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Trends in Primary Breast Cancer Management: Where Are We Going?
Breast Cancer: Strategies for the 1990s 11
0039-6109/90 $0.00
+ .20
Trends in Primary Breast Cancer Management Where Are We Going~
Michael Baum, ChM, FRCS, MD*
The treatment of cancer during any period in the history of medicine has not been based on the whim of a clinician but on the therapeutic consequences of the dominant biologic model of the disease. Until about 30 years ago, cancer treatments were applied according to an inductive paradigm of scientific philosophy. However, in recent years, clinicians have started to apply a falsificationist approach in the search for effective cancer therapy. A randomized controlled trial is the expression of this scientific process at work in clinical medicine. If used correctly, the randomized trial can initiate a hypothetical deductive cascade, which, in addition to testing the claims of competing therapies, is capable of generating new biologic hypotheses. I wish to illustrate this process by referring to 20 years of experience in the clinical trials concerning the treatment of primary carcinoma of the breast and extrapolating from this experience a flight of fantasy in anticipation of what might develop in the next 20 years.
ANATOMIC VERSUS BIOLOGIC MODEL OF BREAST CANCER .
Until the 1960s, the dominant biologic model of breast cancer was of a disease that spread centrifugally along anatomic pathways, with time being the only determinant of prognosis. It followed, therefore, that anatomically based radical operations would be the treatment of choice. Mortality rates from breast cancer remained stubbornly constant in spite of perfect anatomic dissections until a group of scientists proposed an alternative model of biologic determinism. This model suggested that the *Professor of Surgery, The Institute of Cancer Research and the Royal Marsden Hospital, London, England
Surgical Clinics of North America-Vol. 70, No.5, October 1990
1187
1188
MICHAEL BAUM
outcomes of treatment were determined by the extent of microscopic dissemination that occurred before the disease was clinically detectable, and therefore that the extent of local therapy was irrelevant, with the prognosis being determined not by time but by the biologic heterogeneity of the primary tumor. There were two therapeutic sequelae of this revolutionary model: first, that conservative surgery could achieve the same results as radical surgery at the expense of much less morbidity, both physical and psychological, and second, that survival would be improved only as a result of the exhibition of drugs targeted at the putative micrometastases present at the time of diagnosis. Throughout the 1970s, a large number of randomized controlled trials compared radical options with ultraconservative surgery. No significant differences in survival have emerged, and some of these trials are now 20 years mature. We can therefore say that this set of experiments refuted the anatomic hypothesis and have to date supported that of biologic determinism.
EARLY SUCCESSES OF THE BIOLOGIC MODEL Over the last decade, we have witnessed the proliferation of randomized controlled trials comparing local therapy alone with local therapy plus adjuvant systemic therapies. These systemic therapies were modeled on our experience in the management of advanced breast cancer, which demonstrates a 60% response rate for polychemotherapy regimens and a 30% response rate for any form of endocrine manipulation. Furthermore, it has been demonstrated that advanced cancers that are estrogen-receptor negative are virtually unresponsive to an endocrine approach. We can therefore look on trials of adjuvant systemic therapy as addressing one important first-order hypothesis and at least two second-order hypotheses. The first-order hypothesis suggests that any form of adjuvant systemic therapy would improve survival compared with local therapy alone. The second-order hypotheses suggest that chemotherapeutic regimens would be twice as advantageous as endocrine approaches and that the patients whose tumors are estrogen-receptor negative would be wholly unresponsive to adjuvant endocrine therapy. A recent overview of all trials of adjuvant systemic therapy has supported the first-order hypothesis, and we can now say with confidence that the natural history of breast cancer has been perturbed as a result of the administration of systemic therapies. 4 However, the most exciting biologic fallout from these trials is the refutation of the second-order hypotheses. The ideologists, of course, reject these data as experimental error, whereas the theorists embrace these inconsistencies in order to use them in building a new set of biologic conjectures.
