their hospital experience, focusing on the quality of care in medical oncology.

Methods: A qualitative and quantitative study design was implemented with a sample of 58 patients at Smilow Yale New Haven Hospital. Data were collected from patient interviews and observation of rounds.

Results: Two themes emerged: hospital experience and physician communication skills. Within hospital experience, subthemes identified include: attended to (49%), facility/staff (35%), nurses (33%), long wait time (29%), doctors (20%), coordination of care (18%), unnecessary medical procedures (10%), medications (6%), night awakenings (4%), pain (4%), not getting better (4%), and decreased mobility (2%). Within physician communication skills, subthemes identified include: involving the patient and/or family in the care process (41%), method of information sharing (18%), lack of coordination of care (15%), use of medical jargon (10%), attending to patient's needs (8%), and lack of patient's perspective (8%). Patients reported that effective engagement of patients in the care process and attending to patient-specific needs were desired qualities in their hospital experience as well as patient-centered communication with their physician. The quantitative data supported qualitative results with 72% of patients giving the highest score in overall satisfaction with their patient experience.

Conclusion: Physician attentiveness or lack thereof is a defining aspect of the quality of patient experience and physician communication. The results are intended to inform clinical and operational interventions that care providers might incorporate into practice.
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http://dx.doi.org/10.1007/s00520-019-04972-1DOI Listing
April 2020

Association between pre-diagnosis BMI, physical activity, pathologic complete response, and chemotherapy completion in women treated with neoadjuvant chemotherapy for breast cancer.

Breast Cancer 2019 Nov 22;26(6):719-728. Epub 2019 May 22.

Yale University School of Medicine, 300 George St, Suite 120, New Haven, CT, 06511, USA.

Purpose: Physical activity and lower BMI have shown benefit for breast cancer survival, but the association between these factors, pathologic complete response (pCR), and chemotherapy completion is not clear. We evaluated whether BMI and physical activity are associated with pCR and chemotherapy completion during neoadjuvant breast cancer treatment.

Methods: We conducted a retrospective case-control study of women given neoadjuvant chemotherapy for stage I-III breast cancer between 2010 and 2016. A medical record review provided pCR, chemotherapy completion, and patient characteristics. A telephone survey assessed physical activity 1 year before diagnosis. Unconditional logistic regression models identified factors associated with pCR and chemotherapy completion.

Results: In our cohort (n = 243), the average age was 52.9 years (SD 13.0) and mean BMI was 29.5 kg/m (SD 7.0). Seventy-five (31%) patients had pCR and 168 (69%) had residual disease. Patients with pCR had lower mean BMI than those with residual disease (28.2 (SD) vs. 30.1 (SD), P = 0.04). Exercise was associated with completion of chemotherapy (OR 7.6, 95% CI 1.4-41.2, P = 0.02).

Conclusions: Pathologic complete response was associated with lower BMI; chemotherapy completion was associated with exercising at CDC-recommended levels prior to breast cancer diagnosis.
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http://dx.doi.org/10.1007/s12282-019-00974-3DOI Listing
November 2019

The impact of communication style on patient satisfaction.

Breast Cancer Res Treat 2019 Jul 25;176(2):349-356. Epub 2019 Apr 25.

Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA.

Background: Communication between patients and health providers influences patient satisfaction, but it is unknown whether similarity in communication styles results in higher patient satisfaction.

Methods: This study was conducted in the Smilow Cancer Hospital Breast Center. During routine follow-up visits, patients completed a Communication Styles Assessment (CSA), health survey (SF-12), Princess Margaret Hospital Satisfaction with Doctor Questionnaire, and brief demographic form. Physicians and Advanced Practice Providers were also asked to complete the CSA. Patients and providers were blinded to each other's responses. A communication styles concordance score was calculated as the Pearson correlation between 80 binary CSA items for each provider/patient pair. Factors affecting patient satisfaction scores were assessed in mixed-effects models.

