The Evolution of Paradigms for the Management of Breast Cancer: a Personal Perspective1

(CANCER RESEARCH 52, 2371-2383, May I, 1992] Perspectivesin CancerResearch The Evolution of Paradigms for the Management of Breast Cancer: A Personal Perspective1

Bernard Fisher2

National Surgical Adjuvant Breast and Bowel Project Headquarters, Pittsburgh, Pennsylvania 15261

Introduction will develop the disease in her lifetime (1). Surveillance, Epi demiology, and End Results program (SEER) data indicate Although female breast cancer remains a major public health that, as age increases, so does the incidence of breast cancer problem, notable improvements have occurred in its treatment. (2). Whereas, for women 50-54 years of age the incidence is For most of this century, women with primary breast cancer 212 per 100,000, it increases progressively over the next 25 have been treated by radical mastectomy or some variation of years to 435 per 100,000 for women 80 to 84 years old. As that procedure. In recent years lumpectomy has become the ominous as they may seem, these statistics do not begin to recommended operation for most patients. Before the mid- portray the magnitude of the problem. The 75,000 or more 1970s, postoperative adjuvant systemic therapy was not used; women with invasive breast cancer clinically and/or mammo- now it is a major component of treatment strategies. How have graphically diagnosed each year represent only the tip of an these drastic changes come about? Are they the result of anec iceberg. Those women comprise only one cohort of the female dotal recitations of personal experiences or the outcome of population whose breasts contain a spectrum of aberrations, more abstruse circumstances? How are future changes apt to among which are the detected cancers (Fig. 1). occur? Are we to believe that science has little or nothing to do At the top of the spectrum (Fig. 1/4) are women whose breasts with the process? contain invasive and noninvasive cancers of sufficient size to be Science will continue to determine how breast cancer is detected clinically. In that same category are women with perceived and managed in the future. Clinical practice must be palpable benign lesions considered to carry no added risk, as based on a rational foundation that underlies our comprehen well as those whose breasts contain lesions that put them at sion of the disease; this understanding relates to the "science" increased risk for invasive cancer, e.g., atypical ductal or lobular of the time in which we practice. The science of breast cancer hyperplasia, and florid or solid papillary hyperplasia. Near this in 1992 is different from that of 1892, and the science of breast end of the spectrum (Fig. \B) are women with abnormal breasts cancer in the next decade will differ from that of today. As the harboring lesions similar to those above that can be detected burgeoning science of molecular biology unfolds, it is unrealistic only by mammography. Among those with "normal" breasts in to expect that operative procedures and systemic therapy mo the middle of the spectrum (Fig. 1C) are women with the dalities now used to treat breast cancer will remain static, any previously described lesions that are nondetectable but, if ma more than it could have been assumed that surgery would lignant, are likely to eventually become clinically or mammo- remain unchanged during the past century, given the changes graphically identifiable. Near the bottom of the schema (Fig. in our understanding of the disease during that time. ID) are women, considered normal, who may have breast tissue The increased use of mammography and recent advances in that has undergone biological alteration, a term used to encom basic tumor biology (particularly as they relate to cancer etiol pass molecular-biologic, genetic, and biochemical factors that ogy) have resulted in an expanded perception of the breast may play a seminal role in the etiology of invasive breast cancer. cancer problem. This essay will describe how breast cancer If modern concepts of carcinogenesis as they relate to the therapy has evolved and will continue to advance as a conse process of initiation and promotion are applicable to breast quence of transitions from paradigm to paradigm. It will also cancer, there is reason to believe that there are women within present several scientific developments that have the potential the so-called normal population who have "biological breast for creating new paradigms for breast cancer management in cancers." These lesions have not yet become what we recognize the not too distant future. How adequately past, present, and under the microscope as cancers (phenotypic), but they have future paradigms relate to the currently expanding view of the undergone molecular-biologic changes that will result in tumors disease is also considered. that may, at some future time, be diagnosed by current clinical An Expanded Perception of the Breast Cancer Problem. In and mammographie methods. It is here that a single normal 1969, 66,000 new cases of breast cancer were diagnosed and cell is "emancipated" from host controls and thatâ€”as a result 29,000 women died from the disease. By 1975 there were 88,000 of its altered growth regulationâ€”the resulting neoplastic stem new cases and 33,000 deaths, with 1 in 14 women at risk for cell gives rise to a clone of tumor cells. These phenomena and developing the disease. During the 1990s, more than 1.7 million those that follow depend upon a series of complex events women (about 175,000 per year) in the United States will be involving alterations in cellular oncogenes, tumor suppressor newly diagnosed with invasive breast cancer, and about 30% of genes, gene products, and growth factors that can augment or them will ultimately die from it; approximately 1 in 9 women inhibit cell proliferation, and related activities (3-5). As neo plastic growth progresses, new mutations occur and new clones, Received 12/3/91 ; accepted 2/27/92. ' The laboratory and clinical investigations referred to in this publication were which have a growth advantage over their predecessors, appear. supported by USPHS grants from the National Cancer Institute and by grants At some point, genetic alterations may occur which give rise to from the American Cancer Society. 2To whom requests for reprints should be addressed, at National Surgical cells that have acquired competence for establishing mÃ©tastases. Adjuvant Breast and Bowel Project Headquarters. Room 914, Scaife Hall, 3550 Early in the onset of a tumor, angiogenesis, an event necessary Terrace Street. Pittsburgh. PA 15261. for tumor progression, takes place. (6) At the bottom of the 2371

