Melinda L. Irwin - US grants

Ovarian cancer results in more deaths than any other cancer of the female reproductive system. However, improvements in surgical techniques and chemotherapy have led to an increase in the 5-year survival rate from 37% in 1976 to 45% in 2006. Because of advances in therapeutic modalities, the number of ovarian cancer survivors for whom primary goals are to maximize disease-free survival and maintain quality of life (QOL) is growing. As such, survivorship issues are becoming increasingly important. Various studies report poor QOL in ovarian cancer patients. Research is needed to develop and test interventions to improve QOL in ovarian cancer survivors. Currently, the American Cancer Society recommends a physically active lifestyle for cancer survivors to increase disease-free survival from cancer and other chronic diseases, and to improve quality of life. Studies of a strong benefit of physical activity on improving QOL following other types of cancer treatment, e.g., breast cancer, are well documented in the literature; yet very few studies of physical activity and QOL after a diagnosis of ovarian cancer have been published. There are also no published data examining whether physical activity may improve ovarian cancer survival or surrogate markers of survival. Although the impact of exercise on ovarian cancer survival is unknown, it may play a role via weight control, since obesity has been shown in some studies, but not all, to be negatively associated with survival. Results from observational studies also suggest an inverse association between physical activity and risk of ovarian cancer. Possible biological explanations for the associations between obesity and low levels of physical inactivity and ovarian cancer risk and mortality involve the potential role of estrogens, insulin, insulin-like growth factors (IGFs) C-reactive protein (CRP), leptin, CA-125, prolactin, osteopontin, and macrophage inhibitory factor. Given the promising results from our randomized trials of exercise interventions in healthy women and breast cancer survivors, and our QOL interventions in ovarian cancer survivors, a trial examining the impact of exercise in improving QOL and surrogate markers of prognosis in ovarian cancer survivors is warranted. We propose to evaluate, in 230 sedentary women diagnosed with Stage I-III ovarian cancer, the impact of a 6-month, moderate-intensity, aerobic exercise intervention vs. attention control upon QOL and surrogate markers of prognosis. Women will be randomized to an exercise program or attention control group. Women randomized to exercise will participate in 150 minutes of aerobic exercise per week (e.g., five 30-min sessions/wk). We will conduct baseline and 6-month clinic visits to evaluate the effect of exercise on QOL and surrogate markers. Our study, the largest exercise trial in cancer survivors, could be a proof of principal and will provide critical information in understanding the potential mechanisms through which physical activity may impact ovarian cancer risk and prognosis.

DESCRIPTION (provided by applicant): Two thirds of all breast cancers diagnosed in US women express estrogen and/or progesterone receptors. Although 5 years of tamoxifen had long been the standard adjuvant hormonal therapy for women with early- stage, hormone receptor-positive breast cancer, the aromatase inhibitors (AI's) have rapidly supplanted tamoxifen as the hormonal therapy of choice. Several large adjuvant trials have demonstrated that using an AI in place of or after tamoxifen reduced the risk of breast cancer recurrence, as compared to treatment with 5 years of tamoxifen. A recent American Society of Clinical Oncology expert consensus panel recommended that all postmenopausal women with early-stage, hormone-receptor-positive breast cancer receive an AI as part of their adjuvant therapy. However, long term data regarding the safety and toxicity of AIs is largely lacking. Data from the large adjuvant trials evaluating the use of the AI's indicate that arthralgia is one of the major toxicities associated with AI therapy and one of the most common reasons for AI treatment discontinuation. There has been little data regarding effective treatments for arthralgias. In addition to arthralgia, other bone-related adverse effects of AI therapy include bone loss and fractures. Although medications such as bisphosphonates can be used to alleviate bone loss, these drugs also cause significant side effects. Given the efficacy of the AI's, it is essential that better ways to manage the toxicity of these agents be explored. Nonpharmacologic methods of managing the side effects of the AI's are especially desirable. Exercise has been shown to improve bone metabolism in healthy women, and to be beneficial for people with fibromyalgia, osteoarthritis and rheumatoid arthritis; however, no randomized trial has examined the impact of exercise on arthralgia or bone mass in breast cancer survivors taking AIs. In the proposed trial, we plan to evaluate the ability of a walking and strength training exercise program to attenuate side effects of AI therapy. Our trial will randomize 180 postmenopausal breast cancer patients, who have been taking an AI for at least 6 months and are currently experiencing at least mild arthralgia which started after initiating AI therapy, to a yearlong exercise intervention or to an attention control group. We will then examine the impact of exercise on severity of arthralgia, factors mediating the effect of exercise on arthralgia, and other side effects of AI therapy including endocrine-related quality of life and bone mineral density. Women will be randomized to a home- and gym-based exercise program or attention control (health education) group. Women randomized to exercise will participate in 150 min/wk of aerobic exercise and a twice-weekly strength training program. We will conduct baseline, 6- and 12-month clinic visits, as well as 3- and 9-month mailings to evaluate the effect of the intervention on study outcomes. Given the widespread use of the AI's, we believe that our approach is innovative and timely. If our intervention is able to alleviate AI-associated side effects and reduce the number of women who prematurely discontinue them, we believe that our study may prove beneficial for the large number of postmenopausal women diagnosed with hormone receptor-positive breast cancer each year. Our study will also be especially relevant to the mission of NCI and the Office of Cancer Survivorship to improve the quality of life for cancer survivors, support intervention survivorship research, and to ensure best practices for addressing the health needs of survivors. PUBLIC HEALTH RELEVANCE: A recent American Society of Clinical Oncology expert consensus panel recommended that all postmenopausal women with early-stage, hormone-receptor-positive breast cancer (~2/3 of all women diagnosed with breast cancer) receive an aromatase-inhibitor (AI) as part of their adjuvant therapy. Data from the large adjuvant trials evaluating the use of the AI's indicate that arthralgia and bone loss are the major toxicities associated with AI therapy and the most common reasons for AI treatment discontinuation. Our trial will examine the impact of an exercise program on alleviating AI-associated side effects such as arthralgia, bone mineral density, and endocrine-related quality of life, and may prove beneficial for the large number of postmenopausal women diagnosed with hormone receptor-positive breast cancer each year.