FLAWS EXPOSED IN THE PREVAILING MODEL Far from adjuvant systemic chemotherapy being twice as successful as adjuvant endocrine therapy, its only significant advantage to date has been demonstrated in a subgroup of premonopausal women with positive axillary
TRENDS IN PRIMARY BREAST CANCER MANAGEMENT
1189
nodes, accounting for perhaps 15% of the total population of patients with breast cancer.4 To the theorists, these observations have suggested that the lasting benefits of adjuvant chemotherapy may be indirectly mediated via a chemical castration. In contrast, the neoideologists have argued in favor of dose intensification, even to the extreme of dose intensification plus autologous bone-marrow grafting (which one day might be looked on as the medical equivalent of the superradical mastectomy of the past when the surgical ideologists held sway!). Be that as it may, a more intriguing set of refutations has been of the strongly held belief that only patients with estrogen-receptor-positive tumors will benefit from adjuvant endocrine therapy. It is important at this juncture to emphasize that the endocrine therapy tested in the majority of these trials involved the use of the "antiestrogen" tamoxifen, one of a group of nonsteroidal triphenylethylene derivatives. The first trial to show a survival advantage for this drug came from the Novaldex Adjuvant Trial Organization (NATO).2 Measurement of the estrogen-receptor concentration of the primary tumors of patients recruited to this study was a powerful prognostic variable, yet the long-term survival rate after the administration of 2 years of tamoxifen has been identical, irrespective of whether the primary tumors were receptor rich or receptor depleted. Paradoxically, therefore, the greatest absolute advantage has been seen among the patients with estrogen-receptor-negative tumors: a complete reversal of what would have been anticipated. This cannot be random bias, as the world overview of all such trials has reinforced these counterintuitive observations. 4 The ideologists cannot accept these findings, which are dismissed as laboratory error; however, for the purpose of this discussion, I choose to believe them in order to generate yet another set of biologic theories. It is proposed that the triphenylethylene group of drugs binds to a ubiquitous receptor leading to modulation of the production of growth factors that are responsible for stromal epithelial cell interactions. The action of the drug would then be to upregulate the production of growth-inhibitory polypeptides by mesenchymal cells close to the malignant epithelial cells previously shed from the primary breast cancer. Over the last 3 years, Dr. Colletta, a PhD student working in my laboratory, has been investigating these claims in collaboration with Dr. Michael Sporn's group from the US National Cancer Institute in Washington. Recently published experimental results demonstrate that fetal fibroblast cultures lacking an estrogen-receptor mechanism respond to the presence of triphenylethylene derivatives with a production of up to a 30-fold excess of transforming growth factor beta (TGF beta),3 a growth-inhibitory factor capable of destroying epithelial cells at picomolar concentrations. The observations support the presence of another indirect mechanism by which estrogen-receptor-positive and receptor-negative breast cancer cells can be destroyed by contact with activated fibroblast at the site of metastases. I would not suggest for one moment that tamoxifen or its analogue toremifene is the ideal drug for this approach, but I would like to see effort among experimental pharmacologists to develop a new class of drug based on the structure of the triphenylethylenes, exploiting their potential for the
1190
MICHAEL BAUM
induction of inhibitory growth factors from mesenchymal cells. However, the limiting factor in this approach would be the exhaustion of the potential for these cells to respond to such a stimulus. Or, looking at it in another way, the successful development of overt metastatic disease could be an expression of the exhaustion of the natural induction of TGF beta by host cells in the presence of developing cancer. This might then explain why in stage III and stage IV breast cancer, tamoxifen can mediate its effect only by the classic pathway involving the estrogen-receptor mechanism of the tumor cell at the time when mesenchymal cell responses have been exhausted by chronic stimulation in the past. TIME FOR A PARADIGM SHIFT
There is a hierarchy in the quality of evidence that emerges from different strategies in the evaluation of therapy. As far as the role of adjuvant systemic therapy in early breast cancer is concerned, there is an irritating inverse relation between the size of the benefit and the toughness of the test. I have recently returned from an international meeting on adjuvant systemic therapy for early breast cancer that was set among the beautiful cactus forests of sunny Arizona. Among the speakers present, there were those who continue to favor historical controls or computer databases; they continue to demonstrate the most spectacular successes of adjuvant chemotherapy in prolonging survival. Those who favored strictly controlled randomized trials, yet analyzed them according to promising data-derived subsets, also came up with interesting results. Those groups that insisted on a complete analysis of all patients randomized, using overall survival as the only endpoint, demonstrated the least promising results. Finally, Dr. Broder, the Director of the National Cancer Institute, demonstrated that national cancer statistics for mortality rates from breast cancer have hardly changed over the last 15 years in spite of the triumphal attitudes of American medical oncology. Having conceded that adjuvant systemic therapy can perturb the natural history of breast cancer by having a profound influence on time to relapse, the results, expressed as overall reduction in mortality rates, are so modest that there must be sometl:\.ing wrong with the prevailing biologic model. I believe we are in danger of not truly appreciating what the results of 15 years of randomized controlled trials in the treatment of early breast cancer are trying to tell us. Instead of continuing to fine-tune the same old model of micrometastases using the techniques of normal deductive science, maybe the time has arrived to challenge all our major assumptions with a bit of revolutionary science, and it is time for one of Kuhn's paradigm shifts. 