Coverage from the 2007 American Association for Cancer Research (AACR) Conference

The annual meeting of the American Association for Cancer Research (AACR), held in Los Angeles April 14-18, brought together more than 17,000 scientists from around the world. AACR is celebrating its centennial year in 2007, and the theme of the meeting was “A Century of Leadership in Science – A Future of Cancer Prevention and Cures.”

Topics covered included:

Opening Session: “Translating a Century of Science into a Future of Cancer Prevention and Cures
Diet
Health Disparities
Chemotherapy-related Cognitive Dysfunction (“Chemo-brain”)
Cancer Stem Cells
Tumor Microenvironment
Management of Anemia
Breastfeeding and Breast Cancer
Global Hypomethylation and Breast Cancer Risk Factors
Predicting Response to Tykerb®

Opening Session: “Translating a Century of Science into a Future of Cancer Prevention and Cures”
The opening session of the meeting celebrated the progress of the past and hopes for the future. Presentations by experts from several fields provided historical and current perspectives on cancer research.

Dr. Mary-Claire King of the University of Washington--the scientist who proved the existence of the BRCA1 gene-- spoke about inherited predisposition to breast cancer. Mutations in the BRCA1 or BRCA2 genes are believed to account for roughly five percent of all breast cancers. This means that each year in the U.S, roughly 10,000 cases of breast cancer can be attributed to BRCA1 or BRCA2 mutations. Furthermore, several other genes are now known to be linked with familial predisposition to breast cancer as well.

Increased awareness of breast cancer susceptibility genes has raised issues of how to identify women at risk and how to reduce risk. These issues may be particularly challenging for women with gene mutations that only moderately increase risk. Mutations in the CHEK2 gene, for example, result in a roughly two-fold increased risk of breast cancer; this equates to a lifetime risk of breast cancer of roughly 25 percent. Dr. King noted that preventive surgery to remove the breasts or ovaries may not warranted for women with this level of risk, but that these women may wish to consider more intensive surveillance using a combination of mammography and MRI.

Dr. King’s recommendations for the future included the development of a single test to evaluate all known mutations in breast cancer susceptibility genes, noting that the test would clearly need to evolve over time as more mutations were identified. In addition she noted that such a test would be useless if women didn’t have a way to pay for it, and that it will be important to provide insurance coverage for testing and follow-up.

Diet
Many breast cancer risk factors – such as family history – are things we cannot change. This highlights the importance of identifying risk factors that are modifiable, such as diet, physical activity and body weight. Studies suggest that physical activity and maintenance of a health body weight can reduce the risk of several types of cancer, including breast cancer. Furthermore, several aspects of diet may influence the likelihood of cancer.

In a symposium titled “The Role of Dietary Factors in Cancer Etiology and Prognosis,” researchers discussed the roles of vitamin D, phytoestrogens (estrogen-like substances from plant sources), and antioxidants.

Vitamin D Appears to Reduce Cancer Risk
The topic of vitamin D was addressed by Dr. Donald Trump of the Roswell Park Cancer Institute. Dr. Trump gave a brief review of the available evidence regarding vitamin D and cancer, and noted that cancer risk does appear to be higher among individuals with low vitamin D levels. Furthermore, vitamin D deficiency appears to be common. The optimal level of vitamin D and the optimal approach to achieving that level remain uncertain. Vitamin D can be obtained through both sun exposure and dietary sources. Because sun exposure carries a risk of skin cancer, dietary supplementation may be a preferable approach.

Phytoestrogen Research Produces Mixed Results
The topic of phytoestrogens was addressed by Dr. Sheila Anne Bingham of the U.K. Medical Research Council. Phytoestrogens are compounds that are structurally similar to estrogen and occur naturally in plants. It has been hypothesized that phytoestrogens could reduce the risk of breast cancer, but previous studies have produced mixed results, with some studies even suggesting an increased risk. The largest study of diet and cancer conducted to date – the European Prospective Investigation of Cancer (EPIC) has plans to address the link between phytoestrogens and risk of breast cancer. Dr. Bingham noted that particular gene variants may influence the effect of phytoestrogens, and that it will be important to account for these variants.