breast cancer, I became familiar with the work of Thomas KÃ¼hn,a theoretical physicist, philosopher, and historian of science, who described the developmental pathways of physical sciences as transitions from paradigm to paradigm which occur as a result of scientific revolutions (7, 8). KÃ¼hnandothers who have discussed the evolutionary process of science have not given meaningful consideration to how radical changes take place in biology and medicine (9, 10). Some theorists, in fact, contend that Kuhnian revolutions do not occur at all in these â€¢¿Â®Â°oOx^0Â®Â® sciences (11). Others dispute that perspective (12). It is my 2 contention that Kuhn's interpretation of the nature of scientific en9en l1BIOLOGICALCHANGES-".S 00 LU< â€¢¿CD OÂ®"â€¢"O â€¢¿Â»0O -JCE .'. revolution is directly relevant to medicine and that his descrip ~jm QQ*Ã‰uÂ°- tion of the pathway of paradigmatic change can be used to -(GENEGENOTYPIC ALTERATION, illustrate how the treatment of breast cancer has evolved to its â€¢¿.FÂ®*Ã´ â€¢¿*â€¢' "â€¢ DNAetc.)"NO"CHANGES(AT DAMAGE, ujz present state. (I hasten to point out that, although retrospec 9"gzc tively relating progress in medical science to a particular schema FORBREASTRISK CANCER)C is legitimate, following the steps comprising that pathway does not necessarily guarantee success in obtaining new knowledge.) Fig. 1. Spectrum of changes in women with normal and abnormal breasts. â€¢¿, invasive cancers; O, in situ cancers (DCIS, LCIS); Â®,hyperplasia, atypical hyperplasia, sclerosing adenosis; â€¢¿,biologicalcancers; x, fibroadenomas, simple cysts, adenosis, duct ectasia. Developmental Pathways of Science The Transition from Paradigm to Paradigm According to spectrum (Fig. IE) are women who may have no phenotypically KÃ¼hn.Atsome time in history, according to KÃ¼hn,ascientific expressed lesions and no biological changes in their breasts. community acknowledges the existence of scientific achieve These women, despite putatively normal breasts, are at risk for ments so unprecedented that they attract an increasing number of adherents away from the model that governs the community's developing breast cancer even though they may have no defin able risk factors. Although the spectrum depicts a change that activity (Fig. 2). For a time, the new science serves as a foun dation for the practice of these "converts." The model governing could exist in the breast of a particular woman at a particular time, it fails to convey the dynamics of the change that occurs their activity is called a paradigm, a term used to encompass "all of the beliefs, values, and techniques shared by members of over time. It does not indicate how the stepwise progression of a [scientific] community" (7). Although a paradigm is accepted a lesion that travels from one end of the spectrum to the other is instigated or show how much time elapses between the first because it seems better than its competitors, it seldom explains change that gives rise to a cancer and the presence of a cancer all of the enigmas that confront it. Consequently, it provides a that can be detected. variety of problems that must be resolved by its adherents. To The growth rate of a tumor before its clinical detection is do so, they resort to a circumstance known as normal science, obscure, and information regarding its growth after detection which flourishes as long as the paradigm is the exemplar that is imprecise. Doubling times of clinically identifiable tumors governs the activity of the community. Most of the research have been estimated to be between 75 and 130 days. If 100 days conducted by a scientific community is normal science, its aim is selected as the doubling time, and if, as is commonly stated, being to define more precisely the attributes of a paradigm and 1 x IO9cells is the minimum tumor burden required for clinical to make it more acceptable. Such "mopping-up" activities are mainly fact-gathering endeavors carried out by experimentation detection, the time from tumor onset to diagnosis is assumed to span at least 30 tumor doublings, or approximately 8 years. and observation to resolve ambiguities and solve the problems Thus, if the annual rate of detection of invasive cancers is generated by the paradigm. 175,000 new cases, there could be at least a million women in Sooner or later during these investigations, anomalies occur this country with nondetectable biological and pathological breast cancer who are unaware that they have the disease. As a result of this expanded perspective of breast cancer, it seems appropriate to ask, What might be considered early breast cancer? Does "earliness" relate to tumor size? To nodal status? To occult tumors detected by mammography? To noninvasive cancers? To certain molecular-genetic alterations that have taken place but that are, as yet, unidentifiable? To tumors with markers associated with a favorable prognosis? To cancers in women who have lived tumor-free, for example, for 30 years after their removal (a circumstance that gives rise to the well- known pronouncement, "It was gotten early")? Increasing knowledge prohibits formulation of a simple definition of the term early. Consequently, use of the term requires more circum spection than is usual, particularly in a court of law, where punitive action is brought against physicians for failing to treat patients when their tumors were "early." Almost a decade ago, while attempting to put into perspective my 30 years of research vis-Ã -vischanges in the treatment of Fig. 2. The developmental pathways of physical science according to KÃ¼hn. 2312

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER or results from unrelated scientific efforts are reported. These â€¢¿DEDUCTION" give rise to doubt regarding the merit of the paradigm. The NON TESTABLE | awareness by paradigm adherents that "something has gone wrong" results in a crisis, which precedes a scientific revolution. H TESTABLE I KÃ¼hnuses the term revolution because of the similarities be tween the conditions that exist before scientific upheavals and I EXPERIMENTALMETHODOLOGY]"' ' the circumstances that precede political revolutions. In the CLINICAL latter, one segment of society defends the status quo, another TRIALS attempts to introduce a new order, and society is not governed at all. A similar circumstance occurs in scientific revolutions. INFORMATION TO: â€¢¿REJECT When one paradigm competes with another, individuals express â€¢¿MODIFY their uncertainty, discontent, and disillusionment by displaying a willingness to improvise, by trying strategies that may have previously been considered inappropriate, and by engaging in endless debate. The process of paradigmatic change is repetitive. While it is unlikely that one paradigm will ever be completely accepted Fig. i. The inductivist and deductivist origins of past and present breast cancer before another takes its place, a scientific community can be paradigms. governed by only a single paradigm. To reject one is a decision to accept another. To reject one without substituting another is than to the plethora of anecdotal reports of inductivist-gener- to reject science itself, since a paradigm is based on science and ated findings, which result only in clinical confusion. to acknowledge a change in science without accepting the It is important to point out that one of the major deficiencies paradigm that arose from that change is illogical. These truisms in our knowledge of breast cancer relates to the fact that so account for much of the perceived confusion that exists in much of how the disease is perceived comes from information breast cancer management. on demographics, natural history, biology, and treatment ob Despite his emphasis on the importance of scientific achieve tained from patients with tumors large enough to be detected ment in the development of a paradigm, KÃ¼hnfailsto consider by clinical examination and by mammography, i.e., those with how historic scenarios depicting the scientific method relate to end-stage or near end-stage disease (Fig. 1, A and B). Because the science that inspires the paradigm. Although it might be studies designed to test the hypotheses upon which current inappropriate to consider such a connection in the physical paradigms are based were conducted almost exclusively in sciences, there is justification for noting such an association in women with disease at that stage, these paradigms govern the the biological sciences, particularly in medicine. Because a treatment of women with clinically detectable cancers. paradigm governs the activity of the members of a given [sci With the above information as background, it is appropriate entific] community, it is important to examine its origins in to examine how the Kuhnian pathway relates to the evolution order to estimate the credibility of the science that went into of paradigms that currently govern the management of breast its construction (Fig. 3). Was that science a product of inductive cancer. reasoning, as described by Francis Bacon in the early seven teenth century and John Stuart Mill in the nineteenth, or was Paradigms Governing Breast Cancer Management it the result of hypothesis-testing by rigorous experimentation, i.e., deduction, as advocated by Claude Bernard over a hundred The First Surgical Paradigm. This paradigm originated when years ago? The late Sir Peter Medawar aptly stated, "Induction William S. Halsted combined the features of various operations is the arguing from the particular to the general" (13). It is a devised in the late eighteenth century (15) into one operation scheme of reasoning in which ideas, observations, results of that became known in 1890-1891 as the Halsted radical mas experiments, and anecdotal experiences give rise to general tectomy (16-19). Evidence indicating the success ofthat oper statements that do more than summarize the information im ation was derived over the next half-century from anecdotal parted by the data; according to Medawar, "it expands our reports of observational information, i.e., Baconian inductiv- pretensions to knowledge" (13). In the view of the inductivist, ism. Halsted's writings indicate, however, that there may have this enlargement of experience leads to an enlargement of been some biological justification for his efforts. He was influ understanding. Such a misconception continues to plague phy enced by W. Sampson Handley, who contended that cancer of sicians who attach more significance to anecdotal experience the breast spread by extension along lymphatic pathways, pre than is justified. serving continuity with the original growth (20). Handley be Bernard, the French physiologist who focused attention on lieved that tumor permeated, not metastasized to, distant sites deductive scientific research, wrote: "A hypothesis is ... the such as bone, that the bloodstream was of little significance as obligatory starting point of all experimental reasoning," and he a pathway for mÃ©tastases,and that regional lymph nodes were insisted that a hypothesis is of value only if it can be tested an effective barrier to the passage of tumor cells (21). (14). Such testing must be carried out by appropriate experi The anatomical and mechanistic basis for Halstedian cancer ments conducted in the laboratory or, more recently, within surgery gave rise to the "proper" cancer operation, which con randomized clinical trials. These mechanisms provide infor sisted of removing a primary tumor, regional lymphatics, and mation that can lead to rejection, modification, or support of lymph nodes by en bloc dissectionâ€”the hallmark of the oper the hypothesis. The greater the number of investigations that ation. Because cancer was believed to be a local-regional disease, support a hypothesis, the more credible it becomes and the it was considered more curable if the surgeon was more expan more likely that a new paradigm will result. More attention sive in his interpretation of what constituted the "region." must be given to the results obtained from testing a hypothesis Moreover, this concept was time-oriented, and the management 2373

