The American Association of Health Plans (AAHP) established a Women’s Health Task Force composed of health educators, researchers and health policy experts from member plans to discuss directions for women’s health within the managed care industry. With funding from The Commonwealth Fund, the Task Force was asked to examine exemplary programs related to women’s health issues. The task group determined four areas of focus, one of which was breast cancer prevention and treatment.

This report focuses on three health plans that were selected for their exemplary programs related to breast cancer prevention and treatment and presents an overview of the content of each program. The programs include Keystone Mercy Health Plan’s Breast Cancer Screening Outreach Program, Blue Cross Blue Shield of Massachusetts’s Innovative Treatment and Research Project, and Kaiser Permanente (Southern California) Medical Group’s Breast Buddy Peer Support Program.

Lessons learned from the experiences of these exemplary providers include: encouraging provider input early on; developing and encouraging relationships and collaborations within and beyond the health plan, and recognizing the importance of the psychosocial component for women with breast cancer. Other health plans may use these programs as templates for similar types of support for patients diagnosed with breast or other cancers and or other chronic conditions. Journal of Women’s Cancer, 2(4), 171-176, 2000.

Chemoprevention of Breast Cancer: the NSABP’s Breast Cancer Prevention Trial

Breast cancer’s high incidence and mortality rate has stimulated the search for agents with preventive potential. In 1992, the National Surgical Adjuvant Breast and Bowel Project (NSABP) started the Breast Cancer Prevention Trial (P-1) to test tamoxifen, a selective estrogen receptor modulator (SERM) for breast cancer prevention in women at increased risk. In this study, 13,388 women 35 years or older at increased risk for breast cancer according to Gail model risk factors (family history, age and personal history) were randomized to tamoxifen 20 mg per day or placebo for 5 years. Through 69 months of follow-up, tamoxifen reduced risk of invasive breast cancer, primarily ER positive tumors, by 49% (two-sided P<0.00001), and reduced risk of noninvasive breast cancer by 50% (two-sided P<0.002). Additional effects of tamoxifen include reducing incidence of hip, radius and spine fractures; increasing the rate of endometrial cancer (risk ratio 2.53, 95% CI 1.35-4.97), as previously demonstrated; and increasing the rates of vascular events. BCPT results led to Food and Drug Administration (FDA) approval of tamoxifen for reducing breast cancer incidence in high-risk women. The trial’s outcome has elicited much debate. Attempts have been made to reconcile the BCPT results with those of British and Italian trials of tamoxifen versus placebo in high-risk women, in which tamoxifen did not reduce breast cancer incidence. Additionally, methods for balancing benefits with observed risks of tamoxifen for individual women are being developed. Finally, establishing tamoxifen as the standard for breast cancer chemoprevention in high-risk women has led NSABP to begin the Study of Tamoxifen and Raloxifene (STAR). Raloxifene, a second generation SERM approved by the FDA for osteoporosis prevention in post-menopausal women, was selected for STAR based on the Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis study which, comparing raloxifene to placebo, showed a decreased incidence of breast cancer in the raloxifene arm as a secondary endpoint. STAR will randomize 22,000 post-menopausal women at increased risk for breast cancer by Gail criteria to tamoxifen or raloxifene for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures and vascular events. JOURNAL OF WOMEN’S CANCER, 2 (4), 177-191, 2000

Transcytosis of Proteins Across the Mammary Epithelium into Milk

Most of the major organic constituents of milk, including lactose, milk fat, and such proteins as casein, alpha-lactalbumin and lactoferrin are synthesized in the epithelial cell of the lactating mammary gland. However, some important components of milk including immunoglobulins, apolipoprotein B, albumin, and food protein antigens are transferred intact from the interstitial space. IgA transport is the best understood. This dimeric immunoglobulin is manufactured by plasma cells in the interstitial space of the mammary gland. It binds to receptors on the basal surface of the mammary alveolar cell, is internalized and transferred to the apical membrane where it is secreted with a portion of its receptor, called secretory component. The mechanism by which other transcytosed substances are endocytosed and transferred across the mammary alveolar cell is less clear. Fluid-phase transport may result in a milk/blood ratio between 0.12 and 0.2 in mice, inferred from studies of transferrin, apolipoprotein B and J-chain deficient IgA. If this is the case the finding that the albumin blood/milk ratio is close to 1.0 implies that this plasma protein is actively transported into mouse milk. In human and cow’s milk the albumin blood/milk ratio is about 0.01 suggesting that the mechanism may not be present. This ratio also sets an upper limit for fluid phase transcytosis in these species. Nonetheless, the finding of dietary proteins in human milk suggests that the pathway is important in women as well. Whatever the mechanism, mediated or non-specific, the notion that transcytotic pathways carry valuable nutrients, protective and potentially detrimental substances to the neonate and sensitize or tolerize the neonatal immune system to antigens present in the maternal environment requires additional investigation. JOURNAL OF WOMEN'S CANCER, 2 (4), 193-200, 2000.

