Results /Discussion

1. Review of Oncology Studies Funded by the FDA Office of Women’s Health – 1994-2009 Tien Nguyen, Emmanuel Fadiran, Ameeta Parekh, Office of Women’s Health, FDA, 10903 New Hampshire Av, Silver Spring, MD 20993. Cancer Estimated New Cases – 2009 Estimated deaths – 2009 Respiratory 107,280 71,550 Breast 192,370 40,170 Ovarian 21,550 14,600 Endometrial 42,160 7,780 Cervical 11,270 4,070 Vulvar 3,580 900 Vaginal and other female genital cancer 2,160 770 Introduction Results /Discussion Results /Discussion Results/Discussion Results/Discussion The National Cancer Institutes estimated that more than 700,000 American women were expected be diagnosed with cancer and almost 270,000 women were expected die from cancer in 2009. Breast cancer is the second most common type of cancer in women and kills more women in the US than any cancer except lung cancer (Table 1). Uncontrollable risk factors for breast cancer include age, genes, early menarche, late menopause. Cancer research is largely focused on prevention, early detection, treatment, development of biomarkers and diagnostic tests for detection, treatment and response. Additionally due to toxic side effects associated with cancer treatments research in the area of treatment-related toxicities has been extensively studied. From its inception in 1994, the FDA’s OWH has funded 29 oncology studies and 2 workshops relating to oncology. • To date 31 intramural studies have been funded since the inception of the OWH in 1994. • Of the 31 studies; 6 studies are on-going, 2 were workshops, and 4 were unsatisfactorily terminated and no report was located. A total of 19 studies were completed and are included in this summary. • The 19 studies were grouped into 5 categories: • MMTAT (9) • MMTDS (4) • DM (2) • D/P (2) • DA (2) D/P Studies • Important in improving public health, these studies look to improve mechanisms for detection of tumors and tumor progression • P/D studies (n=2): • One study looked at the additional cost of the implementation of the Mammography Quality Standards Act (MQSA) on mammography centers, accreditation bodies and state agencies and showed that total costs of compliance are modest and most facilities will probably be unaffected. • there is adequate capacity to provide the required services in the US • risk of small facilities unable to cope with slight increase in regulatory costs • Assessment of PET imaging procedures to monitor early response to chemotherapy in breast cancer • F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging may be used to monitor progress of chemotherapy. MMTAT Studies (Cont’d) • Profiled sex differences in liver transporter genes that revealed individual and sex differences in transporter genes in the human liver, which can be major determinants in chemotherapy, toxicity, and tolerability. • Female liver samples expressed higher ABC1 transporter (efflux pump) at both RNA and protein levels which can lead to large differences in adverse drug reactions • Found that co-administration of doxorubicin and anti-HER2/neu antibody (Herceptin) does not intensify doxorubicin cardiotoxicity in rats • Investigated the myelotoxicity of alkylating agents to determine if neutropenic nadir is linked to a specific myeloid progenitor. • The results showed that specific time to nadir may not be inversely proportional to the progenitors maturity and drug-specific sensitivity between early and late hematopoietic progenitor cells did not predict the different clinical patterns of neutropenia Figure 1:Estimated New Cases and Deaths for Cancers in Women DA Studies • It is historically difficult to recruit and retain women in clinical trials, especially minority women • DA studies (n=2) • Improved statistical methods to evaluate treatment effects and possibly require smaller study population • application of the Smirnov test that would offer adequate statistical power to detect the direction of a treatment effect in ordered or categorical endpoints. • it is reasonable to use the Smirnov test to analyze tumor response data. • Investigated the utilization of quantitative approaches to leverage prior knowledge on non-small cell lung cancer (NSCLC) trials to help developers better screen drug molecules. • the Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size are consistent prognostic factors for survival. • the survival and tumor dynamic models could be applied to screen compounds and possibly simulate NSCLC clinical trials and optimize trial design. • Sex is not a significant progenitor factor. MMTDS Studies • Research in oncology tries to understand the mechanism of tumor growth, and thereby understand mechanisms to halt or even reverse tumor growth and spread • MMTDS studies (n=4): • Investigated the immunogenicity and carcinogenicity associated with breast implants, and surface properties of silicone implants that may be pro-inflammatory and pro-fibrotic • inflammation and the formation