A Fisher Among Men — Feel the Bern

Fisher

The Editor-in-Chief of a popular breast cancer journal was recently reviewing my commentary in response to a new paradigm proposed to explain the overarching biology of breast cancer. In my invited comments about the proposal, I stated that this new theory addressing breast cancer biology is really just an extension of Fisher Theory. In his suggestions to me, the Editor asked that I explain Fisher Theory, as many readers today might not be familiar with its tenets that include dormant cell theory, common vascular channel theory, host:tumor relationships, and so forth.

Wow. I hadn’t thought about it. He was correct. New clinicians getting on board the train today don’t really need to think about such things. Yet, once upon a time, every respectable breast cancer conference included Dr. Fisher discussing his theory and how he proved its value.

Every time a woman undergoes lumpectomy for breast cancer, the procedure is based on the Fisher Theory of breast cancer biology that originated in the 1950s, largely confirmed in clinical trials in the 1970s and 1980s. Breast conservation emerged – not as a gradual downscaling of doing less and less over time – rather, in response to governing principles as to how breast cancer “worked.” That is, its biology. Thus, one could stop performing Halsted radicals one day, and move directly to lumpectomy the next. And this was based on a biologic paradigm, not a gradual de-escalation of surgical warfare.

Paradigm? The first time I ever heard the word – overworked and misused as it is today – was from Dr. Bernie Fisher at the podium at one of the early breast cancer meetings in the 1980s. In fact, he would sometimes stop to explain the word to audience members unfamiliar with its meaning. Composed of many principles, the broader paradigm of Fisher Theory can be condensed thusly – “Breast cancer is systemic at its inception.” That wording didn’t go over well, and was later more commonly expressed as, “Breast cancer is either local or systemic at its discovery, and is unlikely to progress from local to systemic during the clinical phase of therapy.” As a result, the primary implication is this: In Dr. Fisher’s own words, “Variations in locoregional management are unlikely to have a substantial impact on survival.”

In this paradigm, breast cancer interacts with the immunologic response of its host (the patient), and either the tumor wins or the host wins, but the winner is decided upon tumor removal, no matter what method is used to remove it. Think of it as “biologic predestination.” (my words, not Dr. Fisher’s)

Some distort Fisher Theory as, “Local control doesn’t matter” (not true…think about untreated breast cancer). Or, “Local recurrence rates are the same with mastectomy and conservation (not true – only the conservation group can have a recurrence within breast tissue). This confusion about “local recurrence” is a function – once again – of imprecise language and semantics. But consider this: in the early days of conservation, the NSABP called recurrences within the breast tissue “cosmetic failures.” Indeed, this dismissive terminology was utilized prior to proven equivalency when it came to survival as the endpoint.  When the outrage died down, given that this “cosmetic issue” resulted in (ahem) mastectomy, the NSABP gave it a new name – ipsilateral breast tumor recurrence, or IBTR. And, IBTR can only occur in the conservation group, so this is a parameter NOT equal to mastectomy. When “local recurrence” is defined as “chest wall and axilla,” then yes, the methods are equal. But this definition conveniently excludes the most likely event after breast conservation – in-breast recurrence at the lumpectomy site.

The IBTR (in-breast recurrence) is, granted, held harmless (unless you’re the one undergoing completion mastectomy several years after you thought you were done, and then you discover that the prior radiation is going to prevent you from having tissue expanders, and you will be reconstructed with autologous flaps that no one mentioned as a possibility when they were telling you how conservation and radiation was equal in all respects to mastectomy).

But when it comes to survival, the IBTR is thought to be a “marker” of increased tumor aggressiveness, not the cause of the newly calculated survival rate, which is not as good as the affected patient was originally told. The convincing evidence for association rather than causation lies in the fact that women in multiple clinical trials who were randomized to conservation have the same survival as mastectomy patients, even when the women with IBTRs followed by mastectomy remain in their assigned “lumpectomy” grouping (thanks to the intent-to-treat principle). If IBTRs were causing breast cancer deaths, then the mortality would have been greater in the conservation groups. But that wasn’t the case. Mortality was not affected by IBTRs. It’s only when the individual learns that her prognosis is dimmed somewhat that clinicians struggle to explain this.

Well, to the point. At the time of this writing, Bernard Fisher, MD is still alive, age 99, and would ordinarily have received the Nobel Prize for his courageous stand against rigid Halstedians, and for the prescience to introduce prospective randomized trials into the surgical management of cancer. More than any single individual in the history of breast cancer, he overhauled treatment strategies.

However, after one of his high-volume investigators in Canada falsified data, Dr. Fisher was dragged through the mud by the NCI, and worse, his alma mater, the University of Pittsburgh. In essence, he was demonized. Although he later sued and won a cash settlement and an apology from the University of Pittsburgh, some believe this is why the Nobel committee has egregiously refused to entertain his nomination. Dr. Fisher has won every other award that medicine has to offer, but it’s looking more and more like he won’t be going to Stockholm, given that the Nobel Prize is not awarded posthumously (unless you die in that sweet spot after the announcement but before the presentation).

Well, over the years, some cracks developed in Fisher Theory. Early detection of breast cancer through screening mammography shouldn’t have made a difference in the face of biologic predestination (nihilistic Fisher purists still claim early detection is a total illusion). And, tumor size should not have remained a prognostic indicator, yet look at Dr. Tabar’s 15mm data that suggests this is the watershed point, before which early detection makes its mark. And then, more recent data indicates that radiation after lumpectomy provides a slight survival advantage, something that would not be seen in pure Fisher Theory (although remember those italics I used at the beginning of this editorial — Dr. Fisher did qualify his statement that variations are unlikely to have a substantial impact on survival).

Whether they know it or not, most surgeons and radiologists and radiation therapists operate today under Spectrum Theory (outlined by radiation oncologist, Sam Hellman, MD), which states that, yes, some tumors follow Fisher Theory, yet other tumors form a separate biologic group, located in between “local” and “systemic.” Here, tumors have a Goldilocks biology wherein they progress from local to systemic during the clinical window of opportunity. This window was opened wider with the introduction of screening mammography. These are the cancers that lend themselves to early detection. They are also the cancers that should be carefully eradicated with local therapy. Unfortunately, we don’t know which ones they are, any more than we know which ones are biologically local (today, the “local only” tumors are referred to with the pejorative term – overdiagnosis).

These overarching biologies are not really spoken of much anymore, as everyone ignores the forest and focuses on the wonderful trees of precision medicine, with Luminal A/B, triple negatives, HER2 positives, etc. Yet, these “old” theories guide every step for every physician treating every breast cancer patient today.

So did Dr. Fisher get it right? Well, he was certainly close. And, he was much closer than Halsted whose theory of a predictable, orderly spread of breast cancer prompted the radical mastectomy. Given that Dr. Fisher stood up to an army of surgeons that were protecting the past and the memory of Halsted, he deserves the Nobel Prize for sheer courage, not to mention his tenacity for doing the right thing even when his alma mater betrayed him.

 

For an in-depth look at Fisher Theory and its implications for breast cancer screening, read Mammography and Early Breast Cancer Detection by Alan B. Hollingsworth, MD.  (The best parts are in the Endnotes.)  Order from Amazon or directly from the publisher using Links on this website.

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