Accomplishments: Cancer Prevention and Control Program

Theme I: Elucidating the Genetic Risk of Prostate Cancer

Our research in genetic epidemiology focuses largely on prostate cancer and benefits from the cross-disciplinary synergy provided by the Prostate Center of Excellence. Identifying genes that increase or modify prostate cancer risk is important for understanding the etiology of the disease and will ultimately lead to improved prevention, earlier diagnosis and targeted treatment. The majority of this work focuses on identifying genes that increase prostate cancer risk by applying multiple approaches, including:

• Genetic linkage studies of prostate cancer to identify chromosomal locations that harbor prostate cancer susceptibility genes
•  Positional cloning of prostate susceptibility genes in the identified chromosomal regions
•  Association studies to systematically evaluate genes in several important pathways and throughout the entire genome

Two new areas of research in prediction of risk of prostate cancer include:

• Using an integrated approach to comprehensively assess genes by simultaneously examining all three potential mechanisms (germline changes, somatic genetic changes and epigenetic changes)
• Assessing the joint effects of gene-gene and gene-environmental (dietary) interaction in cancer risk

Another area of research of Jianfeng Xu, MD, PhD, and colleagues focus on is that of genomic-targeted chemoprevention of prostate cancer. Dr. Xu assembled a multidisciplinary research team to address the overarching question of whether a genomic-targeted approach improves outcomes related to chemoprevention of prostate cancer compared to a non-targeted approach. 

Theme II: Studying the Role of Natural Products 

Our Cancer Prevention and Control (CPC) Program has a long history of research in natural products, especially vitamin D and soy, and this research provides an excellent example of our interventional/translational work. More recently, our program is collaborating with members of the Cell Growth and Survival program on research related to omega-3 polyunsaturated fatty acids (PUFAs) and prostate cancer.

Vitamin D

Human prostate cells possess specific receptors for the hormonal form of vitamin D, 1, 25(OH)₂D. Gary Schwartz, PhD, MpH, and colleagues have shown that when human prostate cancer cells are exposed to 1, 25(OH)₂D, 1, 25(OH)₂D promotes their differentiation and inhibits their proliferation, invasiveness, and metastases. These findings have led to human clinical trials of vitamin D and its 1, 25(OH)₂D and 1, 25(OH)₂D analogues as therapy for prostate cancer. 

They have also demonstrated that prostate cells synthesize 1, 25(OH)₂D  from its prohormonal precursor, 25-Hydroxyvitamin D—an  ability previously believed to be exclusive to kidney cells and keratinocytes. This discovery provides a biochemical basis for the inverse relationship between prostate cancer mortality and exposure to sunlight. This autocrine synthesis of 1, 25(OH)₂D opens new possibilities for prostate cancer prevention because, until it is bioactivated by prostate cells, 25-Hydroxyvitamin D is inactive and can be administered more safely than 1, 25(OH)₂D.

Dr. Schwartz extended his findings on vitamin D to another component of the vitamin D endocrine system, serum calcium. He showed that serum levels of calcium prior to the diagnosis of prostate cancer are associated with a 2 to 3 fold-increased risk of prostate cancer mortality. These findings are intelligible because prostate cells possess high affinity receptors for calcium, which has been shown to increase prostate cell proliferation and metastasis. Moreover, the observation that high serum calcium is associated with increased risk of prostate cancer mortality suggests that calcium may be useful in predicting which men are at increased risk of prostate cancer. 

Soy 

Mark Cline, DVM, PhD, and Mara Z. Vitolins, PhD, MpH, RD of CPC are collaborating to determine whether dietary soy in men with prostate cancer has an effect on cell proliferation in neoplastic and adjacent prostate tissues. Dr. Vitolins’ interest in soy also extends to using soy as a meal replacement for weight loss among breast cancer survivors and demonstrates cross-thematic research.