6 There are two categorical assumptions in the prevailing model of carcinoma of the breast: first, that death is the ultimate result of micrometastases, a purely cellular phenomenon present at the time of diagnosis, and second, that breast cancer is a heterogenous disease and more and more effort must be devoted to selecting or tailoring the ideal treatment for each individual case. To persist with these concepts in the faqe of the
TRENDS IN PRIMARY BREAST CANCER MANAGEMENT
1191
current impasse is to ignore what has been happening in the laboratories of the molecular geneticists over the last 5 or 6 years. I believe that breast cancer exhibits an apparent heterogeneity of phenotypes resulting from one or perhaps two genotypic mutations. All the multiplicity of prognostic variables could be looked on as epiphenomena expressing different degrees of amplification of a strictly limited domain on the genome, which itself governs the rate of replication of the cancer celL Therefore, a single therapy aimed at the genetic level might benefit all patients with breast cancers with quantitative rather than qualitative differences in outcome. Furthermore, it is conceivable that there are two types of metastatic phenomena in early breast cancer. First, there are cellular events, according to the conventional model, that respond to conventional therapy and are responsible for the successes of current strategies of adjuvant systemic therapy. In addition, there might be a second wave of metastases, responsible for the intermediate and late relapses of breast cancer, which are a result of transfection of cells in distant organs, such as the liver or bone marrow, with oncogenes capable of self-replication shed from both the primary tumor and its established metastases. Viral-like particles with reverse transcriptase activity have already been detected in circulating monocytes of patients with breast cancer.l Maybe these are bundles of lethal genetic information released from dying tumor cells that ultimately are responsible for the death of the host. The therapeutic consequences of this revolutionary hypothesis are selfevident and eminently testable. Instead of cytotoxic drugs and endocrine therapy, we might need antiviral or gene therapy to make an important impact on the mortality rates from carcinoma of the breast. Laboratory and clinical experiments could easily be designed to refute or confirm these bizarre ideas. It is appropriate to conclude with the words of Craig Henderson, a noted theorist in clinical oncology: "In contrast to other methods of defining reality or truth the end products of scientific reasoning are never sacrosanct. Rather, science is a continuously evolving process and only the process itself is inviolable."s
REFERENCES 1. Al-Sumidaie, AM, Leinster SJ, Hart CA, et al: Particles with properties of retroviruses in monocytes from patients with breast cancer. Lancet 1:5-9, 1988 2. Analysis at Eight Years by Nolvadix Adjuvant Trial Organization: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. 5r J Cancer 57:608-611, 1988 3. Colletta AA, Wakefield KM, Howell FV, et al: Antioestrogens induce the secretion of active transforming growth factor beta from human fibroblasts. Br J Cancer, in press 4. Early Breast Cancer Trialists' Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mort;ility in early breast cancer: An overview of 61 randomized trials among 28,896 women. N Eng! J Med 319:1681-1692, 1988 5. Henderson C: Shouldn't we see the white Hag before we cry victory? Point/Counterpoint 82(2):103-109, 1990
1192
MICHAEL BAUM
6. Kuhn TS: The historical structure of scientific discovery. Science 136:760-764, 1962
Address reprint requests to Michael Baum, ChM, FRCS, MD Department of Surgery Royal Marsden Hospital Fulham Road London SW3, England
0039-6109/90 $0.00
+ .20
Trends in Primary Breast Cancer Management Where Are We Going~
Michael Baum, ChM, FRCS, MD*
The treatment of cancer during any period in the history of medicine has not been based on the whim of a clinician but on the therapeutic consequences of the dominant biologic model of the disease. Until about 30 years ago, cancer treatments were applied according to an inductive paradigm of scientific philosophy. However, in recent years, clinicians have started to apply a falsificationist approach in the search for effective cancer therapy. A randomized controlled trial is the expression of this scientific process at work in clinical medicine. If used correctly, the randomized trial can initiate a hypothetical deductive cascade, which, in addition to testing the claims of competing therapies, is capable of generating new biologic hypotheses. I wish to illustrate this process by referring to 20 years of experience in the clinical trials concerning the treatment of primary carcinoma of the breast and extrapolating from this experience a flight of fantasy in anticipation of what might develop in the next 20 years.