? DESCRIPTION (provided by applicant): Given the rising prevalence of obesity, poor diet and physical inactivity, known in combination as energy balance or energetics, as well as their associations of these factors with cancer, innovative research, clinical care and training of scientists are needed to lower the prevalence of these risk factors and in turn, lower cancer incidence and mortality rates. The overall goal of this NCI R25 research education program is to develop, offer, evaluate and eventually disseminate an annual 5-day transdisciplinary research in energetics and cancer (TREC) training course for postdoctoral fellows and early career investigators with the goal of enhancing the ability of course participants to conduct innovative, transdisciplinary research in energetics and cancer research and clinical care. The proposed course builds upon the NCI TREC Initiative, which was a major scientific research effort that occurred from 2005 to 2016, and will cover topics across the cancer control continuum, including prevention, detection, diagnosis, treatment and survivorship. Funding for TREC will cease in 2016, however our goal is to continue to further the TREC mission of training scientists via the proposed 5- day annual TREC course. The proposed R25 TREC Training Course, led by Melinda Irwin, PhD, MPH (TREC Director of Training and Education from 2005-2016), will include a transdisciplinary team of 20 expert faculty members from diverse backgrounds, bringing together complementary skills and expertise in TREC-related research, mentoring and training. Our proposed course is highly innovative in that currently no training opportunity, course, or workshop exists that focuses on energetics and cancer. The annual 5-day course will provide state-of-the-art, evidence-based energetics and cancer education and training. Training new leaders will assist in dissemination and implementation of effective lifestyle strategies for cancer prevention and control, as they will carry out the translational research to lower the risk, mortality, morbidity and costs associated with cancer.

Many health organizations publish dietary and physical activity guidelines in an effort to help adults and cancer survivors make informed choices related to nutrition and physical activity. These guidelines are based on observational evidence showing that adhering to the guidelines improves breast cancer survival. Yet numerous studies have reported fewer than 30% breast cancer survivors follow the dietary and physical activity guidelines. To our knowledge, no trial has examined, in women newly diagnosed with breast cancer, the effect of adopting and practicing the dietary and physical activity guidelines on adherence to adjuvant treatments and cancer related biomarkers. We propose to examine, in 250 women newly diagnosed with Stage I-III breast cancer who are not practicing the dietary and lifestyle guidelines, and who are scheduled to receive adjuvant chemotherapy, the effect of a 1-year dietary and physical activity guidelines intervention vs. usual care on adherence to adjuvant breast cancer treatments including chemotherapy completion rates and adherence to endocrine therapy. Secondary endpoints include changes in biomarkers, body composition and quality of life. Our application is innovative and clinically meaningful as we propose to intervene soon after diagnosis when prevalence of women following the dietary and physical activity guidelines is low and likely to worsen; examine novel biomarkers and adherence to adjuvant treatments; and use a translational approach of intervening in the breast clinic and via telephone to facilitate in the eventual dissemination and implementation of our intervention. We have strong preliminary data showing a transdisciplinary team approach in recruiting breast cancer survivors into randomized lifestyle interventions during and after treatment with high adherence to the interventions. In summary, if we find our intervention improves adherence to breast cancer treatments, biomarkers and body composition, then our findings could cause a paradigm shift in how breast cancer care is delivered.

