Policy Issues and Recommendations
Efforts to untangle the relationship, if any, between current and future oral contraceptives and breast cancer will be long, slow, and relatively expensive. They will also be tightly linked to whatever progress is made in the overall understanding of the pathogenesis of the disease, including markers of susceptibility and response to oral contraceptive exposure. In view of the high costs, in human and financial terms, associated with a continuously rising incidence of breast cancer and the potential importance of any possible relationship with oral contraceptives, the committee offers recommendations that address four policy areas:
developing a broader array of contraceptives;
assessing knowledge for application in clinical practice; and
filling gaps in biological and epidemiological knowledge.
Taken together, the committee's recommendations call for a new, more explicit level of planning, investment, and commitment—directed toward the study of breast cancer in general and its relationship to steroid hormones—in particular, oral contraceptives.
With oral contraceptives in widespread use, epidemiologists must maintain appropriate surveillance throughout at least the next 20 to 40 years to follow the effects of current formulations of the pill, when
used from an early age, on breast cancer risk. As current formulations are likely to be the highest doses used over the period, the assessment of their effects cannot be cut short. To date, the cohort studies performed in the United Kingdom have been among the best and have yielded the most information. European and Scandinavian populations may continue to be important resources for surveillance: some are particularly stable, and several have prescription records of high quality and long duration. Also, some oral contraceptive formulations bound for the United States are already in use in Europe. In the United States, members of large, stable health maintenance organizations may be similarly important resources for surveillance.
Plans are already being formulated to establish sound Medicare data bases and cohorts to permit studies of the effectiveness of medical interventions (Heithoff and Lohr, 1990). Consideration should be given to ways in which linkages with the new Medicare data bases could be used to explore the influence of earlier oral contraceptive use on breast cancer incidence among older, postmenopausal women.
The Surveillance, Epidemiology, and End Results (SEER) Program monitors community-wide cancer incidence among women of all races. These registries are the nation's resource for epidemiological studies. They must maintain and, if necessary, expand their capacity to support the necessary epidemiological studies of the influence of oral contraceptive use on breast cancer incidence among U.S. women of different races and cultures.
The surveillance that needs to continue to cover oral contraceptive use and all reproductive cancers will be particularly demanding. The Cancer and Steroid Hormones (CASH) Study conducted by the Centers for Disease Control cost approximately $13.7 million. Even this sizable study, however, was not large enough to answer questions concerning the risk of breast cancer in subgroups of users. Future studies must (1) involve many thousands of cases and controls to permit statistically valid analyses of subgroups of users (e.g., individuals who used the pill prior to their first pregnancy), and (2) follow sufficient numbers of women for many years to measure how long any possible effect persists after discontinuing oral contraceptive use. These are studies of daunting size that cannot be conducted on an ad hoc basis. Nevertheless, they must be undertaken—and the necessary resources must be set aside to conduct them—to protect the health of American women.
European and North American research data on breast cancer and oral contraceptives have been complementary. There is enough variation in both exposure to oral contraceptives and opportunities for surveillance among the countries gathering data that a coordinated future research plan offers worldwide benefits. For example, if the prospective study by the United Kingdom Royal College of General Practitioners were continued, it might throw important light on the duration of any relationship between reproductive cancers and oral contraceptive use, as well as on any possible interaction between use of the pill and breast cancer in women over 50 years of age. If the Royal College researchers and U.S. investigators were to reanalyze their data and pool their results, they could well realize the complementary potential of their studies.
Surveillance Requirements of the Food and Drug Administration
At present, a considerable imbalance exists between the investment required by the Food and Drug Administration (FDA) in premarketing testing of a new drug and the investment made in postmarketing surveillance. Indeed, although FDA regulates premarketing testing in great detail, it has never required specific postmarketing studies by the manufacturers of oral contraceptives. Yet, the information from premarketing testing alone cannot answer questions about rare adverse or beneficial effects, such as those central to any consideration of oral contraceptives and reproductive cancers.
The Phase III clinical trials of new drugs required by FDA for new drug application approval cost between $10 and $30 million per trial and are paid for by the developers, or manufacturers. In the special case of contraceptives, where industry is sometimes reluctant to take a leadership role (National Research Council/Institute of Medicine, 1990), part or all of the cost may be met by the federal government (e.g., the National Institutes of Health [NIH] or the Agency for International Development [AID]). All of the postmarketing surveillance of oral contraceptives that has been conducted thus far has been supported by foundations, by NIH or AID, or by the European medical research councils. Although postmarketing surveillance is funded at a much lower level than premarketing testing, it has produced practically all the key clinical information that has led to safer preparations (e.g., low estrogen dose pills) and greater selectivity in use (e.g., avoiding use of the pill by women who smoke). Therefore, the com-
mittee recommends that the FDA consider premarketing and postmarketing requirements as an integrated whole and devise ways of spreading the investment already required by manufacturers, and ultimately paid for by users, in such a way as to maximize the information on safety that will result.
DEVELOPING A BROADER ARRAY OF CONTRACEPTIVES
The success and popularity of oral contraceptives as a means of avoiding conception are both a tribute to their efficacy and a reflection of the paucity of effective alternative means, particularly for young women. The committee underscores the urgent need for research and development of a broader array of contraceptives (see NRC/IOM, 1990), including more effective barrier methods and nonsteroidal methods. It is not feasible to wait for resolution of the uncertainty about oral contraceptives as a potential risk factor for breast cancer before energizing research and development on alternative methods of contraception. In the face of uncertainty, those couples wishing to eschew oral contraceptives in favor of other methods of contraception must be served—and sooner, not later. Unless immediate steps are taken to develop a broader array of safe and effective contraceptives, the choice of contraceptives in the United States in the next century will be the same as it is today (NRC/IOM, 1990).