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER of breast cancer was an "emergency." The concept gave rise to answer all of the questions it posed and because no anomalies the Halstedian paradigm, which, for almost a century, governed arose to challenge its tenets. the management not only of breast cancer but of most solid Origin and Development of the Current Surgical Paradigm. If tumors as well (15). the first surgical paradigm was related to tumor growth and It is appropriate to designate Halsted's efforts as a paradigm spread, new knowledge questioning that facet of tumor biology as defined by KÃ¼hnbecause it arose from beliefs, techniques, might have been expected to challenge the reigning paradigm. and achievements that attracted an ever-widening group of Such was, indeed, the case. During the 1950s and 1960s, new adherents. It became universally accepted because of lack of perceptions of metastatic mechanisms arose. Our contributions, competition and because proponents indoctrinated succeeding as well as those of others, led us to formulate a new hypothesis generations, who adopted it without qualification. It is not regarding tumor mÃ©tastasesand to test our theory in several surprising that it remained intact for a protracted period despite clinical trials. what, in retrospect, might be viewed as weakness in its scientific When we began our studies in the late 1950s, the prevailing origins. theory was that lymph-borne tumor cells had one destinationâ€” the lymph nodesâ€”that tumor cells in the blood vascular system The Halstedian paradigm provided an abundance of problems to be resolved. Normal science flourished. Almost all efforts lodged in the first capillary bed they encountered, and that were directed toward formulating a more precise definition of tumor cells disseminated in an orderly pattern based upon the operative procedure (15). Arguments, still considered re temporal and mechanical considerations. Our findings 26 years spectable today in some circles, related to how thin skin flaps ago indicated that the blood and lymphatic systems are so should be, how extensive an axillary dissection should be carried interrelated that it is impractical to consider them as independ out, and whether supraclavicular and/or internal mammary ent routes of neoplastic dissemination, a major departure from nodes should be removed. Expansion of the operation was in the theory of tumor cell dissemination at the time (22, 23). We keeping with the hypothesis. Super-radical surgery, more ade proposed that mÃ©tastasesare not dictated only by anatomical quately than the radical mastectomy, embodied the principles considerations but are, instead, influenced by intrinsic factors in tumor cells and by the organs to which they gain access, a on which the hypothesis was based. Aside from the fact that thesis supported and broadened by recent expansion of knowl more expansive operations neither provided a basis for chal lenging Halsted's principles nor aided in the understanding of edge in molecular biology. Consequently, we proposed that tumor cells are not spread in an orderly pattern, a theory the disease, the technical aspects of the operation were beyond contrary to that which provided the basis for the Halstedian the average surgeon, since he was without the support systems necessary to perform them. For these reasons, super-radical paradigm. Our experiments reported in 1966 revealed for the first time surgery did not attract enough converts and, thus, failed to (24) that RLNs3 are not an effective barrier to tumor cell replace radical mastectomy. dissemination, as Virchow proposed in 1863 (21). In the 1960s The Halstedian paradigm also dictated radiation therapy. It we adopted the thesis that the RLN is an indicator of host- was believed that, because residual tumor cells could be de tumor relations and that negative nodes reflect conditions that stroyed by radiation therapy, regional irradiation following inhibit the occurrence of mÃ©tastaseselsewhere, whereas positive mastectomy had a greater likelihood of effecting a cure than lymph nodes indicate an interrelationship between host and did mastectomy alone. Less extensive operations, such as mod- tumor that permits the development of distant mÃ©tastases. ified-radical and simple mastectomy, followed by irradiation, Thus, RLNs are not the instigators of distant disease. To were done because some believed that they better fulfilled consider RLNs merely as mechanical receptacles for tumor Halstedian principles or because of frustration with the inability cells and way stations for further dissemination is an anachron of radical mastectomy to cure more patients. The same dissat ism (25, 26). isfaction provided a rationale for performing breast-conserving Our findings failed to coincide with the prevailing theory of operations followed by irradiation. Sporadic reports demon metastatic mechanisms that provided justification for the Hal strated that patients could, indeed, survive disease-free for many stedian paradigm. Consequently, based on our concept of tumor years after breast-preserving surgery. However, because the dissemination, which differed from that of Halsted, we formu practice of local tumor excision was not based upon any new lated a hypothesis proposing a biological basis for breast cancer biological principles, because no studies had been conducted to treatment that was antithetical to the mechanistic principles compare the merits of this operation with more radical proce upon which surgery and radiation therapy were based (27). Our dures, and because proponents of the Halstedian paradigm hypothesis contends that operable breast cancer is a systemic could see no reason to replace the mastectomy with it, breast disease involving a complex spectrum of host-tumor interrela conservation failed to receive adequate support. tions and that variations in local-regional therapy are unlikely As in the first half of the twentieth century, normal science to affect survival. Unlike Halsted's, our theory is not time between 1945 and 1970 was concerned primarily with "fine- oriented. (Although many of these concepts may be self-evident tuning" the Halstedian paradigm (15). New principles of host today, such was not the case in the 1950s and 1960s.) and tumor biology were noticeably absent (the concept of breast As noted, hypothesis-testing is an integral facet of the scien cancer as a systemic disease remained obscure), and, as a result, tific method and is necessary in order to support or reject a no new exemplar surfaced to attract a sufficient number of theory. While the Halstedian hypothesis was accepted without surgeons away from the Halstedian paradigm. Disagreements such testing, we have had the opportunity to conduct two that occurred among disciples of the same paradigm were clinical trials not only to obtain data regarding the credibility related not to the paradigm itself but to variations in nuances of our hypothesis but also to provide information regarding the of treatment proposed to strengthen it. When the era is viewed 3The abbreviations used are: RLN, regional lymph node; NSABP, National in retrospect, it appears that the Halstedian paradigm persisted Surgical Adjuvant Breast and Bowel Project; IBTR. ipsilateral breast tumor so long because the normal science associated with it failed to recurrence; ER, estrogen receptor; DCIS. duct carcinoma in situ. 2374