CANCER PREVENTION AND CONTROL RESEARCH PROGRAM  PROGRAM CODE: CPC     PROJECT SUMMARY/ABSTRACT    The mission of CPC is to prevent and control cancer by identifying factors that contribute to cancer  development and outcomes, and conducting interventions to address these factors. The Specific Aims of our  program are to: 1) identify lifestyle, environmental, and genetic risk factors in the etiology of cancer;? 2) assess  the patterns of care received by patients with cancer to identify effective strategies to improve patient  outcomes, and 3) conduct and evaluate lifestyle behavioral interventions for cancer prevention and control.  Dr. Melinda Irwin is Associate Director for Population Sciences and co-­leads the CPC program along with Dr.  Xiaomei Ma. Dr. Irwin?s expertise is in lifestyle behavioral interventions, so she oversees research related to  Aim 3. Dr. Ma?s expertise is in etiology and outcomes, so she oversees CPC research related to Aims 1 and 2.  Together, Drs. Irwin and Ma facilitate the collaboration of CPC members with members from other research  programs and disease-­aligned research teams (DARTs) with the goal of stimulating transdisciplinary research  that will impact cancer risk and mortality rates within and beyond the state of Connecticut.   Currently, there are 38 CPC members, with primary appointments in 11 departments and three schools. Our  cancer-­related funding (direct cost only) has increased 5% from $6.4M in the previous cycle to $6.7M in the  current cycle, of which $5.6M (84%) was peer reviewed and $2.5M was from NCI. Of the 793 cancer-­related  publications by CPC members from July 2012 to June 2017 (with 30% and 24% involving intra-­ and inter-­ collaborations), many have had a major impact on clinical and/or public health practice. Drs. Gross and Yu?s  (Radiobiology and Radiotherapy [RR] program) findings of early toxicity from proton beam therapy for prostate  cancer was cited in the decision by Blue Shield of California to stop reimbursing proton beam therapy for  prostate cancer. Dr. Niccolai?s HPV vaccination research has improved vaccination rates and has local, state,  and national impact. Drs. Irwin, Sanft, Cartmel, and Chagpar?s work, showing benefits of exercise and weight  loss on cancer biomarkers and treatment-­related side effects, is changing cancer care delivery with  implementation of lifestyle/behavior counseling in the clinic.   YCC and CPC leadership have developed a strategic plan to guide our future initiatives, with the primary goal  of adding depth and breadth to our existing strengths in cancer outcomes and lifestyle/behavioral research.  Goals within the next five years include recruitment of additional faculty in cancer outcomes and dissemination  and implementation research;? the submission of a P01 focused on randomized trials of energy balance in  cancer survivors;? two T32 applications on 1) obesity research and 2) cancer etiology, outcomes and  survivorship research;? and participating in submission of more SPORE applications with CPC members  leading projects.  

PROJECT SUMMARY/ABSTRACT The Yale Cancer Prevention and Control (CPC) Training Program requests five years of support for an innovative, multi-disciplinary and translational training program at the Yale School of Public Health (YSPH) and Yale Cancer Center (YCC). Currently, Yale only has one T32 training grant in cancer research, and it focuses on cancer biology training for basic scientists. Given the long history of successful CPC research and training by Yale faculty, and a critical need to train outstanding CPC scientists to advance our fight against cancer, we are excited to re-establish a CPC Training Program at Yale. Our Yale CPC Training Program will leverage strength from a Pre-Doctoral Program within YSPH, and a Post-Doctoral Program within YCC that draws from many disciplines but is administratively housed within YSPH. The Yale Cancer Prevention and Control (CPC) Training Program aims to educate, train and mentor pre- and post-doctoral fellows in five thematic areas critical to CPC: cancer etiology, cancer outcomes, lifestyle behavioral interventions, implementation science and community-engaged research. These five areas were selected because they are critical domains in the spectrum of CPC research, they leverage strengths of our faculty, and they will ensure that T32 trainees with diverse interests will achieve pivotal growth through the program and become leaders in novel, impactful CPC research. Fellows will also directly participate and interact with the seven YCC Research Programs and 14 YCC Disease-Aligned Research Teams, which are composed of scientists and clinicians conducting cancer research and delivering cancer care. Fellows will work with 22 Yale CPC Training Program Primary Faculty members, who collectively have expertise in our five thematic areas. The Primary Faculty members come from 13 different departments across Yale, and have trained 50 pre-doctoral and 126 post-doctoral fellows over the last ten years, with a strong majority working in cancer-related careers. The 22 Primary Faculty currently have more than a combined $25M of research funds. Our training program will include a comprehensive mentoring program, participation in active CPC research internships/rotations through the five thematic areas, a structured CPC Fellows Seminar Course, and additional integration with resources from Yale. Our program will select the most highly qualified and diverse candidates who wish to pursue a career in cancer prevention and control, and numerous procedures have been put in place to ensure the recruitment, quality mentorship, and retention of under-represented minority fellows. At the conclusion of their training, it is our goal that individuals supported by this T32 will have developed the knowledge and skills necessary to function independently, and that they will develop and carry out innovative, impactful studies filling key gaps in CPC research, potentially changing the standard of care and impacting policy. Ultimately, public health will benefit through the preparation of an exceptional cadre of investigators committed to careers in cancer prevention and control.