It is worth noting that when new, systemically active methods of contraception are introduced, they will be surrounded by some of the same uncertainty about long-term effects that was first associated with oral contraceptive use. It will take many years of careful study to acquire as much information about a completely new method of contraception as is now available about oral contraceptives.
ASSESSING KNOWLEDGE FOR APPLICATION IN CLINICAL PRACTICE
Health care providers and patients are compelled to make clinical decisions about the use of oral contraceptives based on the best knowledge available to them. The committee finds that, at the outset of the 1990s, the best available knowledge about oral contraceptives and breast cancer does not support any fundamental change in clinical practice with respect to the use of oral contraceptives. This finding is subject to an important caveat: the knowledge base must be reassessed at regular intervals, in light of new research results (e.g., those forthcoming from the World Health Organization and the National
Cancer Institute). The committee recommends that, three years hence, and at regular intervals thereafter, an NIH consensus conference reassess recommendations for oral contraceptive use based on reevaluation of up-to-date information about the relationship between oral contraceptives and breast cancer. Two institutes in particular, the National Institute of Child Health and Human Development and the National Cancer Institute, would be appropriate lead institutes to judge when consensus conferences should be held.
Research results should be periodically assessed for new evidence of short- and long-term safety and carefully analyzed to provide clinicians with current information on the safest oral contraceptive use for younger and older women. There is also a need for continuous improvement of the dissemination of new and existing information about oral contraceptives and breast cancer among health care providers and women who use oral contraceptives. Multiple channels, through which providers and women can receive up-to-date information, must be opened and maintained. These channels include continuing medical education courses, the technical bulletins and other activities of the American College of Obstetricians and Gynecologists and other professional organizations, the activities of state and local health departments, services delivered by the health units of colleges and high schools, and the “one-on-one” contacts so common to the health profession. The committee emphasizes the obligation of health care providers to offer adequate, accurate information to women seeking contraception and to counsel them regarding the current state of ambiguity with respect to the relationship between oral contraceptives and breast cancer. Only then can fully informed choices be made in clinical practice.
FILLING GAPS IN BIOLOGICAL AND EPIDEMIOLOGICAL KNOWLEDGE
The committee believes that a multidisciplinary research approach is necessary to resolve the relationship between oral contraceptives and breast cancer. Research on a broad front could well produce insights that would lead to some reduction in the incidence of breast cancer, in the same way that research throughout the past three decades has led to insights and changes of lifestyle that are today believed to be reducing the incidence of heart disease in America. With no single, “magic bullet” likely to prevent or cure breast cancer, the committee recommends a broad program of expanded studies on breast function and pathophysiology from the perspectives of endocrinology, biochemistry, molecular genetics, nutrition, cytology, and tissue culture.
Basic research in the biology of the breast is identified by the committee as a priority. As one author (McCarty, 1989) notes, “That so much effort has been concentrated on the study of the abnormal with so little knowledge of normal physiology is an aberration. . . . One is struck by the paucity of existing understanding of ‘normal ' breast development, and the myriad factors influencing the proliferation of normal breast epithelium.”
Research is especially needed on the transition from normal to abnormal growth—including, for example, research on the role of local growth factors and newly detected extracellular matrix proteins, estrogen metabolism (e.g., the products of the 16α-hydroxysteroid metabolic pathway), and oncogenes. As basic resources for this research, in vitro model systems that employ normal breast tissue are needed, in which the effects of contraceptive steroids can be directly examined.
Epidemiological research priorities include a large, case-control (retrospective) study with sufficient statistical power to resolve the assessment of small increases in relative risk of breast cancer. One such study is currently being conducted by the National Cancer Institute; it involves primarily women below the age of 45. A study of postmenopausal women—who experience the bulk of breast cancer— is needed to elucidate the effects of both oral contraceptive use alone, and oral contraceptive use followed by hormone replacement therapy. As oral contraceptive formulations and use patterns of the pill change, future case-control studies will be required; the committee has outlined seven strategies that are likely to improve these future studies (see Chapter 2). The launching of appropriate, cost-effective new cohort (prospective) studies is equal in priority to the conduct of case-control studies. There are no substitutes for analytical, observational epidemiological studies in resolving the relationship of oral contraceptives and breast cancer, and great attention should be given to identifying the organizational settings (e.g., health maintenance organizations) in which they can be implemented. Efforts must also be made to establish coordinated international plans (particularly American-British plans) for case-control and cohort studies to monitor the long-term safety of current and widely used new formulations.
Biological markers, as they become more generally available, should be incorporated into epidemiological protocols. Consistent with a multidisciplinary approach to better understanding of the causes of breast cancer, there is a need for research that uses biological markers within the context of epidemiological study designs, using innovative as well as traditional research tactics.
The expensive, complex program of studies necessary to reveal the relationship (if any) between oral contraceptives and breast cancer will inevitably draw on funding from several sources. The cost of such action must be weighed against the sobering costs of inaction: increased suffering and loss of life, the cost of treating breast cancer, and the cost of mammography screening programs, which lead to earlier detection but not to primary prevention. With oral contraceptives now being used by an estimated 10.7 million American women (Mosher and Pratt, 1990), any adverse or beneficial interaction with breast cancer would be highly significant. Furthermore, any proven relationship or, what is equally important, any perceived relationship, would also have a marked effect on contraceptive practice in the United States. This country already has a higher rate of unintended pregnancies than many Western European nations. One in 10 American teenage girls becomes pregnant each year, with abortion a consequence for many. A sudden switch from oral contraceptives to less effective methods —if such a change were based on false interpretation of oral contraceptive risk—would be a public health disaster. Alternatively, if a shift were based on genuine findings, it would require considerable strengthening of family planning services to ensure a smooth transition.