Omega-3 Polyunsaturated Fatty Acids (PUFAs)  

For more than two decades, epidemiologic studies have identified associations between dietary fat and risk of cancer. Building on traditional strengths of Wake Forest School of Medicine (WFSM) in the research of lipids, as well as the interests of recently recruited faculty, a particularly strong interdisciplinary and interprogrammatic team was developed within the Cancer Center to pursue this important connection between dietary lipids and cancer of the prostate and breast. Recently, major accomplishments in this area have come from researchers in the Cell Growth and Survival Program. Dr. Vitolins of CPC is collaborating with this group. The research is focused on how omega-3 polyunsaturated fatty acids (PUFAs) inhibit, whereas omega-6 PUFAs stimulate, prostate cancer cell growth. Data from this group also suggest that omega-3 PUFA from botanical sources (mainly linolenic acid) are not as effective as omega-3 PUFA from marine sources (mainly eicosapentaenoic acid and docosahexaenoic acid) in suppression of prostate cancer.

Theme III: Investigating Tobacco and Other Environmental Risk Factors for Cancer 

Tobacco Control 

Tobacco exposure remains one of the most important behavioral and environmental risk factors for cancer.

With respect to tobacco use among college students, results of work by Erin Sutfin, PhD, and Mark Wolfson, PhD, revealed that college administrators felt that reducing exposure to secondhand smoke should be a high priority on their campus. 55 percent of student health center directors reported screening students about tobacco use at every visit and 80 percent reported offering cessation counseling for those who wish to quit.

These findings were used by Dr. Sutfin as preliminary data to support an R21 grant application to implement tobacco cessation services in student health centers on college campuses. Drs. Wolfson and Sutfin are also collaborating with John Spangler, MD, MPH, who has a long history of work in the area of smokeless tobacco. The tobacco industry targets college-aged students to use these products. The goal of a current research project is to understand patterns of smokeless tobacco use among college students. Dr. Sutfin plans to expand her work with college students to study the prevalence of smoking at Hookah bars and use of e-cigarettes.

On the international front, the project “Building Capacity for Tobacco Research in Hungary” is an R01 research and capacity building project. The project has engaged 15 Hungarian scientists who are carrying out 11 tobacco-related research projects throughout the country. The U.S.-based team supports the research teams by making tailored recommendations on each team’s research design and instruments, by convening annual networking meetings, and by providing access to training opportunities. Scientists from Semmelweis University (Budapest), Davidson College, and WFSM are collaborating on this project.   

One unique component of our research in tobacco is Thomas Arcury, PhD, who works with Hispanic farmworkers. Farmworkers in North Carolina are exposed to nicotine from contact with mature tobacco plants; this exposure can result in acute nicotine poisoning, called green tobacco sickness. Data from “Green Tobacco Sickness among Minority Farmworkers” showed that this condition is a major health problem for seasonal and migrant farmworkers. 

Other Environmental Risk Factors 

Dr. Arcury’s epidemiologic research was used to develop successful grant proposals testing intervention programs to reduce exposure to carcinogenic pesticides among Hispanic migrant farmworkers, and to reduce exposure to indoor air pollutants (including environmental tobacco smoke) among farmworker children.

Theme IV: Enhancing Cancer Survivorship by Improving Cancer-Related Quality of Life, Symptom Management, and Access to Care Among Cancer Survivors 

Cancer survivorship is a key theme of our Program. Our research in this area focuses on epidemiologic studies of cancer survivors and intervention studies to decrease symptoms and improve health behaviors.

Postdoctoral Training Grant 

One of our key accomplishments under this theme is the receipt of an National Institutes of Health (NIH) grant to train postdoctoral researchers in cancer survivorship. The Primary Investigator of this grant is Dr. Nancy Avis. Other Program faculty includes Michelle Naughton, PhD, of CPC and William Blackstock, MD, of the Clinical Program.

This cancer control postdoctoral training program is unique in its focus on cancer survivorship. It is a 2 to 3 year postdoctoral program for physicians, social/behavioral scientists, and epidemiologists aimed at developing investigators with new research skills focused on the design and implementation of cancer survivorship research.

The program is multidisciplinary and collaborative with respect to its faculty and training approach, the research projects of trainees, and the backgrounds of the trainees themselves.

The training program provides a specialized curriculum in cancer survivorship and a tailored program for each trainee that combines formal course work and hands-on experience in survivorship research under the guidance of well-qualified mentors. The tailored program can also lead to an MS degree in Clinical and Population Translational Science.

All trainees receive formal training in cancer survivorship and NIH grant preparation, and participate in interdisciplinary seminars and interest groups. The program provides practical training in research including working in an interdisciplinary team, selecting a research design, ethics in research, guidelines for the use of human subjects in research, grant preparation, patient recruitment, collecting and analyzing data, presentations at scientific meetings, and writing manuscripts for publication.