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER justification for continuing to use Halstedian principles of Halstedian paradigm are being ruled by the science of a previous cancer surgery. The first trial (NSABP B-04), implemented in era. In that regard, it is important to emphasize that the 1971, evaluated the outcome of patients having invasive breast lumpectomy is an operation that has abandoned every principle cancer and no clinical evidence of axillary node involvement. of the Halstedian paradigm. In the lumpectomy, the surgeon In that trial, almost 1700 women were randomized among three removes only an amount of normal breast tissue necessary to different treatment regimens: conventional Halstedian radical provide tumor-free specimen margins as demonstrated by the mastectomy, total (simple) mastectomy with local-regional ir pathologist. The aim is to ensure that gross tumor is not left radiation but no axillary dissection, or total mastectomy with unremoved. A lumpectomy is completely different from a quad- no irradiation and removal of axillary nodes only if they became rantectomy. The latter is a procedure that continues to embody clinically positive. The significant aspect of that study was that the principles of the Halstedian paradigm, i.e., it employs en 40% of the patients treated by radical mastectomy had histo- bloc dissection and removal of the pectoralis minor muscle and logically positive nodes. Thus, about 40% of those in the other fascia (33). It is either an effort to compromise by using prin two groups had positive axillary nodes that were not removed. ciples of both paradigms simultaneously, which is antithetical Despite the therapeutic nonconformity and the fact that positive to Kuhn's principle that a scientific community can be governed nodes were unremoved, no significant difference in overall by only a single paradigm, or it is a procedure aimed at fine- treatment failure, distant metastasis, or survival was noted tuning the Halstedian paradigm. among the three groups after more than 14 years of follow-up The new breast cancer paradigm has introduced a new set of (28-30). These findings supported our alternative hypothesis problems requiring resolution to strengthen its tenets. Normal and corroborated our long-held contention that tumor-bearing science has become active. Technical questions about how much nodes are "indicators," not "instigators," of metastatic disease. normal breast should be removed in a lumpectomy, whether Because the findings from B-04 negated the radical mastec breast irradiation is necessary for all patients, whether certain tomy and its principles, they provoked uncertainty about the tumor characteristics or host factors preclude the conduct of a merits of the Halstedian paradigm as an exemplar for breast lumpectomy, and whether systemic chemotherapy will reduce cancer therapy and, thus, provided the impetus for a Kuhnian the incidence of postlumpectomy breast recurrence have be crisis, which resulted in aberrant responses among disciples of come the object of study. Differences that have occurred in the Halstedian paradigm. Of primary importance, the findings studies conducted to resolve these issues are not to be construed eliminated most of the biological considerations that might as uncertainties regarding the credibility of the paradigm. have contraindicated evaluating breast-conserving operations. A recently conducted investigation, which is part of the Until that time, any justification for breast preservation had normal science associated with the new paradigm, has produced been based upon arguments derived from anecdotal experiences. important findings regarding the significance of an IBTR fol To reevaluate our hypothesis and, at the same time, appraise lowing lumpectomy (32). This study was carried out to address the worth of lumpectomy and axillary dissection, we initiated a the reluctance of many physicians to accept the lumpectomy. second trial (NSABP B-06) in 1976. In that study, nearly 2000 Despite the similarity in distant disease-free survival and sur women were randomly assigned to total mastectomy, lumpec vival between lumpectomy and mastectomy patients, many tomy alone, or lumpectomy followed by breast irradiation. All physicians feared that patients treated by lumpectomy who had axillary dissection. After more than 9 years of follow-up, subsequently developed an IBTR would be at increased risk for despite the fact that 43% of the women treated by lumpectomy distant mÃ©tastasesbecause any tumor that might not be re without breast irradiation and 12% of those who underwent moved during the primary operation would grow and dissemi lumpectomy and breast irradiation experienced an IBTR, there nate cancer cells during the time between the operation and was no significant difference in distant disease-free survival or recognition of the IBTR. (These physicians are still disciples of survival among the three groups (31, 32). (Obviously, none of the Halstedian paradigm.) Our findings, recently reported, in the women treated by total mastectomy had an IBTR.) This led dicate that, with the diagnosis of an IBTR after lumpectomy, a to the conclusion that no causal relation exists between an patient is, indeed, at increased risk for distant disease (3.41 IBTR and distant disease or survival, a finding similar to that times greater) than she was before the IBTR was recognized, described for axillary node involvement in B-04. Most impor but this increased risk is not because of disseminated tumor tant, the B-06 findings further supported the biological princi cells that could have been avoided had a mastectomy been ples that had resulted in the formulation of the alternative performed. An IBTR is a marker of a risk for distant disease hypothesis and provided justification for lumpectomy. Because present at the time of primary tumor removal, and that risk of these changes, even more physicians began to doubt the merit would have been the same even if radical surgery had been of the Halstedian paradigm. Thus, the crisis that arose after carried out initially. Mastectomy or breast irradiation after publication of the B-04 findings expanded and became a Kuhn lumpectomy eliminates or reduces the opportunity for identifi ian revolution. A rÃ©Ã©valuationofprior fact had necessitated a cation of a marker of risk (an IBTR) for distant disease but restructuring of prior theory. does not reduce the development of distant disease. The rela With the erosion of the Halstedian paradigm, many of its tionship of an IBTR to distant metastatic disease is analogous disciples (as well as those yet uncommitted to any paradigm) to that of a woman without breast cancer who learns on one accepted the validity of the B-04 and B-06 findings, and a new particular day that her sister has been diagnosed with the paradigm for the management of breast cancer evolved. Evi disease. On that day, the "normal" sister becomes at greater dence to indicate that it has become established is inherent in risk for developing breast cancer than she was the day before, the statement issued after a NIH consensus conference in June even though her increased risk existed before her sister's diag 1990, when it was concluded that breast preservation is the nosis. Thus, although mastectomy and breast irradiation follow preferable treatment for women with stages I and II breast ing lumpectomy prevent expression of the marker, they do not cancer (1). To use Kuhn's analogy, it would seem that those lower the risk of distant disease any more than treating the currently governed in their treatment of breast cancer by the sister who has breast cancer with an effective preventive agent 2375

