1. VOLUME 27 NUMBER 15 MAY 20 2009
JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L
Double Helix of Breast Cancer Therapy: Intertwining
the Halsted and Fisher Hypotheses
Rachel Rabinovitch and Brian Kavanagh, Department of Radiation Oncology, University of Colorado Denver, Aurora, CO
It takes 25,000 years for light from the Double Helix Nebula to NSABP B-04 study2 challenged Halstedian philosophy by comparing
reach Earth. Astronomers gazing on its spiral arms know that the place radical mastectomy (the standard treatment of the day) with simple
where it seems to be located is actually a place where it has already mastectomy and regional irradiation and with simple mastectomy
been. Fortunately for patients with cancer, whose lives are measured in alone (ie, no treatment to the axillary lymph nodes). The lack of
shorter segments of the space-time continuum, progress in oncology difference in disease-free and overall survival between the arms despite
occurs at a pace much quicker than that of transgalactic signaling. differences in regional recurrence exposed a major chink in the Hals-
Nevertheless, waiting for the light to come into view can still require tedian armor. As Dr Fisher himself stated, “the B-04 findings sup-
patience and time, and it just might be that the place in which we now ported our alternative hypothesis and corroborated our previous
find ourselves is a place we have seen before. contention that variations in the treatment of locoregional disease
We were led to our most recent viewpoint by Dr Bernard Fisher, were unlikely to affect survival.”2
whose National Surgical Adjuvant Breast and Bowel Project (NSABP) The firm commitment of the NSABP to the model that local
has performed landmark studies advancing treatment of breast cancer therapy and local disease control cannot affect survival outcomes
for more than five decades. Dr Fisher can be credited for much of the (given the presumed presence of occult systemic disease) is evident in
direction and clarity of this research effort; few organizations have the design of the subsequent B-06 trial,3 which established breast
been fortunate enough to have a single visionary at the helm for so conservation as a standard approach to early-stage breast cancer. This
long. Dr Fisher’s many accomplishments include the promotion of trial compared total mastectomy with segmental mastectomy with or
the scientific process and the randomized clinical trial to obtain an- without breast irradiation. Interestingly, according to the guidelines of
swers to questions directly affecting clinical care. Outcomes of the
that protocol, disease recurrence in the breast after breast-conserving
NSABP trials have been evaluated as puzzle pieces, filling in a picture
surgery was treated with mastectomy and considered merely a “cos-
and contributing to his understanding of cancer biology. He has
metic failure;” recurrence in the breast was not even scored as an
always been one of the first to advocate for redirection of scientific
event affecting disease-free survival. Furthermore, for patients in
inquiry on the basis of this changing picture. Like the old axiom he
the B-06 study experiencing ipsilateral breast tumor recurrence
once quoted—“that which is logical is apt not to be true, and that
(IBTR), the protocol specified that other than salvage mastectomy,
which is true often seems illogical”1— he has made it clear that scien-
“no other therapy will be permitted without evidence of tumor
tific reality is not always readily intuitive.
elsewhere. This includes radiation therapy, systemic therapy such
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 as chemotherapy, hormonal therapy, and castration.”3 Local re-
hypothesis of breast cancer. In this model, breast cancer is considered currences were not considered potential sources of subsequent
a systemic disease at time of diagnosis, a condition requiring treatment metastatic spread.
of the entire patient rather than just the source organ. Ultimate man- There is now, however, a sizable body of evidence, much of it
ifestation of systemic (metastatic) disease is the result of tumor and originating from within the NSABP itself, suggesting a need to re-
patient heterogeneity and the complex interactions between them. evaluate the Fisher hypothesis and consider bringing Halsted back
This theory diverges dramatically from the Halsted hypothesis, the into view. Data in this issue of Journal of Clinical Oncology reported
established paradigm of the preceding 100 or so years, named for the by Anderson et al,4 taken together with numerous other analyses,
surgeon who performed the first radical mastectomy in 1882. Halsted reveal a constellation of provocative observations. A sampling of
and his disciples saw breast cancer as a disease spreading in an orderly these include:
and typically contiguous manner: from breast to lymph nodes and ● Lumpectomy followed by breast irradiation, as compared
only then to distant metastatic sites. This concept supported the use of with lumpectomy alone, was associated with a marginally
extensive local surgery (ie, radical mastectomy) to remove all contig- significant decrease in deaths due to breast cancer (P .04),”
uous regional disease; this was expected to yield the greatest cure rates. as reported in the 20-year follow-up of the NSABP B-06 trial.5
The Fisher hypothesis was formulated after the integration of ● The risk of distant disease for patients treated on the NSABP
years of laboratory and clinical investigations. The degree to which this B-06 trial was 3.41 times greater in patients who developed
paradigm shift was original and dramatic cannot be overstated. The IBTR than in patients who did not.6
2422 © 2009 by American Society of Clinical Oncology Journal of Clinical Oncology, Vol 27, No 15 (May 20), 2009: pp 2422-2423
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Copyright © 2009 American Society of Clinical Oncology. All rights reserved.

2. Editorial
● In the NSABP adjuvant trials, the hazard rate for mortality In the end— or maybe in another beginning—after many years
after IBTR was 4.49 in estrogen receptor–negative node- of searching the skies, we have arrived at a necessarily double-stranded
negative patients and 2.33 in estrogen receptor–positive node- approach that involves both local and systemic considerations. As we
negative patients, as reported by Anderson et al.4 continue to explore the universe for new breast cancer treatments, we
● In the NSABP adjuvant trials, the hazard rate for mortality should be open to illumination from new and old sources. To para-
after IBTR was 2.58 in node-positive patients, as reported by phrase a passage from the late Douglas Adams, something of an
Wapnir et al.7 authority on galactic travel, let’s keep hoping that even if we don’t go
● There was a highly significant reduction in the annual breast where we intend to go, we’ll end up where we need to be.12
cancer mortality rate for patients treated with radiotherapy
after lumpectomy versus lumpectomy alone (breast cancer AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
death rate ratio, 0.83; 95% CI, 0.75 to 0.91; 2P .0002), as The author(s) indicated no potential conflicts of interest.
reported in a meta-analysis by Early Breast Cancer Trialists’
AUTHOR CONTRIBUTIONS
Collaborative Group.8 Conception and design: Rachel Rabinovitch
● In numerous trials and meta-analyses, improved regional Manuscript writing: Rachel Rabinovitch, Brian Kavanagh
control with postmastectomy radiotherapy was associated Final approval of manuscript: Rachel Rabinovitch
with improved survival.9
There is little room for doubt that patients who experience IBTR REFERENCES
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