Laboratory and clinical research in breast cancer--a personal adventure: the David A. Karnofsky memorial lecture.

Abstract

Abstract This report highlights the series of laboratory and clinical investigations conducted by us during the past quarter of a century which have resulted in the replacement of old concepts of tumor biology with others that have been instrumental in altering the therapy of primary breast cancer. The results of our studies prior to 1968, directed toward a better understanding of metastatic mechanisms, dispelled many of the popularly held hypotheses regarding tumor cell dissemination. They led us to conclude that (a) regional lymph nodes do not trap disseminated tumor cells, (b) there is no orderly pattern of tumor cell dissemination based upon temporal and mechanical considerations, (c) patterns of tumor spread are not solely dictated by anatomical considerations but are influenced by intrinsic factors in tumor cells as well as in the organs to which they gain access, and (d) regional lymph node cells are capable of destroying tumor cells. Negative nodes are the result of the latter and/or because tumor cells traverse nodes rather than that a tumor had been removed prior to dissemination of its cells. The positive lymph node reflects a host-tumor relationship which permits development of metastases rather than that it is an instigator of distant disease. Additional studies have provided ample evidence to indicate that regional lymph nodes are of biological rather than anatomical importance in cancer. They also indicated that it is likely that a tumor (breast cancer) is a systemic disease from its inception. Concomitant with the laboratory studies, a series of “first-generation” breast cancer clinical trials provided evidence concordant with findings from the former. As a result, there emerged a hypothesis alternative to that upon which the primary management of solid tumors has been based for almost 100 years, i.e., the principles of Halsted. The opportunity to test the “alternative” hypothesis became available via a second-generation breast cancer clinical trial begun in 1971. Findings from that trial have important biological implications and provide additional support for the various components of the alternative hypothesis. Increasing evidence emphasizes the heterogeneity of human breast cancers. To continue to consider such tumors as representative of a single disease is inappropriate. It has been demonstrated by us that tumor heterogeneity is not merely an interesting biological observation but that it possesses therapeutic significance as well. The results from three clinical trials indicate that, just as there is heterogeneity between and within primary tumors, so are metastatic microfoci dissimilar and so is their response to chemotherapy disparate. Our observations that patients with putatively greater tumor burdens may be better responders and that increasing the number of drugs may not necessarily improve results are inconsistent with current concepts which provide the basis for the use of adjuvant chemotherapy and suggest that they require reappraisal. The findings indicate that metastatic cellular heterogeneity is an important factor to be considered when assessing therapeutic response. Failure of all populations of patients to respond uniformly to therapy provides a different perspective for assessment of the use of adjuvant therapy. A chemotherapeutic agent, or a combination of agents, can be used as a “probe” to identify subpopulations of patients whose metastases contain cells with common or differing biological properties. A probe capable of defining responders and nonresponders to the therapy used provides direction to the next stage of investigation, determination of the reason for the difference of response. With such information, patients can be selected for a particular therapy. There then appears a rationality to the seemingly irrational use of chemotherapy regimens in the myriad of clinical trials being carried out. An alternative approach is to define in the laboratory the variable biological characteristics of tumor cells, which then permits the choice of therapeutic agents that affect cells possessing that discriminant. The two research approaches, i.e., the use of therapy as a probe and the elucidation of biological information regarding tumor cells, are not exclusive of each other. They are so intertwined that each provides an impetus to the other. There is reason for cautious optimism relative to the curing of more patients with breast cancer in the near future. This will come about because of the use of therapy based upon biological considerations rather than empiricism. Patients will be subsetted according to tumor-host biological properties rather than to clinical manifestations of the disease. Clinical staging as we now know it is apt to become obsolete. It cannot be too strongly emphasized that advances in breast cancer therapy are, short of luck, likely to result only from a better understanding of the biology of the disease. Only by application of the scientific method in both the laboratory and the clinic, as is exemplified by this report, is this likely to come about.