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER before she develops the disease would eliminate the risk of support to the hypothesis regarding the use of adjuvant therapy. breast cancer in her normal, untreated sibling. The results of As a consequence, a new paradigm governing the management this study strengthen the paradigm by providing information of breast cancer arose. Treating patients who were free of that confirms the biological nature of breast cancerâ€”particu identifiable metastatic disease with systemic adjuvant therapy larly as local recurrence relates to metastatic diseaseâ€”and because some of them might develop distant disease in the support our theory proposed more than two decades ago. More future was a revolutionary departure from prior treatment over, they continue to justify lumpectomy. strategy and became a new exemplar. In this section, I have demonstrated how a paradigmatic shift Further support for the validity of the systemic therapy has occurred in breast cancer management. I have indicated paradigm was provided by investigations demonstrating the how laboratory research in the biology of metastasis gave rise efficacy of the nonsteroidal antiestrogen tamoxifen (43-52). to a hypothesis that was tested by clinical trials and how the Subsequent to extensive study of that drug in experimental findings from these endeavors refuted the principles that re systems, and following its demonstrated benefit in patients with sulted in a paradigm that governed breast cancer management metastatic breast cancer, clinical trials were undertaken in for more than three-quarters of a century. With a shift in the Europe and the United States to evaluate tamoxifen alone or surgical paradigm and an increasing awareness over the past in combination with chemotherapy for the treatment of stages two decades that the curability of breast cancer relates to more I and II breast cancer. Two British randomized trials compared effective systemic therapy, greater emphasis has been given to the outcome of patients receiving no systemic therapy with that the use ofthat modality. The current systemic therapy paradigm of those receiving tamoxifen (43,44). By indicating that tamox has evolved in a manner similar to that described for the surgical ifen has an overall advantage that is independent of nodal, paradigms. menopausal, or ER status, findings from both trials aided in Origin and Development of the Current Systemic Therapy strengthening the paradigm. Paradigm. Observations in the mid-1950s indicated that cancer Normal science flourished. Laboratory and clinical investi cells could be found in the circulating blood during surgical gations were undertaken to answer questions about the use of removal of tumors (34) and that chemotherapeutic agents had systemic therapy. Clinical trials have been conducted to com a cytotoxic effect on disseminated tumor cells in experimental pare treatment regimens; to define optimal duration of therapy animals (35). These findings led to the hypothesis that adjuvant and/or drug dose; to evaluate timing and routes of drug admin chemotherapy would lower tumor recurrence and improve the istration; to determine the relation of host and tumor factors survival of breast cancer patients. That hypothesis was first (e.g., age, tumor size, hormone-receptor content, tumor growth tested in a clinical trial begun by the NSABP in 1958. The kinetic characteristics, markers of gene expression, and histo premise of this trial was that chemotherapy administered during lÃ³gica!type) to therapeutic response; and to assess the effect of and for a short period after operation would destroy tumor cells chemotherapy in conjunction with other modalities (radiation disseminated as a result of the surgery. Although study results therapy, hormonal agents, and biological response modifiers). demonstrated both a decrease in tumor recurrence and an As a result, information has accumulated which, on occasion, improvement in survival of premenopausal, node-positive pa has resulted in disagreement and even confusion among physi tients after 10 years of follow-up, disappointment with the cians who treat breast cancer patients. It is often not appreciated overall findings led to the conclusion that the hypothesis had that these responses are not the result of anomalies that weaken not been supported (36). Consequently, aside from a few excep the credibility of the paradigm but, rather, the consequence of tions, practitioners were not attracted to systemic adjuvant investigations conducted to strengthen it. Evidence to indicate therapy, and, therefore, no paradigm arose to govern its use. that the systemic therapy paradigm is firmly entrenched is best Nevertheless, the observations obtained from this trial are exemplified by the results obtained from systematic overviews important. They provided the first evidence that the natural of findings from multiple trials (meta-analyses) (51) and by history of breast cancer could be perturbed by adjuvant chemo conclusions from several consensus conferences conducted by therapy and that there were differences in the response of the NIH. patient cohorts to a therapyâ€”a prediction of future findings. NIH consensus conferences held in 1985 (53) and 1990 (1) Subsequent events revealed that the original hypothesis was lent support to the paradigm when they concluded that adjuvant valid but that the premise upon which the trial was based was chemotherapy and hormonal therapy are effective treatments inappropriate. The eradication of surgically disseminated tumor for breast cancer patients. Considerable evidence was provided cells was probably less important than the response of existing to justify the use of chemotherapy in premenopausal and post- micrometastases to cytotoxic agents. menopausal patients who were node-negative and had ER- Mendelsohn in 1960 (37) and Skipper and associates in the negative tumors. Premenopausal and postmenopausal women early 1970s (38-40) defined the concept of a growth fraction in with node-negative, ER-positive tumors also benefited from a tumor cell population and provided an array of tumor growth tamoxifen. It was recommended that established combination kinetic principles that were instrumental in formulating a hy chemotherapy be used for the treatment of premenopausal pothesis that postulated the value of adjuvant chemotherapy. women with positive nodes, regardless of their tumor hormone The first trial to evaluate adjuvant therapy and to test this receptor status. For postmenopausal women with positive nodes hypothesis was begun by the NSABP in 1971. In that study, L- and positive tumor hormone receptor levels, tamoxifen has phenylalanine mustard was administered after radical mastec become the treatment of choice. Recently, however, the addition tomy to patients with positive axillary nodes. The results, of chemotherapy to tamoxifen has been found to be more reported in 1975, indicated that such therapy could alter the effective than tamoxifen alone in postmenopausal patients with natural history of patients with primary breast cancer (41). That positive nodes and ER-positive tumors (54). Chemotherapy has conclusion was confirmed by findings from the Milan study, been recommended for the treatment of postmenopausal pa carried out by Bonadonna and associates using cyclophospha- tients with positive nodes and ER-negative tumors. An overview mide, methotrexate, and 5-fluorouracil (42). Both trials lent of 61 randomized trials among 28,896 women conducted by 2376