Impact of Dietary Antioxidants on Treatment Success is Uncertain
Dr. Christine Ambrosone of the Roswell Park Cancer Institute spoke about antioxidants, genetics and breast cancer risk and outcomes. Dr. Ambrosone noted that due to genetic variation, individuals may have different needs for, and responses to, dietary antioxidants from fruits and vegetables. Dr. Ambrosone also discussed the complex roles that antioxidants may play during breast cancer treatment. There is some evidence that women with greater inherent antioxidant ability (due to specific gene variants) have a worse response to radiation therapy and certain types of chemotherapy; oxidative damage may contribute to the success of these treatments, and antioxidant enzymes may interfere with this process. The impact of dietary antioxidants on treatment success, however, is still uncertain. At least some evidence suggests that dietary antioxidants may actually contribute to oxidative damage and improved treatment response in cancer cells (although the opposite effect of reduced treatment efficacy is still a possibility). Dr. Ambrosone is currently conducting a study to explore the effects of dietary supplements on treatment toxicity and cancer recurrence in breast cancer patients.

Relationship Between Diet and Cancer is Complex
In a helpful follow-up session, experts in the field of nutrition and epidemiology discussed why studies of diet and cancer often produce inconsistent results. Dr. Walter Willett of the Harvard School of Public Health contrasted the clear and consistent links that have been observed between diet and cardiovascular disease and diabetes with the far less consistent results that have been observed for diet and cancer. A possible explanation for this discrepancy may be the timing of the dietary assessment. For cancer, it’s possible that diet in early life and adolescence may play a key role, whereas more recent diet may be important for diseases such as heart disease and diabetes. Few studies conducted to date have been able to evaluate early-life diet. Dr. Willett, along with fellow presenter, Dr. Alan Kristal of the Fred Hutchinson Cancer Research Center, also noted that cancer is likely to be a more complex disease than conditions such as heart disease. A recurrent theme at the 2007 AACR meeting is that cancer is an extremely heterogeneous disease; even within a single organ, such as the breast, cancers in different individuals can have very different characteristics. The relationship between diet and cancer may vary greatly across these different subtypes of cancer, obscuring a relationship with cancer overall.

Studies Evaluate Benefits of Cruciferous Vegetables and Soy
Other studies presented at the AACR meeting also tackled the topic of diet and cancer. In a study highlighted at a press conference on diet and cancer, researchers evaluated two components of cruciferous vegetables (such as broccoli) and soy that may be protective against breast and ovarian cancer.¹ Diindolylmethane (DIM) is a compound that results from the digestion of cruciferous vegetables, and genistein is a component of soy. In a study of breast and ovarian cancer cells, these compounds reduced the production of proteins that contribute to the spread of breast and ovarian cancer. One of the authors of the study noted “We think these compounds might slow or prevent the metastasis of breast and ovarian cancer, which would greatly increase the effectiveness of current treatments. But we need to test that notion in animals before we can be more definitive.” It is also important to note that the amount of DIM and genistein used in this study was higher than could be achieved through diet alone.

Researchers Find No Risk Reduction Associated with B Vitamins
Researchers with the Women’s Health Study evaluated the link between B vitamins and risk of breast cancer.² The study measured blood levels of three B vitamins -- folate, vitamin B6, and vitamin B12 -- in women with and without breast cancer. Overall, there was no indication that higher levels of any of the three vitamins reduced the risk of breast cancer.

Overweight and Obese Women Have Worse Overall and Recurrence-Free Survival Rates
The relationship between weight and breast cancer prognosis was assessed in a study of 613 women with locally advanced (stage III) breast cancer.³ Eighteen percent of the study participants had inflammatory breast cancer (IBC). Body weight was categorized as normal or underweight (body mass index less than 25), overweight (body mass index between 25 and 29) or obese (body mass index of 30 or greater). Women with IBC were more likely to be obese than other women with locally advanced breast cancer. Among all study participants combined, overweight and obese women had worse overall and recurrence-free survival than lower-weight women.

Health Disparities
Cancer incidence and survival in the U.S. continues to vary by race and ethnicity. African-American women are less likely to be diagnosed with breast cancer than white women, for example, but are more likely to die of the disease. Possible explanations for health disparities include differential access to health care and language and cultural barriers, and could also include differences in gene expression or tumor biology.