ANATOMIC VERSUS BIOLOGIC MODEL OF BREAST CANCER .
Until the 1960s, the dominant biologic model of breast cancer was of a disease that spread centrifugally along anatomic pathways, with time being the only determinant of prognosis. It followed, therefore, that anatomically based radical operations would be the treatment of choice. Mortality rates from breast cancer remained stubbornly constant in spite of perfect anatomic dissections until a group of scientists proposed an alternative model of biologic determinism. This model suggested that the *Professor of Surgery, The Institute of Cancer Research and the Royal Marsden Hospital, London, England
Surgical Clinics of North America-Vol. 70, No.5, October 1990
1187
1188
MICHAEL BAUM
outcomes of treatment were determined by the extent of microscopic dissemination that occurred before the disease was clinically detectable, and therefore that the extent of local therapy was irrelevant, with the prognosis being determined not by time but by the biologic heterogeneity of the primary tumor. There were two therapeutic sequelae of this revolutionary model: first, that conservative surgery could achieve the same results as radical surgery at the expense of much less morbidity, both physical and psychological, and second, that survival would be improved only as a result of the exhibition of drugs targeted at the putative micrometastases present at the time of diagnosis. Throughout the 1970s, a large number of randomized controlled trials compared radical options with ultraconservative surgery. No significant differences in survival have emerged, and some of these trials are now 20 years mature. We can therefore say that this set of experiments refuted the anatomic hypothesis and have to date supported that of biologic determinism.
EARLY SUCCESSES OF THE BIOLOGIC MODEL Over the last decade, we have witnessed the proliferation of randomized controlled trials comparing local therapy alone with local therapy plus adjuvant systemic therapies. These systemic therapies were modeled on our experience in the management of advanced breast cancer, which demonstrates a 60% response rate for polychemotherapy regimens and a 30% response rate for any form of endocrine manipulation. Furthermore, it has been demonstrated that advanced cancers that are estrogen-receptor negative are virtually unresponsive to an endocrine approach. We can therefore look on trials of adjuvant systemic therapy as addressing one important first-order hypothesis and at least two second-order hypotheses. The first-order hypothesis suggests that any form of adjuvant systemic therapy would improve survival compared with local therapy alone. The second-order hypotheses suggest that chemotherapeutic regimens would be twice as advantageous as endocrine approaches and that the patients whose tumors are estrogen-receptor negative would be wholly unresponsive to adjuvant endocrine therapy. A recent overview of all trials of adjuvant systemic therapy has supported the first-order hypothesis, and we can now say with confidence that the natural history of breast cancer has been perturbed as a result of the administration of systemic therapies. 4 However, the most exciting biologic fallout from these trials is the refutation of the second-order hypotheses. The ideologists, of course, reject these data as experimental error, whereas the theorists embrace these inconsistencies in order to use them in building a new set of biologic conjectures.