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER the Early Breast Cancer Trialists' Collaborative Group dem By 1987, clinical information and several hypotheses derived onstrated reductions in mortality due to treatment when ta- from biological studies provided justification for the conduct of moxifen was compared with no tamoxifen or when any chemo a trial (NSABP B-18) to evaluate the worth of preoperative therapy was compared with no chemotherapy (51). chemotherapy for the treatment of stages I and II breast cancer. Although adjuvant therapy has not cured all patientsâ€”or Almost all of the clinical findings have come from the use of even all patients within a defined cohortâ€”and is often accom such therapy in the treatment of head and neck tumors (57), panied by toxicity, there have been sufficient benefits to justify esophageal tumors (58), osteosarcoma (59), and locally ad its use. Until new modalities demonstrate greater efficacy, it is vanced (stage III) breast cancers (60). Of particular importance appropriate to treat patients according to the current systemic was the National Cancer Institute study in stage III breast therapy paradigm. As previously noted, to abandon the para cancer patients treated with a complex preoperative chemo digm without a replacement is to abandon science. Current therapy regimen (61). A complete response occurred in 50% dissatisfaction with the use of systemic therapy is similar to and a partial response in 40% of breast tumors. (The study was that expressed in the era of the radical mastectomy and to that conducted not to evaluate preoperative chemotherapy but to now being voiced by some regarding lumpectomy. ascertain the value of cell synchronization in conjunction with In summary, the treatment of breast cancer is currently being chemotherapy.) Several groups of investigators have evaluated governed by two independent paradigms. One is concerned with or are investigating preoperative therapy in patients with op eradicating local manifestations of the disease without compro erable (stages I and II) breast cancer (62-64). In the Milan mising prospects for cure while maintaining the best possible study (64), which was not a randomized trial, preoperative cosmesis. The other serves as the exemplar for the eradication chemotherapy was administered to women with breast cancer of systemic disease. who were candidates for mastectomy because the largest di It is highly unlikely that either paradigm will endure for a ameter of their tumors was >3 cm. The aim was to reduce the protracted period of time. Laboratory and clinical research is size of the tumors so that these women might be treated by expanding knowledge so rapidly that the half-life of perma breast conservation instead of mastectomy. Sufficient "tumor nency is becoming shorter and shorter! The following section shrinkage" was reported to have occurred in 127 of 157 women, is a commentary on current investigative efforts that have the allowing for breast preservation. It is of interest that 79% of potential for either altering currently entrenched paradigms or the patients had tumors <5 cm, a size that, according to NSABP for creating new paradigms for breast cancer management. criteria, would have made them initially eligible for lumpec tomy. This study, and all others using preoperative chemother Preludes to New Paradigms apy, failed to determine whether such therapy more effectively controls disseminated disease than does the same therapy ad One pathway of current breast cancer investigation relates to ministered postoperatively. the development of progressively more effective regimens for One of the hypotheses that justified our study relates to the treatment of clinically detectable disease. New therapeutic concepts promulgated by Skipper in the 1970s (38-40); among modalities such as taxol (a complex natural product derived these were propositions suggesting that responses of primary from the bark of the Pacific yew tree), antigrowth factors, and metastatic tumors to chemotherapy may differ. None of immunomodulators, or tumor-infiltrating lymphocytes may the numerous trials conducted since that time were designed to one day require evaluation by means of large clinical trials (55). confirm or reject the tenets of the Skipper hypothesis. If the Tumor-infiltrating lymphocytes, for example, may be used to principles of this hypothesis are supported by our study, failure introduce cytotoxic agents like tumor necrosis factor directly to observe a complete or partial primary tumor response to to tumor cells or to genetically alter tumor cells in order to chemotherapy may not necessarily portend a lack of control of suppress their growth. Such approaches may be tested alone or distant disease. in conjunction with current and new chemotherapeutic agents Another theory that provides a biological rationale for eval and hormonal therapies of proven value. Studies evaluating uating preoperative therapy was formulated from findings ob methodologies for overcoming drug resistance and for modu tained in experimental systems which indicate that primary lating the action of chemotherapeutic agents based upon phar tumor removal affects the growth kinetics of mÃ©tastases.Our macological principles are in progress, as is the testing of investigations and those of others have demonstrated that, after currently available modalities in novel ways. Examples of the removal of a primary tumor, an increase in the labeling index latter are two interrelated NSABP trials now under way; one of a distant tumor focus occurs, resulting in an increase in evaluates the worth of preoperative (neoadjuvant) chemother tumor size (65). We have determined that the stimulation of apy, and the other tests the worth of dose intensification and/ cell growth after removal of the tumor is due to the presence of or increased total dose of chemotherapy. Findings from these a serum growth factor (66) and that chemotherapy, tamoxifen, studies could result in another paradigmatic shiftâ€”the creation or radiation therapy given before the operation prevents the of a unified paradigmâ€”which could profoundly alter current kinetic perturbation (67). Consequently, these agents more breast cancer management. effectively suppress tumor growth and prolong survival than The Creation of a Unified Paradigm. In 1975, after demon when they are administered after removal of the tumor. strating that adjuvant chemotherapy was effective in eradicating A third hypothesis providing justification for testing preop occult distant mÃ©tastases,we conjectured that the use of such erative chemotherapy proposes that, as a tumor cell population therapy would permit less extensive surgical procedures (56). It increases, an ever-expanding number of drug-resistant pheno- seemed reasonable to predict that, as systemic therapy im typic variants that are more difficult to eradicate arise due to proved, the surgical and adjuvant chemotherapy paradigms spontaneous mutation. This thesis maintains that the increase would eventually unite and become a single "unified" exemplar in resistant cells can be minimized by administering combina and that surgery, as a result, would partially or even completely tions of non-cross-resistant drugs as soon as possible, i.e., when disappear from use. a tumor population contains the fewest number of cells (68). 2377

As a result of these hypotheses and the available clinical The Creation of a Paradigm for the Treatment of Noninvasive information, in October 1988, the NSABP implemented a study Cancer. Because, as has already been indicated, almost all (B-18) to determine whether (a) preoperative chemotherapy knowledge about invasive and noninvasive breast cancer has, will more effectively prevent tumor recurrence and prolong until recently, been obtained from patients with clinically de survival than does the same therapy administered postopera- tectable tumors, physicians are at a disadvantage when called tively, (b) the primary tumor response to preoperative chemo upon to make decisions about the management of occult can therapy correlates with the prevention of recurrence and pro cers, particularly those that are noninvasive. The present con longation of survival, (e) preoperative chemotherapy will permit fusion about how best to treat DCIS is due to the fact that there more conservative surgery and decrease the incidence of IBTR is insufficient biological and natural history information to following lumpectomy, and (d) downstaging of axillary nodal formulate a paradigm that governs the treatment of the type of status will occur. More than 1100 patients with operable breast DCIS currently being detected with increasing frequency by cancer, all diagnosed by fine-needle aspiration or core biopsy, mammography. The Halstedian paradigm is inappropriate, and have been randomized to receive either operation followed by the new surgical paradigm advocating lumpectomy has not been systemic therapy or the same systemic therapy followed by fully accepted. As KÃ¼hnindicates, when such a situation occurs, operation. It is our view that, until information from this or anarchy is apt to exist. It is not uncommon for a patient with another large trial indicates that local-regional disease benefits DCIS to receive diverse recommendations for her treatment from the use of preoperative therapy are not accompanied by that range from unilateral or bilateral mastectomy with or an unfavorable distant disease-free survival and/or survival without axillary dissection to lumpectomy with or without outcome, this therapeutic approach should be limited to the breast irradiation. An incongruous situation has resulted. clinical trial setting. Whereas mastectomy is becoming less justifiable for treatment The second study conducted by the NSABP that has impli of invasive breast cancer, it is more often advocated for DCIS, cations for creating a unified paradigm was designed to deter the rationale being that the operation performed to prevent mine whether intensifying and/or increasing the total dose of a invasive breast cancer should be more radical than surgery demonstrated effective postoperative chemotherapy regimen performed to "cure" the disease. The turmoil regarding therapy will more effectively eradicate distant disease. In that trial, in is related to the absence of definitive information about the order to use higher doses of drug, colony-stimulating factor is frequency of synchronous or metachronous multicentricity or used in conjunction with the chemotherapy. If a greater benefit mult Â¡locality(in situ or invasive) in the ipsilateral or contralat- is obtained using high-dose therapy than has been observed eral breast associated with DCIS. In addition, it remains uncer following current "standard" doses of the same therapy, the tain how frequently multicentric or multifocal lesions become high-dose regimen will be administered preoperatively. If, as a clinically significant, whether DCIS is an obligatory preliminary consequence, a substantial number of patients show a reduction step in the development of invasive cancer, and whether all in primary tumor size and an improvement in distant disease- DCIS becomes invasive. Should the progression from DCIS to free survival and survival, a new paradigm, which unifies the invasive cancer relate to somatic genetic events, as is currently treatment of local, regional, and systemic disease, is likely to speculated, it becomes important to determine whether the become established. Even if a decrease in primary tumor size is changes can be monitored by any method other than histopa- unaccompanied by an improvement or a deficit in distant dis thology, e.g., oncogene expression. ease-free survival or survival, preoperative therapy would be In 1985 we instituted a clinical trial to obtain natural history justified if its administration permits the use of less extensive information that might address some of these issues. A second surgical procedures. In those cases where clinical and mam ary objective of the study was to test the hypothesis that, in mographie examinations indicate that preoperative chemother patients with localized DCIS which can be completely removed apy has completely eradicated a primary tumor, breast irradia by lumpectomy, the addition of postoperative breast irradiation tion without surgery after completion of the chemotherapy may would effectively prevent recurrence of the disease. While there be adequate to prevent breast tumor recurrence. is currently no definitive information to indicate that breast Despite its demonstrated benefit, how durable is a single irradiation either does or does not effectively eradicate DCIS, paradigm for breast cancer management that advocates preop there is indirect evidence from a variety of sources (69-74) to erative therapy? As more women are examined periodically indicate its possible value. with better mammographie equipment, more tumors will be After that study completed patient accrual, a second trial was identified when they are even more occult than those currently instituted using women with more extensive DCIS than that in being detected. Consequently, fewer women will have cancers women who were entered into the first study. That trial was for which the paradigm dictating the use of preoperative therapy conducted to test a hypothesis that relates to the prevention of applies. Because the natural history of patients with occult ipsilateral invasive breast cancers subsequent to treatment of tumors is uncertain, it is also unclear (although probably un DCIS by lumpectomy. The purpose for treating local or diffuse likely) whether systemic therapy, as it is currently used, should DCIS is to prevent such a lesion from progressing to invasive be used in their treatment. On the other hand, occult tumors cancer and to eliminate a focus of invasive cancer that might may be the ones that can be cured in all instances by such exist in conjunction with the DCIS. Although mastectomy therapy. Despite this uncertainty, the surgeon's role in the effectively accomplishes that goal, other strategies used with management of such patients will diminish and may even breast conservation may be equally effective. Because breast become obsolete. It is likely that the paradigm that will govern irradiation following lumpectomy for invasive cancer effectively the management of such lesions will be dominated by the prevents its recurrence, and because tamoxifen likewise inter radiologist, who detects the lesion, localizes it, removes cells feres with the development of invasive cancer in both the for cytological examination, and who, subsequent to patholog ipsilateral and contralateral breast, these modalities, used with ical examination, destroys it by a procedure such as laser breast conservation, may have a place in the management of therapy applied directly to the site of the lesion. DCIS, particularly in patients with extensive disease. 2378