The 2007 AACR meeting included several studies – and a major lecture – on issues related to health disparities.

Genetic Differences May Account for Some Disparities
Preliminary findings from a study highlighted at an AACR press conference on health disparities suggest that differences between African American and white women in the expression of two genes may predispose African American women to more aggressive breast cancer.⁴ Dr. Lori Field, one of the researchers involved with the study, noted in a prepared statement that the differential gene expression “could promote cell growth and could potentially provide greater growth advantage to breast cells in African Americans compared to Caucasians.” These initial results were based on findings in normal breast tissue. The researchers are also evaluating gene expression in tissue from breast cancers. Dr. Field noted “If we see that there are differences in the breast tumors, we may find new molecular targets to which therapy can be tailored specifically to African American women.”

Family History and Breast Cancer in African American Women
A second study reported on the link between family history and risk of breast cancer in African American women.⁵ Although a family history of breast cancer is known to increase the risk of breast cancer in white women, less is known about strength of the link in African American women. The results were based on surveys of roughly 59,000 African American women who participated in the Black Women’s Health Study. Study participants who had a mother or sister with breast cancer were 79 percent more likely to develop breast cancer than study participants who did not have a family history of breast cancer. Risk was particularly elevated for women under the age of 35 who had a family history of breast cancer.

Race Information May Be a Placeholder for Understanding Population Differences
Issues of race and science were also discussed by Dr. Harold P. Freeman of the Ralph Lauren Center for Cancer Care and Prevention. Dr. Freeman spoke on “The Meaning of Race in Science and Society” during the AACR-Minorities in Cancer Research Jane Cooke Wright Lecture. He proposed that health disparities likely stem from at least three major forces: poverty, social injustice, and culture (belief systems, values, and behaviors). Dr. Freeman also addressed the controversial issue of whether race is a biologically important entity that should be used in science. He explained that there is no clear genetic basis for racial classification. Ancestry and migration patterns can influence genetic makeup, but he contended that these factors are different than race. Nevertheless, he did not discourage the use of information about race in research; rather, he emphasized the need to disentangle social and political meanings of race from assumptions about biology. Dr. Freeman noted that while people are different, race is not the category that helps us to understand how they are different. Race may simply be a place-holder as we seek to understand the real underlying differences between population groups. “In science,” he said, “we have the power to look deeper.”

Chemotherapy-related Cognitive Dysfunction (“Chemo-brain”)
Patients undergoing chemotherapy have long complained of a phenomenon commonly known as “chemo-brain.” Chemo-brain refers to changes in cognitive function, such as loss of memory and inability to think clearly or perform some daily functions. Researchers have not been able to pinpoint the cause of these changes, but current studies are evaluating brain structure and function in order to better understand the effects of chemotherapy on the brain.

A symposium titled “Chemotherapy-related Cognitive Dysfunction: An Emerging Area of Translational Research” brought together neuroscientists and oncologists to discuss the effects of chemotherapy on the brain and cognitive function. The discussion focused on the subset of patients who experience persistent cognitive problems, often consisting of problems with memory and concentration. Although these self-reported problems are not always apparent on neuropsychological testing, PET imaging of the brain suggests that chemotherapy may alter brain function. The way in which chemotherapy might affect the brain remains unclear, however. A direct toxic effect on the brain is one possibility, but cognitive dysfunction could also be influenced by chemotherapy-induced menopause or other mechanisms. In addition, it’s possible that genetic susceptibility plays a role in who develops cognitive dysfunction, and researchers are exploring various candidate genes. For breast cancer patients, it’s also important to determine how the combination of hormonal therapy and chemotherapy affects cognitive function, and this research is also underway.

Cancer Stem Cells
Stem cells are self-renewing cells from which other types of cells develop. Cells known as cancer stem cells have been found in several types of cancer, including breast cancer, and are thought to play a key role in the growth of these cancers. Although cancer stem cells may make up only a small part of a tumor, some research suggests that eliminating these cells is necessary for successful cancer treatment. Unfortunately, cancer stem cells appear to be resistant to many conventional cancer therapies. Researchers hope that by identifying the weaknesses of these cells, effective new therapies can be developed.