Trainees have opportunities to collaborate with our Community Clinical Oncology Programs (CCOP) Research Base , the Maya Angelou Center for Health Equity, multi-site studies and cooperative groups, and the Program in Integrative Medicine. Study populations include underserved, elderly, Native American, and rural populations. Trainees have the opportunity to experience basic, clinical and population research environments, as well as take advantage of the interdisciplinary activities and full resources of the Cancer Center. 

Symptom Management 

An important area of our survivorship work is the use of complementary/integrative therapies for symptom management. Studies of acupuncture and yoga to reduce hot flashes in women, and of soy products and Effexor to reduce hot flashes among men undergoing hormonal treatment for prostate cancer, are ongoing.  We also conduct research on yoga for reducing fatigue and other symptoms for breast cancer and brain tumor survivors. 

Department of Defense (DOD) Behavioral Center of Excellence in Breast Cancer                       

The DOD-funded Behavioral Center of Excellence in Breast Cancer explores Quality of Life (QOL) issues for breast cancer survivors across the lifespan. The DOD Center contains 3 separate but interrelated research projects:  

• “Menstrual Cycle Maintenance and Quality of Life After Breast Cancer Treatment: A Prospective Study” (PI: Michelle Naughton, PhD)
• “Investigating Mechanisms to Explain Age Associated Differences in Quality of Life among Breast Cancer Patients,” (PI:  Nancy Avis, PhD)
• “Research on Optimal Recovery Practices in Breast Cancer (RESTORE)”  (PI Dr. Roger Anderson; Co-I Shannon Mihalko, PhD) to improve QOL and reduce lymphedema among breast cancer survivors             

Cancer and Cognition 

Concern over cognitive effects of treatment, especially chemotherapy, is high among cancer survivors. Scientific studies have raised concerns that some chemotherapeutic regimes may lead to short-term or even long-term alterations in cognitive function.

This important area of research is one that we plan to address in a future research agenda (see section IV.)  Already-completed work by Sally Shumaker, PhD, colleagues at Wake Forest serves as a starting point for future work in cancer and cognition.

In 2009, Dr. Shumaker and colleagues published the initial findings from Co-STAR, an ancillary study to the National Surgical Adjuvant Breast and Bowel Project’s Study of Tamoxifen and Raloxifene (STAR) study. 

STAR was a randomized clinical trial of tamoxifen 20 mg/day or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. Co-STAR was conducted among women in STAR who were aged 65 and older and who had no previous diagnosis of dementia. 

The study compared the effects of these two selective estrogen receptor modulators (SERMs) on global and domain-specific cognitive function, and no significant differences in cognitive test performance between the raloxifene and tamoxifen groups (Legault J Clin 2009). Because the STAR trial was designed without a placebo control group, the Co-STAR study similarly had no placebo arm. Thus, if both tamoxifen and raloxifene had a beneficial or adverse effect on cognitive function in Co-STAR, such an effect would not have been evident. 

However, because the instruments used to measure cognitive function in Co-STAR paralleled those used in the Women’s Health Initiative Memory Study (WHIMS), it was possible to compare, in exploratory analyses, the two treatment groups in Co-STAR with the treatment groups in WHIMS; one of which was a placebo group (the other was a group who received hormone therapy involving conjugated equine estrogens (CEE). 

Results from these analyses, published in 2010, suggest that CEE, tamoxifen, and raloxifene all may induce small but detectable negative effects on cognition across two to three years of therapy in women aged 65 years and older, and that these negative effects may be larger in women with lower pretreatment levels of cognitive function.

These results add importantly to the body of work on tamoxifen, which is a common chemotherapeutic agent in the treatment of breast cancer. Trials of the effects of tamoxifen on cognitive function are usually performed among women with breast cancer who are often receiving other chemotherapeutic agents or adjuvant therapies, and thus these studies do not usually allow for examination of the effect of tamoxifen alone on cognition, as the comparative analyses of the combined Co-STAR and WHIMS cohorts allowed. 

Treatment Access, Effectiveness and Follow-up Care 

A major part of our survivorship theme is the documentation of medical care and health outcomes among cancer survivors. This area includes research on access to care, treatment effectiveness, late effects of cancer, and racial, socioeconomic, and geographic disparities in cancer burden and cancer treatment.