Because experimental evidence supports the thesis that ta- hardly a testament to the current impact of mammography (1). moxifen possesses both antiinitiator (75) and antipromoter Another concern is that, after the removal of mammographi- capabilities (76, 77), that drug may inhibit the progression of cally diagnosed tumors too small to be detected clinically, DCIS to invasive cancer. Recent evidence that tamoxifen may women will be at increased risk for the development of second possess antiangiogenesis properties may be important, since it breast cancers and, thus, require continued surveillance. Most is postulated that angiogenesis is required for the progression frustrating is the realization that organized mammographie from noninvasive to invasive breast cancer (78). Thus, the programs with sophisticated equipment used on a regular basis hypothesis that governs our second study relates to the thesis by well-trained personnel are unlikely to be available to a that, with the use of tamoxifen and radiation therapy for substantial number of women in this country. The hundreds of eliminating associated invasive cancer, the clinical significance thousands of women worldwide who live with and die of breast of DCIS may become similar to that of atypical hyperplasia or cancer treated either in the most rudimentary way or not at all to that of a woman with a family history of breast cancer. because they lack access to health care are unlikely to be The findings from both of these studies are likely to provide benefactors of mammography. These comments are not to be the basis for formulating a paradigm to govern the treatment interpreted as criticisms of mammography; indeed, much of DCIS. Until then, it seems appropriate that the surgical greater effort must be directed toward promoting it. Such effort paradigm associated with the use of lumpectomy for the treat is justified, however, only if systems are available to properly ment of invasive breast cancer should govern the management treat women who have abnormalities detected as a consequence. of this disease. As is shown in Fig. 1, there is a time when a phenotypically Comments Regarding the Mammographie Detection of Occult, expressed breast cancer exists prior to its detection and, even Invasive Breast Cancer. As has already been pointed out, one before that, a time when cancer as we recognize it has not principal research strategy directed at making breast cancer a occurred, even though the molecular-genetic components for less significant public health problem is aimed at devising such an event may exist. Neither the two research strategies progressively better regimens for the systemic treatment of discussed herein nor current paradigms governing breast cancer clinically detectable disease. Another strategy is directed toward are apt to be relevant for patients with either biological or the identification of a greater number of nonclinically detecta occult, nondiagnosable cancers. ble, phenotypically expressed, occult, invasive breast cancers by A third investigative approach that might be contemplated is more widespread mammographie screening with the best meth one directed toward devising strategies capable of interfering odology currently available. This approach should result not with the initiation and/or the growth (promotion) of breast only in an increased incidence of breast cancer but also in a cancers so that they never become clinically or mammographi- change in the distribution of the size of tumors that are discov cally evident. Is now the time to consider implementing such a ered; i.e., the percentage of small cancers will increase. If current strategy? If so, has enough experimental and clinical informa thinking is correct, patients with tumors detected by mammog- tion been obtained to justify formulating a hypothesis that can raphy before their clinical appearance should be more curable be appropriately tested and that, if supported, could give rise after their tumors are removed. Theoretically, as this strategy to a new paradigmâ€”one that relates to prevention of the comes closer to achieving its goal, the first strategy becomes disease? The following section of this essay considers these less important, andâ€”taken to the extremeâ€”obsolete, since questions. clinically detected tumors would no longer exist. Current bio The Origins of a Breast Cancer Prevention Paradigm. There logical concepts indicate, however, that as a result of genetic is a consensus that enough information from laboratory and alteration some occult tumors detected by mammography have clinical investigations is available to permit the formulation of populations of cells that have already attained competence for a hypothesis which contends that an appropriate intervention successfully establishing mÃ©tastases,have not yet achieved that (such as a low-fat diet, retinoids, or tamoxifen) can prevent the capability but will do so as their cells continue to replicate, or occurrence of biological or phenotypically expressed breast will never demonstrate that capacity, even after they are de cancers. When deciding whether or not a particular agent tected by clinical examination. (A substantial proportion of should be evaluated in a cancer prevention study, there should patients with clinically detected cancers do not develop met- be evidence of its worth for preventing the initiation and/or astatic disease during their lifetime.) Thus, if current concepts promotion of undiagnosable breast cancer. While several can are correct, it would seem that the value or limitations of didates merit evaluation, one agent particularly worthy of ap mammography relate not so much to the number of clinically praisal is the nonsteroidal antiestrogen tamoxifen, currently the occult tumors detected as to the biological nature of the cells most widely prescribed antineoplastic agent used to treat breast in the tumors that are discovered. Perhaps, with more diligent cancer in the United States. An extensive body of literature use of better methodology than is now available, it will be exists on the pharmacokinetics. metabolism, and antitumor possible to detect and remove more tumors whose cells have effects of tamoxifen in experimental animals and in humansâ€” not yet undergone the biological changes required for them to results that provide support for evaluating the worth of that attain the metastatic capability that would occur if the tumors drug as a breast cancer preventive agent (79-82). Although were not recognized and not removed. tamoxifen acts as an estrogen antagonist, it may also act as a Pragmatic concerns exist about the extent to which mam partial-to-full agonist. The precise mechanism(s) by which it mography as an independent intervention is likely in the next achieves its antitumor effect are unknown. The drug appears to decade or so to become the paradigm for eliminating breast act primarily by competing with estradiol for receptor sites in cancer as a major health problem. Despite extensive encourage the cell nucleus, causing estrogen blockade that leads to growth ment of women to have mammograms, it is estimated that, in inhibition of malignant cells (83). Several alternative mecha the United States, of the new patients diagnosed with invasive nisms of action have been described. Tamoxifen may inhibit breast cancer in 1990, only 50% had stage I disease, whereas cell proliferation by modulating the production of transforming 20-25% demonstrated stage II and 20-25% stage III cancersâ€” growth factors (Â«and fi) that help regulate breast cancer cell 2379