of a thick capsule are attributable to nonspecific foreign body reaction that may be carcinogenic and associated with the surface properties of silicone implants. • Examined tumor necrosis proteins and interferon-inducible protein-10 (IP-10) and a monokine, Mig in mice • both IP-10 and Mig have very similar anti-tumor effects and are essentially indistinguishable from each other which may be a vascular effect. • Both Mig and IP-10 groups showed visible response but the tumors did not completely regress or stop growing, therefore this study may lead to the development of more efficacious anticancer treatments • Investigated photocarcinogenicity testing in transgenic mice to determine the threshold level of solar similar light (SSL) to guide SSL dosing in future research studies. • transgenic mouse does not appear to provide improvement over current models for evaluating the photocarcinogenic potential of pharmaceuticals and does not appear to be highly response to genotoxic carcinogens. Figure 1: Studies by Categories: 19 studies were divided into 5 categories: MMTAT, MMTDS, DM, D/P, and DA. Conclusions Materials and Methods OWH has supported studies that have had regulatory impact and have led to better understanding of treatment toxicities and tumor development. Furthermore, these studies also identified socio-economic associations that may contribute to higher mortality in certain female groups to better target detection and prevention programs. OWH funded studies support continued research on macro (population studies, demographics) and micro (mouse model, pharmacokinetics and pharmacodynamics) levels. Since its inception in 1994, the OWH has supported cancer research and continues to do so today with several ongoing studies. Approximately 50% of all completed intramural studies have been published in peer-reviewed journals such as the Journal of Internal Medicine, Carcinogenesis, and Toxicology. There are still many questions to be answered in the oncology arena and the OWH has stepped up to support better mechanistic and clinical understanding of cancer. • All OWH funded intramural oncology studies from 1994 – 2009 were retrieved from the OWH database and files in October 2009. • Satisfactorily completed studies with final reports or publications were evaluated for their findings for cancer preventions, developments, treatments and response. Additionally, studies on treatment-related toxicities, patient demographic characteristics and novel approaches for data analysis were evaluated. • Incomplete/unsatisfactorily completed studies (e.g. PI resigned, terminated, withdrawal of funds, etc.), on going studies, workshops and seminars were not reviewed or summarized for this project. • Studies were grouped into 5 categories: • Molecular mechanism of treatment associated toxicities (MMTAT) • Molecular mechanism of tumor development & suppression (MMTDS) • Demographics (DM) • Detection/Prevention (D/P) • Data Analysis (DA) DM Studies • Understanding population data and trends will help target and personalize treatments for better outcomes in women. • DM studies (n=2): • Classified culture-specific foods consumed by African-American women in rural south. The study used a novel method to recruit underserved African-American women in the rural south to participate in a trial to identify modifiable risk factors. This study developed a food consumption frequency questionnaire and administered it over the phone, and was one of the first studies to look at African-American women in the rural south and their consumption of culture specific food. Figure 2: Funding by Categories: Funding, and percent, of total funding for 19 studies by category MMTAT Studies • Toxicity is a major limiting factor in cancer treatment, and is a large area of research in oncology • MMTAT studies (n=9): • Investigated the toxicity and uterine endothelial hyperplasia associated with tamoxifen & derivatives • reported a severe adverse event related to the pro-estrogenic side effects of tamoxifen • Contributed to the Black Box Warning in 2002 - “Serious and life-threatening uterine malignancies” • Showed no significant ↑ or ↓ in 7,12-dimethylbenz[a]anthracene (DMBA)-induced genotoxicity and carcinogenic of soy isoflavones in rats • One study looked to see if income level was related to mammography use in women with full financial coverage. The results showed that 100% mammography utilization was not enough to ensure equivalent use of screening mammography in the HMO study group. Identified relationship of household income to mammography screening, and suggested coverage for mammography services is not enough to ensure equivalent use of screening across the whole population References • www.nlm.nih.gov • www.cdc.gov • http://www.cancer.gov/ • SEER Cancer Statistics Review 1975-2006, National Cancer Institute • http://www.nlm.nih.gov/medlineplus/breastcancer.htm • www.google.com; breast cancer Research Funding