FLAWS EXPOSED IN THE PREVAILING MODEL Far from adjuvant systemic chemotherapy being twice as successful as adjuvant endocrine therapy, its only significant advantage to date has been demonstrated in a subgroup of premonopausal women with positive axillary
TRENDS IN PRIMARY BREAST CANCER MANAGEMENT
1189
nodes, accounting for perhaps 15% of the total population of patients with breast cancer.4 To the theorists, these observations have suggested that the lasting benefits of adjuvant chemotherapy may be indirectly mediated via a chemical castration. In contrast, the neoideologists have argued in favor of dose intensification, even to the extreme of dose intensification plus autologous bone-marrow grafting (which one day might be looked on as the medical equivalent of the superradical mastectomy of the past when the surgical ideologists held sway!). Be that as it may, a more intriguing set of refutations has been of the strongly held belief that only patients with estrogen-receptor-positive tumors will benefit from adjuvant endocrine therapy. It is important at this juncture to emphasize that the endocrine therapy tested in the majority of these trials involved the use of the "antiestrogen" tamoxifen, one of a group of nonsteroidal triphenylethylene derivatives. The first trial to show a survival advantage for this drug came from the Novaldex Adjuvant Trial Organization (NATO).2 Measurement of the estrogen-receptor concentration of the primary tumors of patients recruited to this study was a powerful prognostic variable, yet the long-term survival rate after the administration of 2 years of tamoxifen has been identical, irrespective of whether the primary tumors were receptor rich or receptor depleted. Paradoxically, therefore, the greatest absolute advantage has been seen among the patients with estrogen-receptor-negative tumors: a complete reversal of what would have been anticipated. This cannot be random bias, as the world overview of all such trials has reinforced these counterintuitive observations. 4 The ideologists cannot accept these findings, which are dismissed as laboratory error; however, for the purpose of this discussion, I choose to believe them in order to generate yet another set of biologic theories. It is proposed that the triphenylethylene group of drugs binds to a ubiquitous receptor leading to modulation of the production of growth factors that are responsible for stromal epithelial cell interactions. The action of the drug would then be to upregulate the production of growth-inhibitory polypeptides by mesenchymal cells close to the malignant epithelial cells previously shed from the primary breast cancer. Over the last 3 years, Dr. Colletta, a PhD student working in my laboratory, has been investigating these claims in collaboration with Dr. Michael Sporn's group from the US National Cancer Institute in Washington. Recently published experimental results demonstrate that fetal fibroblast cultures lacking an estrogen-receptor mechanism respond to the presence of triphenylethylene derivatives with a production of up to a 30-fold excess of transforming growth factor beta (TGF beta),3 a growth-inhibitory factor capable of destroying epithelial cells at picomolar concentrations. The observations support the presence of another indirect mechanism by which estrogen-receptor-positive and receptor-negative breast cancer cells can be destroyed by contact with activated fibroblast at the site of metastases. I would not suggest for one moment that tamoxifen or its analogue toremifene is the ideal drug for this approach, but I would like to see effort among experimental pharmacologists to develop a new class of drug based on the structure of the triphenylethylenes, exploiting their potential for the
1190
MICHAEL BAUM
induction of inhibitory growth factors from mesenchymal cells. However, the limiting factor in this approach would be the exhaustion of the potential for these cells to respond to such a stimulus. Or, looking at it in another way, the successful development of overt metastatic disease could be an expression of the exhaustion of the natural induction of TGF beta by host cells in the presence of developing cancer. This might then explain why in stage III and stage IV breast cancer, tamoxifen can mediate its effect only by the classic pathway involving the estrogen-receptor mechanism of the tumor cell at the time when mesenchymal cell responses have been exhausted by chronic stimulation in the past. TIME FOR A PARADIGM SHIFT
