Double Helix of Breast Cancer Therapy: Intertwining the Halsted and Fisher Hypotheses

It takes 25,000 years for light from the Double Helix Nebula to reach Earth. Astronomers gazing on its spiral arms know that the place where it seems to be located is actually a place where it has already been. Fortunately for patients with cancer, whose lives are measured in shorter segments of the space-time continuum, progress in oncology occurs at a pace much quicker than that of transgalactic signaling. Nevertheless, waiting for the light to come into view can still require patience and time, and it just might be that the place in which we now find ourselves is a place we have seen before. We were led to our most recent viewpoint by Dr Bernard Fisher, whose National Surgical Adjuvant Breast and Bowel Project (NSABP) has performed landmark studies advancing treatment of breast cancer for more than five decades. Dr Fisher can be credited for much of the direction and clarity of this research effort; few organizations have been fortunate enough to have a single visionary at the helm for so long. Dr Fisher’s many accomplishments include the promotion of the scientific process and the randomized clinical trial to obtain answers to questions directly affecting clinical care. Outcomes of the NSABP trials have been evaluated as puzzle pieces, filling in a picture and contributing to his understanding of cancer biology. He has always been one of the first to advocate for redirection of scientific inquiry on the basis of this changing picture. Like the old axiom he once quoted—“that which is logical is apt not to be true, and that which is true often seems illogical”—he has made it clear that scientific reality is not always readily intuitive. At the scientific core of Dr Fisher’s work is his self-described alternative hypothesis, known to most of us as the systemic or Fisher hypothesis of breast cancer. In this model, breast cancer is considered a systemic disease at time of diagnosis, a condition requiring treatment of the entire patient rather than just the source organ. Ultimate manifestation of systemic (metastatic) disease is the result of tumor and patient heterogeneity and the complex interactions between them. This theory diverges dramatically from the Halsted hypothesis, the established paradigm of the preceding 100 or so years, named for the surgeon who performed the first radical mastectomy in 1882. Halsted and his disciples saw breast cancer as a disease spreading in an orderly and typically contiguous manner: from breast to lymph nodes and only then to distant metastatic sites. This concept supported the use of extensive local surgery (ie, radical mastectomy) to remove all contiguous regional disease; this was expected to yield the greatest cure rates. The Fisher hypothesis was formulated after the integration of years of laboratory and clinical investigations. The degree to which this paradigm shift was original and dramatic cannot be overstated. The NSABP B-04 study challenged Halstedian philosophy by comparing radical mastectomy (the standard treatment of the day) with simple mastectomy and regional irradiation and with simple mastectomy alone (ie, no treatment to the axillary lymph nodes). The lack of difference in disease-free and overall survival between the arms despite differences in regional recurrence exposed a major chink in the Halstedian armor. As Dr Fisher himself stated, “the B-04 findings supported our alternative hypothesis and corroborated our previous contention that variations in the treatment of locoregional disease were unlikely to affect survival.” The firm commitment of the NSABP to the model that local therapy and local disease control cannot affect survival outcomes (given the presumed presence of occult systemic disease) is evident in the design of the subsequent B-06 trial, which established breast conservation as a standard approach to early-stage breast cancer. This trial compared total mastectomy with segmental mastectomy with or without breast irradiation. Interestingly, according to the guidelines of that protocol, disease recurrence in the breast after breast-conserving surgery was treated with mastectomy and considered merely a “cosmetic failure;” recurrence in the breast was not even scored as an event affecting disease-free survival. Furthermore, for patients in the B-06 study experiencing ipsilateral breast tumor recurrence (IBTR), the protocol specified that other than salvage mastectomy, “no other therapy will be permitted without evidence of tumor elsewhere. This includes radiation therapy, systemic therapy such as chemotherapy, hormonal therapy, and castration.” Local recurrences were not considered potential sources of subsequent metastatic spread. There is now, however, a sizable body of evidence, much of it originating from within the NSABP itself, suggesting a need to reevaluate the Fisher hypothesis and consider bringing Halsted back into view. Data in this issue of Journal of Clinical Oncology reported by Anderson et al, taken together with numerous other analyses, reveal a constellation of provocative observations. A sampling of these include: ● Lumpectomy followed by breast irradiation, as compared with lumpectomy alone, was associated with a marginally significant decrease in deaths due to breast cancer (P .04),” as reported in the 20-year follow-up of the NSABP B-06 trial. ● The risk of distant disease for patients treated on the NSABP B-06 trial was 3.41 times greater in patients who developed IBTR than in patients who did not. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 15 MAY 2