Originally published as JCO Early Release 10.1200/JCO.2009.21.8453 on April 6 2009

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

Department of Radiation Oncology, University of Colorado Denver, Aurora, CO

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"¹—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 study² 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."²

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,³ 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."³ 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 re-evaluate the Fisher hypothesis and consider bringing Halsted back into view. Data in this issue of Journal of Clinical Oncology reported by Anderson et al,⁴ 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.⁵
  
• 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.⁶
  
• In the NSABP adjuvant trials, the hazard rate for mortality after IBTR was 4.49 in estrogen receptor–negative node-negative patients and 2.33 in estrogen receptor–positive node-negative patients, as reported by Anderson et al.⁴
  
• In the NSABP adjuvant trials, the hazard rate for mortality after IBTR was 2.58 in node-positive patients, as reported by Wapnir et al.⁷
  
• There was a highly significant reduction in the annual breast cancer mortality rate for patients treated with radiotherapy after lumpectomy versus lumpectomy alone (breast cancer death rate ratio, 0.83; 95% CI, 0.75 to 0.91; 2P = .0002), as reported in a meta-analysis by Early Breast Cancer Trialists' Collaborative Group.⁸
  
• In numerous trials and meta-analyses, improved regional control with postmastectomy radiotherapy was associated with improved survival.⁹
  

There is little room for doubt that patients who experience IBTR have a significantly increased risk of death. The benefit of breast radiotherapy in maintaining a cancer-free breast is not only cosmetic. Furthermore, even after mastectomy, regional control is still necessary to optimize the chance for long-term survival. Breast cancer recurrence cannot merely be an indicator of aggressive disease, as explained by the Fisher hypothesis, if local therapies affect ultimate distant disease dissemination.

There have been several other visionaries over the years who have proposed similarly rebellious theories of solid tumor dissemination. In 1995, for example, Hellman and Weichselbaum¹⁰ advanced the concept of oligometastases in JCO, describing an intermediate phase of cancer progression falling somewhere between the hypotheses of Halsted and Fisher. They hypothesized that there exists an opportunity for local therapy—targeting limited and measurable sites of metastatic disease—to meaningfully affect disease-free and overall survival. This concept has already been evaluated in prospective clinical trials, with provocatively encouraging results to date.¹¹

Ultimately, the demonstrated benefits of successful local therapy to the primary site, and perhaps also to sites of oligometastatic disease, would not be visible without effective systemic therapies and vice versa. Shifting patterns of disease recurrence are the signs of newly effective local or systemic therapies; improvements in disease control imparted by one therapy complement and magnify the importance of moving forward with another. In the earliest years of the NSABP, when patients were generally diagnosed with higher rates and burdens of occult systemic disease and treated with far fewer and less effective systemic therapies, local disease management indeed had little impact on ultimate treatment outcome. Today, with downward stage migration of newly diagnosed breast cancer, and much broader use of highly effective layered chemotherapy and endocrine therapy, the impact of local disease control is coming into telescopic focus.

In the end—or maybe in another beginning—after many years of searching the skies, we have arrived at a necessarily double-stranded approach that involves both local and systemic considerations. As we continue to explore the universe for new breast cancer treatments, we should be open to illumination from new and old sources. To paraphrase a passage from the late Douglas Adams, something of an authority on galactic travel, let's keep hoping that even if we don't go where we intend to go, we'll end up where we need to be.¹²

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Rachel Rabinovitch

Manuscript writing: Rachel Rabinovitch, Brian Kavanagh

Final approval of manuscript: Rachel Rabinovitch

REFERENCES

1. Fisher B: Laboratory and clinical research in breast cancer: A personal adventure—The David A. Karnofsky memorial lecture. Cancer Res 40:3863–3874, 1980.[Abstract/Free Full Text]

2. Fisher B: From Halsted to prevention and beyond: Advances in the management of breast cancer during the twentieth century. Euro J Cancer 35:1963–1973, 1999.[CrossRef]

3. Fisher B, Bauer M, Margolese R, et al: Five-year results of a randomized clinical trial comparing total mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 312:665–673, 1985.[Abstract]

4. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27:2466–2473, 2009.[Abstract/Free Full Text]

5. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241, 2002.[Abstract/Free Full Text]

6. Fisher B, Anderson S, Fisher ER, et al: Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 338:327–331, 1991.[CrossRef][Medline]

7. Wapnir IL, Anderson SJ, Mamounas EP, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 24:2028–2037, 2006.[Abstract/Free Full Text]

8. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087–2106, 2005.[Medline]

9. Overgaard M, Nielsen HM, Overgaard J: Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol 82:247–253, 2007.[CrossRef][Medline]

10. Hellman S, Weichselbaum RR: Oligometastases. J Clin Oncol 13:8–10, 1995.[Free Full Text]

11. Milano MT, Zhang H, Metcalfe SK, et al: Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer Res Treat [epub ahead of print on August 22, 2008].

12. Adams D. The Hitchhiker's Guide to the Galaxy. London, United Kingdom: Pan Books, 1979.

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