Two studies presented at the 2007 AACR meeting suggested that specific genes may play a role in the number and function of mammary (breast) stem cells. A role for the PTEN and HER2 genes in the self-renewal of mammary stem cells was reported by Dr. Hasan Korkaya of the University of Michigan’s Comprehensive Cancer Center.⁶ Defects in these genes – which have previously been linked with aggressive breast cancer -- appear to increase mammary stem cell populations. Another study from the University of Michigan suggests that the BRCA1 gene may also be involved in mammary stem cell function.⁷ Dr. Suling Liu and colleagues found that inhibition of the BRCA1 gene resulted in an increase in the number of mammary stem cells. The links between these genes and mammary stem cells may help guide the development of therapies that target cancer stem cells.

Tumor Microenvironment
The microenvironment of a cancer refers to the setting in which a cancer grows. Cancer does not develop in isolation; cancer cells interact with surrounding cells, and these interactions play an important role in cancer development and progression. Altering the microenvironment may offer an additional approach to cancer prevention as well as treatment.

Dr. Mina Bissel, of the Lawrence Berkeley National Laboratory, has long championed the importance of the tumor microenvironment, and spoke on the topic during the Tenth Annual Pezcoller Foundation-AACR International Award for Cancer Research Lecture. Dr. Bissel noted that in order to understand cancer, we must do more than understand the genome; we must also understand the structure and function of the tissue environment in which cancer occurs. As she put it, “Half the secret of the cell is outside the cell.” Dr. Bissel has based her work on the study of the mammary gland – one of the few tissues that undergoes organizational and functional changes during adult life.

Inflammation
Inflammation is thought to play a role in the development of certain cancers, prompting interest in the role of anti-inflammatory drugs in cancer prevention. Commonly-used anti-inflammatory drugs include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen.

Two studies presented at the 2007 AACR meeting highlighted the role of inflammation in cancer. Researchers with the Iowa Women’s Health Study collected information about aspirin and non-aspirin NSAID use from more than 22,000 postmenopausal women.⁸ Compared to women who did not use aspirin, women who reported regular aspirin use were 16 percent less likely to develop cancer and 13 percent less likely to die from cancer. Regular aspirin use also reduced the risk of death from heart disease. In contrast, regular use of non-aspirin NSAIDS did not appear to be protective against cancer or heart disease. These different results for aspirin and non-aspirin NSAIDS were unexpected. The researchers also caution that this is only a single study, and should not necessarily be used to make decisions about aspirin or other NSAID use.

According to a study conducted in mice, the lung inflammation that occurs in patients with asthma may increase the risk of lung metastasis (the spread of cancer from another part of the body, such as the breast, to the lungs).⁹ These findings raise the possibility (not yet substantiated) that corticosteroid treatment of asthma could reduce the risk of lung metastases in patients with breast and other cancers. The researchers are now beginning to look at the links between asthma and lung metastases in women with breast cancer.

Management of Anemia
Anemia is a common side effect of chemotherapy and cancer. It is characterized by low levels of circulating red blood cells, which are responsible for delivering oxygen to tissues throughout the body. Common symptoms of anemia are severe fatigue, shortness of breath, diminished activity levels, and a reduced overall feeling of well-being.

Severe anemia often requires treatment with blood transfusions, which have associated risks of infection, rejection, and increased medical costs. Furthermore, severe anemia may cause a delay in cancer treatment, resulting in less favorable chances of a cure or optimal long-term survival.

The results of a phase III trial clinical trial presented at AACR suggest that among cancer patients who develop anemia as a result of their cancer (rather than as a result of chemotherapy), use of the red blood cell booster Aranesp® (darbepoetin alfa) does not reduce the need for blood transfusions and may increase the risk of death.¹⁰ These results, however, appeared to vary by type of cancer. Treatment with Aranesp did not appear to influence survival among women with breast cancer. Dr. John Glaspy, the lead author of the study, noted that the results of the study do not support the use of red blood cell boosters such as Aranesp among cancer patients who are not receiving chemotherapy.