Results: In total, 330 patients were invited to participate; of these 289 enrolled and 245 returned surveys. One hundred seventy-four completed all survey components, and 18 providers completed the CSA. Among the factors considered, physical health score (effect size = 0.0058, 95% CI 0.00051 to 0.0011, p = 0.032) and employment status (0.12, 95% CI - 0.0094 to 0.25, p = 0.069) had the greatest impact on patient satisfaction. However, patients who were not employed and less physically healthy had significantly elevated satisfaction scores when their communication style was more similar to their provider's (1.52, 95% CI 0.66 to 2.38, p = 0.0016).

Conclusions: Patients who were physically healthy and employed were generally more satisfied with their care. The similarity in communication styles of patients and providers had a greater impact on patient satisfaction for patients who were less physically healthy and not employed.
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http://dx.doi.org/10.1007/s10549-019-05232-wDOI Listing
July 2019

Endocrine-related quality of life in a randomized trial of exercise on aromatase inhibitor-induced arthralgias in breast cancer survivors.

Cancer 2019 07 6;125(13):2262-2271. Epub 2019 Mar 6.

Yale School of Public Health, New Haven, Connecticut.

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 < .001), and fatigue-specific (score, 5.8 vs 0.5; P < .001) subscales compared with the usual care group. The results indicated a stronger effect at 12 months versus 6 months after the intervention.

Conclusions: Combined aerobic and resistance exercise, such as treadmill walking and strength training, improved endocrine-related and overall QOL among breast cancer survivors who were experiencing adverse side effects from AIs. Because adverse side effects associated with AI use are quite common and this is the main reason for treatment discontinuation, this nonpharmacologic intervention could benefit many breast cancer survivors and increase successful adherence to AIs in breast cancer treatment.
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http://dx.doi.org/10.1002/cncr.32051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731173PMC
July 2019

Survivorship, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 10;16(10):1216-1247

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocial consequences of cancer and cancer treatment to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period. This portion of the guidelines describes recommendations regarding the management of anthracycline-induced cardiotoxicity and lymphedema. In addition, recommendations regarding immunizations and the prevention of infections in cancer survivors are included.
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http://dx.doi.org/10.6004/jnccn.2018.0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438378PMC
October 2018

Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

NPJ Breast Cancer 2018 17;4:26. Epub 2018 Aug 17.

15Columbia University Medical Center, New York, NY USA.

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice.
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http://dx.doi.org/10.1038/s41523-018-0074-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098077PMC
August 2018

Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study.

Breast Cancer Res Treat 2018 Nov 30;172(1):105-112. Epub 2018 Jul 30.

Yale Cancer Center, Yale University School of Medicine, 333 Cedar St, PO Box 208032, New Haven, CT, 06520-8032, USA.

Purpose: Some studies suggest that telomere shortening may be associated with increased breast cancer risk and mortality. Obesity is also associated with increased breast cancer risk and mortality. Few studies have examined changes in telomere length in overweight or obese breast cancer survivors. The purpose of our study was to examine the effect of a 6-month diet- and exercise-induced weight loss intervention versus usual care on telomere length in breast cancer survivors.

Methods: 151 breast cancer survivors with body mass index (BMI) ≥ 25 kg/m were randomly assigned to a 6-month weight loss intervention (n = 93) or to usual care (n = 58). Fasting blood samples, height, weight, physical activity, and diet were measured at baseline and 6-months. Relative telomere length (RTL) was measured by quantitative-polymerase chain reaction (qPCR) done on buffy coat-extracted genomic DNA. Mean baseline to 6-month changes were compared between groups (intention-to-treat) using generalized estimating equations.

Results: Complete telomere data were available in 125 participants. Women were 58 ± 8 years, with BMI 33.0 ± 6.2 kg/m and were 2.9 ± 2.5 years from diagnosis; 90% were non-Hispanic white, and 76% had stage 0/I breast cancer. After 6 months, women randomized to weight loss had 3% telomere lengthening compared to 5% shortening in the usual care group (p = 0.12). Among women with stage 0/I, the intervention group experienced 7% telomere lengthening compared to 8% shortening in the usual care group (p = 0.01). No intervention effect was observed in women with stage II/III breast cancer.

Conclusion: Our findings suggest a weight loss intervention in stage 0 and 1 breast cancer survivors may lead to telomere lengthening, compared to a shortening in their usual care counterparts.
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http://dx.doi.org/10.1007/s10549-018-4895-7DOI Listing
November 2018

Exercise and weight loss interventions and miRNA expression in women with breast cancer.