There is a hierarchy in the quality of evidence that emerges from different strategies in the evaluation of therapy. As far as the role of adjuvant systemic therapy in early breast cancer is concerned, there is an irritating inverse relation between the size of the benefit and the toughness of the test. I have recently returned from an international meeting on adjuvant systemic therapy for early breast cancer that was set among the beautiful cactus forests of sunny Arizona. Among the speakers present, there were those who continue to favor historical controls or computer databases; they continue to demonstrate the most spectacular successes of adjuvant chemotherapy in prolonging survival. Those who favored strictly controlled randomized trials, yet analyzed them according to promising data-derived subsets, also came up with interesting results. Those groups that insisted on a complete analysis of all patients randomized, using overall survival as the only endpoint, demonstrated the least promising results. Finally, Dr. Broder, the Director of the National Cancer Institute, demonstrated that national cancer statistics for mortality rates from breast cancer have hardly changed over the last 15 years in spite of the triumphal attitudes of American medical oncology. Having conceded that adjuvant systemic therapy can perturb the natural history of breast cancer by having a profound influence on time to relapse, the results, expressed as overall reduction in mortality rates, are so modest that there must be sometl:\.ing wrong with the prevailing biologic model. I believe we are in danger of not truly appreciating what the results of 15 years of randomized controlled trials in the treatment of early breast cancer are trying to tell us. Instead of continuing to fine-tune the same old model of micrometastases using the techniques of normal deductive science, maybe the time has arrived to challenge all our major assumptions with a bit of revolutionary science, and it is time for one of Kuhn's paradigm shifts. 6 There are two categorical assumptions in the prevailing model of carcinoma of the breast: first, that death is the ultimate result of micrometastases, a purely cellular phenomenon present at the time of diagnosis, and second, that breast cancer is a heterogenous disease and more and more effort must be devoted to selecting or tailoring the ideal treatment for each individual case. To persist with these concepts in the faqe of the
TRENDS IN PRIMARY BREAST CANCER MANAGEMENT
1191
current impasse is to ignore what has been happening in the laboratories of the molecular geneticists over the last 5 or 6 years. I believe that breast cancer exhibits an apparent heterogeneity of phenotypes resulting from one or perhaps two genotypic mutations. All the multiplicity of prognostic variables could be looked on as epiphenomena expressing different degrees of amplification of a strictly limited domain on the genome, which itself governs the rate of replication of the cancer celL Therefore, a single therapy aimed at the genetic level might benefit all patients with breast cancers with quantitative rather than qualitative differences in outcome. Furthermore, it is conceivable that there are two types of metastatic phenomena in early breast cancer. First, there are cellular events, according to the conventional model, that respond to conventional therapy and are responsible for the successes of current strategies of adjuvant systemic therapy. In addition, there might be a second wave of metastases, responsible for the intermediate and late relapses of breast cancer, which are a result of transfection of cells in distant organs, such as the liver or bone marrow, with oncogenes capable of self-replication shed from both the primary tumor and its established metastases. Viral-like particles with reverse transcriptase activity have already been detected in circulating monocytes of patients with breast cancer.l Maybe these are bundles of lethal genetic information released from dying tumor cells that ultimately are responsible for the death of the host. The therapeutic consequences of this revolutionary hypothesis are selfevident and eminently testable. Instead of cytotoxic drugs and endocrine therapy, we might need antiviral or gene therapy to make an important impact on the mortality rates from carcinoma of the breast. Laboratory and clinical experiments could easily be designed to refute or confirm these bizarre ideas. It is appropriate to conclude with the words of Craig Henderson, a noted theorist in clinical oncology: "In contrast to other methods of defining reality or truth the end products of scientific reasoning are never sacrosanct. Rather, science is a continuously evolving process and only the process itself is inviolable."s
REFERENCES 1. Al-Sumidaie, AM, Leinster SJ, Hart CA, et al: Particles with properties of retroviruses in monocytes from patients with breast cancer. Lancet 1:5-9, 1988 2. Analysis at Eight Years by Nolvadix Adjuvant Trial Organization: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. 5r J Cancer 57:608-611, 1988 3. Colletta AA, Wakefield KM, Howell FV, et al: Antioestrogens induce the secretion of active transforming growth factor beta from human fibroblasts. Br J Cancer, in press 4. Early Breast Cancer Trialists' Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mort;ility in early breast cancer: An overview of 61 randomized trials among 28,896 women. N Eng! J Med 319:1681-1692, 1988 5. Henderson C: Shouldn't we see the white Hag before we cry victory? Point/Counterpoint 82(2):103-109, 1990
1192
MICHAEL BAUM
6. Kuhn TS: The historical structure of scientific discovery. Science 136:760-764, 1962
Address reprint requests to Michael Baum, ChM, FRCS, MD Department of Surgery Royal Marsden Hospital Fulham Road London SW3, England