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1992 American Association for Cancer Research. EVOLUTION OF PARADIGMS FOR THE MANAGEMENT OF BREAST CANCER proliferation (84); binding to cytoplasmic antiestrogenic bind related to the fact that age is one of the strongest risk factors; ing sites, increasing intracellular drug levels (85); increasing sex rates increase steeply from age 30 to 60 and then plateau. hormone-binding globulin, which may decrease the availability Moreover, postmenopausal women have a substantial and in of free estrogen for diffusion into tumor cells (86); increasing creasing risk of coronary artery disease. levels of natural killer cells (87); and decreasing circulating When the trial was in the planning stage, it became increas insulin-like growth factor 1 which may, in turn, modify the ingly evident that younger women should be included. Not only endocrinological regulation of breast cancer cell kinetics (88). does a sizable proportion of the morbidity and mortality of It has recently been reported that tamoxifen may act as an breast cancer occur in younger women, but there are also well- inhibitor of tumor angiogenesis (78). established risk factors for breast cancer in women under 60 Tamoxifen impairs tumor initiation. When laboratory ani mals were treated with it, carcinogen-induced mammary tumors that identify those with projected lifetime risks sufficiently great to merit their inclusion in the trial. Moreover, because years did not appear (75). Investigations using a variety of models may elapse between a tumor's inception and its detection, a have evaluated the effect of tamoxifen on tumor promotion and have shown that, when tamoxifen is given after a carcinogen preventive intervention may be more effective in women at an but before the appearance of a tumor, it prevents the occurrence early age, even though tumors may appear later in life. In that of a palpable tumor as long as administration of the drug is regard, women with a first-degree relative who had breast cancer maintained (76, 77). when premenopausal are apt to develop the disease at an earlier Studies have demonstrated a benefit from tamoxifen admin age. In premenopausal patients, tamoxifen appears to be more istration in the treatment of advanced breast cancer (89-92) effective in reducing the incidence of contralateral breast cancer, and in stages I and II disease when the drug has been used as life-threatening toxicity from the drug is rare, and non-life- postoperative adjuvant therapy (43-51). The significant reduc threatening toxicity is much the same as in postmenopausal tion in the incidence of cancers of the contralateral breast with patients. These observations support its use in younger women. tamoxifen is particularly relevant when it is considered as a In addition, because younger women at increased risk for breast preventive agent (43, 47, 93-95). cancer are often subjected to alternative therapies, such as The ideal tumor preventive agent should produce minimal bilateral mastectomies, which are worse than the side effects toxicity during prolonged therapy. Adverse reactions to tamox observed from tamoxifen, they should not be denied the oppor ifen are relatively rare and only infrequently severe enough to tunity to participate in the trial. Finally, the generalizability of require discontinuing treatment. Although doses of tamoxifen the findings would be seriously limited if premenopausal women many times greater than those given to humans have been found to increase the incidence of liver tumors in animals (96- were excluded from participation in the study. If a benefit was observed in a trial using only postmenopausal women, would 98), no such increase has been reported in humans treated with conventional doses (20 mg/day). It is likely that the risk of those findings justify use of the drug in a premenopausal thromboembolic events and endometrial cancer will be no population, or would another study involving many years of greater after prolonged tamoxifen administration than it is after uncertainty be required before it could be used? Thus, there is the use of estrogen-replacement therapy in normal women. ample evidence for allowing women aged 35-59 years who have When considering the use of tamoxifen as a breast cancer a substantially increased risk of breast cancer the option of preventive agent, its effect on coronary artery disease and participating in the study. osteoporosis cannot be ignored. Estrogen administration has A logistic regression model (107) will be used to estimate, by combining individual risk factors, each potential participant's been associated with an alteration in serum lipoproteins, i.e., a decrease in cholesterol and low-density lipoproteins with an composite risk of developing breast cancer. Her percentage increase in high-density lipoproteins and with decreased mor probability of developing breast cancer over her lifetime, ad tality from coronary artery disease. Tamoxifen results in similar justed for competing mortality risks by initial age and years of lipid changes (99-103). Thus, it may also favorably affect follow-up, will also be determined. The variables selected for mortality from that disease. Similarly, since estrogen lowers inclusion in the model are number of first-degree relatives with the incidence of fractures by decreasing the bone rÃ©sorption breast cancer, nulliparity or age at first live birth, number of that accompanies surgical or natural menopause (104,105), the benign breast biopsies, age at menarche, atypical hyperplasia, estrogen agonist effect of tamoxifen may prevent bone loss and lobular carcinoma in situ. (106). It has been estimated that osteoporosis affects 24 million If a benefit from tamoxifen is demonstrated, a drastic para women in the United States and that 1.3 million fractures occur digmatic change in the treatment of breast cancer could resultâ€” each year as a result. Consequently, a clinical trial conducted a change from current therapy, which is directed toward the to evaluate the worth of tamoxifen as a breast cancer preventive disease at or near end stage, to treatment of the disease when agent should concomitantly assess its effect in reducing mor it is nondetectable by any available means, and, perhaps, even tality from coronary artery disease and in decreasing the risk before phenotypic expression has occurred. Most significantly, of fractures due to osteoporosis. the impact of the findings from this trial on the health of Tamoxifen has been selected by the NSABP as the agent to evaluate in a prevention trial in which 16,000 women will be women in the United States and elsewhere could be substantial. randomized so that 8,000 will receive placebo and 8,000 ta It cannot be too emphatically emphasized, however, that the moxifen, both groups at 20 mg daily. The study population will implementation of a trial to evaluate the worth of a hypothe consist of women 60 years of age or older and those aged 35 to sisâ€”and an agentâ€”does not provide physicians with an impri 59 who have additional breast cancer risk factors, such that matur to administer, outside of the clinical trial setting, the their minimum predicted risk of developing breast cancer within therapy being tested in the trial. Before that can occur, the the next 5 years is at least as great as that of women aged 60 pathways of science must be carefully traversed and a new years or older. The choice of women 60 years of age or older is paradigm established. 2380

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2383

Bernard Fisher

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