Breast Cancer Res Treat 2018 Jul 6;170(1):55-67. Epub 2018 Mar 6.

Yale School of Public Health, New Haven, CT, 06510, USA.

Purpose: Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics.

Patients And Methods: We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight-loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers.

Results: Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = - 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified "Estrogen-mediated S-phase entry" (HOPE p = 0.003; LEAN p < 0.001) and "Molecular mechanisms of cancer" (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI-associated and intervention-responsive miRNAs and contain obesity and cancer-relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC.

Conclusion: While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk.
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http://dx.doi.org/10.1007/s10549-018-4738-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444907PMC
July 2018

Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I-III HER2-positive breast cancer.

Breast Cancer Res Treat 2018 Jun 2;169(2):333-340. Epub 2018 Feb 2.

Yale Cancer Center, Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA.

Purpose: The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy.

Methods: The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon's two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively.

Results: The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60-91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13-46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases.

Conclusions: Eighty percent of HR-negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2-targeted therapy during the taxane phase only of sequential taxane-anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2-targeted therapies combined with chemotherapy in the neoadjuvant setting.
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http://dx.doi.org/10.1007/s10549-017-4653-2DOI Listing
June 2018

Comparison of Residual Risk-Based Eligibility vs Tumor Size and Nodal Status for Power Estimates in Adjuvant Trials of Breast Cancer Therapies.

JAMA Oncol 2018 Apr 12;4(4):e175092. Epub 2018 Apr 12.

Yale Cancer Center, Yale University, New Haven, Connecticut.

Importance: Many large adjuvant clinical trials end up underpowered because of fewer than expected events in the control arm. Ensuring a minimum number of events would result in more informative trials.

Objective: To calculate individualized residual risk estimates using residual risk prediction software and assess whether defining eligibility based on a minimum residual risk threshold could increase the reliability of clinical trial power calculations compared with eligibility criteria based on tumor size and nodal status.

Design, Setting, And Participants: We estimated residual risk in 443 consecutive patients with early-stage breast cancer and assessed clinical trial power as a function of residual risk distribution among the accrued patients. We defined residual risk as the risk of recurrence that remains despite receipt of standard-of-care therapy; this risk is determined by baseline prognostic risk and by the improvement from adjuvant therapy. We performed trial simulations to examine how the power of a 2-arm, 1:1 randomized clinical trial would change as the residual risk distribution of the trial population that met eligibility criteria based on tumor size and nodal status changes. We also simulated trials that use a minimum residual risk value as eligibility criterion.

Main Outcomes And Measures: Residual risk; clinical trial power as a function of residual risk distribution among the patients.

Results: In the 443 patients (mean [SD] age, 56.1 [12.3] years; range, 23-89 years), baseline prognostic and residual risks differed substantially: 328 (74%) patients had more than 20% baseline risk of recurrence; however, after adjustment for treatment effect only 12 (27%) had more than 20% residual risk. We assessed residual risk distribution in patient cohorts that met tumor size- and nodal status-based eligibility criteria for 3 currently accruing randomized adjuvant trials; the median residual risks were 28% (interquartile range [IQR], 25%-31%), 22% (IQR, 15%-28%), and 22% (IQR, 15%-28%), respectively, indicating that the power of these trials could vary unpredictably. Simulations showed that trials that use anatomical risk-based eligibility criteria can become underpowered if they accrue patients with low residual risk despite all participants meeting eligibility requirements. Using a minimum required residual risk threshold as eligibility criterion produced more reliable power calculations.

Conclusions And Relevance: When tumor size and nodal status are used to determine trial eligibility, the residual risk of recurrence can vary broadly, leading to unstable power estimates. The success of future adjuvant trials could be improved by defining patient eligibility based on a minimal residual risk of recurrence, and these trials can achieve a prespecified power with smaller sample sizes.
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http://dx.doi.org/10.1001/jamaoncol.2017.5092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885272PMC
April 2018

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Jan;16(1):66-97

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
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http://dx.doi.org/10.6004/jnccn.2018.0001DOI Listing
January 2018

Impacts of Early Guideline-Directed 21-Gene Recurrence Score Testing on Adjuvant Therapy Decision Making.