Other Selected Presentations:

Breastfeeding and Breast Cancer
To evaluate the relationship between reproductive factors and the risk of hormone receptor-positive and hormone receptor-negative breast cancer, researchers collected information from 995 women with breast cancer and 1498 women without breast cancer.¹¹ All women were age 55 or older, and had participated in the Women’s Contraceptive and Reproductive Experiences Study. According to Dr. Giske Ursin, one of the study authors, the most important finding of the study is that breastfeeding appears to lessen the increased risk of breast cancer that comes from having children later in life. This suggests that women who delay childbearing may wish to consider breastfeeding when they eventually do have children. Breastfeeding reduced the risk of both hormone receptor-positive and hormone receptor-negative breast cancer.

Global Hypomethylation and Breast Cancer Risk Factors
Environmental factors encountered over the course of a lifetime can produce non-inherited changes to DNA that alter a woman’s risk of breast cancer. A study conducted by researchers at Columbia University evaluated exposures and DNA changes among women born in New York between 1959 and 1966. The type of DNA change that the researchers assessed is known as methylation. Methylation alters the activation of genes. The researchers found that the probability of an aberrant type of methylation known as global hypomethylation varied by breast cancer risk factors such as race and birth size, as well as by smoking status. Study author Mary Beth Terry noted “We see this as a first step to understand why measures from birth might be related to adult diseases much later in life.”

Predicting Response to Tykerb®
Researchers have identified gene expression signatures linked with the likelihood of response to the targeted drug Tykerb® (lapatinib).¹² Tykerb targets two proteins that often function abnormally in breast cancer cells—HER2 and EGFR. Although the results presented at AACR need to be confirmed, this study is indicative of work that is underway to further individualize cancer treatment. If pre-treatment tests are able to indicate that a woman is unlikely to respond to a particular treatment, she can be spared the side effects of that treatment, and can choose to focus on other therapeutic approaches.

References:

¹ Hsu EL, Hankinson O. A Novel Mechanism for the Chemoprotection by 3,3-diindolylmethane (DIM) and genistein for breast and ovarian cancers. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 4217.

² Lin JSL, Lee IM, Cook NR et al. Plasma Folate, Vitamin B6, Vitamin B12 and Risk of Breast Cancer in Women. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 860.

³ Dawood S, Broglio K, Kau S-W, Hortobagyi GN, Cristofanilli M. Prognostic Value of Body Mass Index (BMI) in Locally Advanced Breast Cancer (LABC). Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 796.

⁴ Field LA, Love BJ, Kane J et al. Differential Gene Expression in Normal Breast Tissue from African American and Caucasian Women. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 43.

⁵ Palmer JR, Adams-Campbell LL, Boggs DA, Rosenberg L. Familial Breast Cancer in a Cohort of 59,000 African-American Women: The Black Women’s Health Study. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 2500.

⁶ Korkaya H, Iovino F, Wicha MS. PTEN and HER2 Regulate Self-renewal and Invasion of Human Mammary Stem Cells. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 1287.

⁷ Liu S, Ginestier C, Bontu G, Wicha MS. BRCA1 Regulates Human Mammary Stem Cell Self-renewal and Differentiation. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 5700.

⁸ Bardia A, Ebbert JO, Vierkant RA et al. Association of Aspirin and Non-aspirin NSAIDs with Cancer Incidence and Mortality in a Large Prospective Cohort Study. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 3400.

⁹ Taranova AG, McGarry MP, Jacobsen EA et al. Chronic Allergen Provocation Results in a Significant Increase in the Rates of Lung Metastasis that is Dependent on Inducted Pulmonary Inflammation. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 2553.

¹⁰ Glaspy J, Smith R, Aapro M et al. Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Darbepoetin Alfa (DA) for the Treatment of Anemia in Patients not Receiving Chemotherapy or Radiotherapy. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract LB-3.

¹¹ Lord SJ, Bernstein L, Johnson K et al. Parity, Breastfeeding and Breast Cancer Risk by Hormone Receptor Status in women with Late Age at First Birth – A Case-Control Study. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 2610.

¹² Kuo W-L, Guan Y, Hu Z et al. Molecular Predictors of Drug Response in Breast Cancer. Presented at the 2007 meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007. Abstract 4963.