Role of Proteases in Breast Cancer

Breast cancer is one of the most commonly diagnosed cancer in women worldwide, and it is a leading cause of cancer-related death. In the United States this year, nearly 180,000 women will be diagnosed with breast cancer, and approximately 45,000 will die from the disease. Most of the deaths due to breast cancer are not due to the primary tumor in the breast, but are instead due to the metastatic disease that is found in more advanced disease. Current treatment consists primarily of surgery and radiation therapy. This may be followed by adjuvant chemo- or hormonal therapy designed to suppress the recurrence of the primary tumor and of metastatic disease. Because of the importance of the metastatic process to the survival of patients, much attention has been paid in recent decades to the biology that underlies these events. Initially it was appreciated that cancer cells must acquire the ability to degrade the basement membrane (BM) that surrounds normal breast epithelial tissue as well as endothelial cells. Cancer cells must also remodel the extracellular matrix (ECM) in the adjacent stroma in order to gain access to blood vessels or lymph channels for their dissemination to distant sites. Proteases of many types (serine, metallo-, cysteine, and aspartyl) have been shown to play a role in the degradation of one or another component of the BM or ECM. In addition, many of these proteases have been shown to increase the motility and invasiveness of breast cancer cells in vitro. Many in vivo studies also have shown a number of proteases to be important in tumor growth and metastasis in animal models. In recent years, however, researchers have come to appreciate that the role of proteases in cancer invasion and metastasis may be much more complex than once thought. Evidence has emerged for the involvement of proteases in numerous processes that may affect the ability of breast cancer to grow and spread. These processes include tumor angiogenesis, cancer cell growth through autocrine or paracrine signaling, cell adhesion, cell survival, and apoptotic cell death. The significant correlation between the levels of components of a number of proteolytic systems and measures of patient prognosis testify that the findings in the laboratory have relevance for the recurrence and spread of breast cancer in patients in the clinical setting. In addition to finding new prognostic markers to guide decisions regarding adjuvant therapy, an active search is underway to identify novel therapeutics that target the action of proteases to inhibit the growth, cell survival and spread of cancer. In this review we will consider several of the major proteolytic systems that have been implicated in breast cancer metastasis, including the plasminogen activator/plasmin serine proteases, the matrix metalloproteases, and the cathepsin proteases of the cysteine and aspartyl type. We will examine the roles of these systems in varied aspects of cancer cell biology, such as matrix degradation, invasion and metastasis, tumor angiogenesis, cell adhesion, cell growth, cell survival, and apoptotic cell death. Additionally, we will look at these systems as potential therapeutic targets and prognostic markers in breast cancer. JOURNAL OF WOMEN’S CANCER, 2 (4), 201-216, 2000.

Immunotherapy and Gene Therapy of Gynecologic Cancers. II: Cervical Cancer

Cervical carcinoma is the second most common cause of mortality from cancer among women worldwide, with a higher incidence in lower socioeconomic regions and groups. Non-specific immune stimulators , such as Sizofiran, OK-432 and LC-9018, have long been investigated as a means to activate immune defenses against cervical cancer cells, but appear to have only a limited value in the treatment of this disease. During the last decade, however, a shift towards more specific immunization approaches has taken place. This was mainly based in that substantial evidence accumulated suggesting that the human papillomavirus (HPV) would be etiologically related to cervical cancer, specially the types HPV16 and HPV18. The HPV16 and HPV18 early regions 6 and 7 (E6 and E7) are consistently expressed in cervical tumor cells, and their carcinogenic effect would be mediated through the binding to the tumor suppressor p53 and RB proteins . Epitopes derived from E6 and E7 proteins are being currently tested in several vaccine-based approaches . Gene therapy approaches using E6 and E7 antisense or ribozyme molecules are also being undertaken. Journal Of Women’s Cancer Vol 2 (4), 217-225, 2000.