J Oncol Pract 2017 12 19;13(12):e1012-e1020. Epub 2017 Oct 19.

Yale University School of Medicine; Yale New Haven Hospital-Smilow Cancer Hospital, New Haven, CT.

Purpose: The 21-gene recurrence score (RS) assay is used to help formulate adjuvant chemotherapy recommendations for patients with estrogen receptor-positive, early-stage breast cancer. Most frequently, medical oncologists order RS after surgery. Results take an additional 2 weeks to return, which can delay decision making. We conducted a prospective quality-improvement project to assess the impact of early guideline-directed RS ordering by surgeons before the first visit with a medical oncologist on adjuvant therapy decision making.

Materials And Methods: Surgical oncologists ordered RS testing following National Comprehensive Cancer Network guidelines at time of diagnosis or at time of surgery between July 1, 2015 and December 31, 2015. We measured the testing rate of patients eligible for RS, time to chemotherapy decisions, rates of chemotherapy use, accrual to RS-based clinical trials, cost, and physician acceptance of the policy and compared the results to patients who met eligibility criteria for early guideline-directed testing during the 6 months before the project.

Results: Ninety patients met eligibility criteria during the testing period. RS was ordered for 91% of patients in the early testing group compared with 76% of historical controls ( P < .001). Median time to chemotherapy decision was significantly shorter in the early testing group (20 days; 95% CI, 17 to 23 days) compared with historical controls (32 days; 95% CI, 29 to 35 days; P < .001). There were no significant differences in time to chemotherapy initiation, chemotherapy use, RS-based trial enrollment, or calculated costs between the groups.

Conclusion: Early guideline-directed RS testing in selected patients is an effective way to shorten time to treatment decisions.
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http://dx.doi.org/10.1200/JOP.2017.022731DOI Listing
December 2017

Diet, Physical Activity, and Body Weight in Cancer Survivorship.

Med Clin North Am 2017 Nov 23;101(6):1151-1165. Epub 2017 Aug 23.

Department of Medical Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address:

Diet, physical activity, and body weight have been shown to play an important role in cancer survivorship. The impact of each of these lifestyle factors differs slightly among cancer types, and adherence to recommended diet and physical activity guidelines has been associated with positive outcomes, including decrease in the risk of cancer recurrence and improvement of quality of life. Although there are compelling data that appropriate diet, physical activity, and body weight have beneficial effects in cancer survivorship, additional trials are needed to understand the relationship.
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http://dx.doi.org/10.1016/j.mcna.2017.06.004DOI Listing
November 2017

Does lymph node status influence adjuvant therapy decision-making in women 70 years of age or older with clinically node negative hormone receptor positive breast cancer?

Am J Surg 2017 Dec 18;214(6):1082-1088. Epub 2017 Sep 18.

Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.

Background: Women ≥70 years old with clinically (c) lymph node (LN) negative (-), hormone receptor (HR) positive (+) breast cancer are recommended not to be routinely staged with a sentinel LN biopsy. We sought to determine how this affects adjuvant decision-making.

Methods: Statistical analyses were performed to determine the association of LN evaluation with adjuvant chemotherapy and radiation therapy in cLN-, HR + breast cancer patients in the National Cancer Database.

Results: Between 2004 and 2013, there were 193,728 patients aged 70-90 with cLN-, HR + breast cancer; 15.0% were LN+. LN + patients were more likely to receive chemotherapy (28.3% vs. 5.5%, p < 0.001), hormonal therapy (83.6% vs. 71.4%, p < 0.001), post-lumpectomy radiation therapy (81.4% vs. 73.6%, p < 0.001) and post-mastectomy radiation therapy (30.3% vs. 5.1%, p < 0.001).

Conclusion: 15% of patients aged 70-90 will be LN+. These patients more frequently receive systemic and radiation therapy. LN status may affect treatment in these patients.
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http://dx.doi.org/10.1016/j.amjsurg.2017.07.036DOI Listing
December 2017

Survivorship, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 09;15(9):1140-1163

Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period.
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http://dx.doi.org/10.6004/jnccn.2017.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865602PMC
September 2017