In a broader sense, the themes discussed here are important whenever the results of Scientific Inquiry have important impacts in the wider world. Policy decisions are the result of political contests; the application of scientific insights will be only a modest ingredient for this recipe.
Norman Wolmark MD practices at Allegheny General Hospital in Pittsburgh, where he is the Chairman of the Department of Human Oncology. His credentials also include Professor of Human Oncology at the Drexel University College of Medicine. He has gained the most renown for his leadership role with the long-running National Surgical Adjuvant Breast and Bowel Project (NSABP) -- the focus of this talk.
The following text was transcribed from the audio recording (registration required) of Genomic Health's Analyst Day, held on the afternoon of November 12, 2009 in Manhattan. It begins at about the 1 hour, 14 minute mark, and runs to about 1:29:00.
To my knowledge, these remarks are otherwise unpublished. Dr. Wolmark gave a Grand Rounds presentation at the NIH Clinical Center on Sept. 9, 2009 touching on some of these themes; that is Episode 2009-021.
Dr Wolmark's lecture (links added, minimal editorial cleanup) --
The main advancement relative to changing the state of the art has been the ascent of the randomized prospective clinical trial. This represented the clinician’s opportunity to advance the state of the art using the scientific method, in an unbiased, disinterested, totally objective fashion. It was in fact the clinician’s laboratory.UPDATE 12/4/09 -- Dr. Wolmark caught a couple of spelling errors; corrected.
It was a method that was to deliver us from the age of tyranny, the age of authoritarianism, when an individual could ascend to the professorial pulpit and -- armed with a retrospective anecdotal case series, based on his personal charisma, or the prestige of the institution that he represented -- could virtually dictate the standard of care for generations to come.
You think that this is a parable that I’m telling you about? It isn’t! This is how the standard of care for breast cancer was evolved!
William Stewart Halsted in 1895 popularized the radical mastectomy. A mutilating operation that removed the breast, and the underlying muscles, and the lymph nodes, en bloc: based on his biological perception of the disease. He viewed breast cancer as a disease that disseminated in a local-regional fashion, by tentacles, connected to the primary tumor. So, if he saw a patient with a liver metastasis, according to this hypothesis, that metastasis arrived at the liver by direct extension, connected to the primary tumor. So it was perfectly logical for Halsted to have evolved a mutilating operation, removing muscles because muscles were covered by fascia, and the fascia was the conduit of spread. The evil fascia.
We’re still infatuated with it today! Our basic operations for many solid tumors are based on that biologic perception of the disease.
It’s interesting that in 1898, William Stewart Halsted stood up to address the august American Surgical Association. He thanked them for embracing his operation, and his biological perspectives. And we can only conclude that he either was asleep or he was out of the room. Because following his presentation, there was an individual, Rudolph Matas of New Orleans, who stood up.
Dr. Matas said that it is not the number of local recurrences, but the number of cures that should be used as a metric for the value of an operative procedure. He understood that patients were not dying because of inattention to operative detail. They were dying because they already had micrometastatic disease at the time of the operation!
He said that the words used to describe the operation as "radical" or complete -- radical from the Latin "radic," the root -- in the sense that they root out all the evil -- was illusory and inappropriate.
And, of course, his commentary never got published! He was purged from the historical annals of breast cancer! The voice from Johns Hopkins Hospital was far more persuasive, far more pervasive, far more authoritative, than that solitary whisper from Tulane.
1898. Two mutually exclusive hypotheses. The scalpel versus the hypodermic needle. Therapy based on empiricism versus therapy based on molecular markers.
We think we have made great advancements? These two hypotheses were proposed in 1898. And they were suppressed.
It wasn’t until 1971 that these two hypotheses were resurrected. It was done by Bernie Fisher, who deserves a great deal of credit. He had the courage to resurrect these hypotheses, not as an exercise, but to test them using the scientific method -- using the randomized prospective clinical trial.
It was in 1971 that we started the "BO era" [of the NSABP] with the BO-4 trial, which compared the radical mastectomy to a heretical, lesser operation, where the lymph nodes were left behind.
That led to the next step in the retreat from radical mastectomy, the BO-6 trial. It was started in 1976, mastectomy versus preserving the breast, to test these two mutually exclusive hypotheses. And the survival for the lesser procedures was identical to the radical mastectomy!
This wasn’t simply an issue of doing breast-preserving operations. It had enormous biological implications. Because if one accepted the lesser operative procedure, one had to change one’s biological perspective of the disease!
The outcomes of these trials convinced surgeons of the modern era, once and for all, that it was not operative nuances that explained the differences in survival. If we were going to make gains in the cure rate for breast cancer and other solid tumors, we would have to address the systemic component of the disease: the micrometastases that were already extant at the time that patient was treated in the operating room.
This led to the first trial using adjuvant therapy, which was started in 1972. We used two years of oral LPAM [L-phenylalanine mustard], and showed a statistically significant advantage. This supported the alternate hypothesis.
And so, with the retreat from radical mastectomy, we had the ascent of systemic therapy. The two are inextricably intertwined, because they are one and the same part of the alternate hypothesis. That opened the floodgates for a series of adjuvant therapy trials that followed. CMF [cyclophosphamide, methotrexate and fluorouracil] supplanted LPAM in 1976. In the seventies, we went on to address the value of adding tamoxifen for Estrogen-Receptor-positive patients in study NSABP B-09. We published those results in 1981.
In the 1980s, we introduced anthracyclines into the adjuvant setting. In the 90s, taxane. In the past decade, we have worked on "variations on a theme" with taxane. Dose-dense therapy? Do we give agents in combination? Should we give them sequentially? And currently, we are reassessing the value of anthracycline.
Until now, I have been avoiding the basic paradigmatic question. Have we crossed the elusive threshold between therapy based on empiricism and therapy based on molecular discriminants?
The answer is that we have.
The years between 2003 and 2005 were pivotal. The first example was NSABP protocol B-31, where we studied node-positive breast cancer patients whose tumors overexpressed or amplified the HER2/neu gene. [We investigated the use of the drug Herceptin, which blocks the cancer-promoting activity of the her2neu gene]. We started that trial in 2000.
And at the first interim analysis, when we combined that data with North-Central 9831, there was that magic, fleeting moment of Eureka! We saw enormous differences--absolute differences of 18% in favor of Herceptin! [For the first time, targeting a specific molecular discriminant worked.] We had a P value [for statistical significance] that had 11 zeroes after the decimal place! We submitted our report of this clinical trial to the New England Journal of Medicine.
They said, "You can’t put 11 zeroes after the decimal place. Our policy only allows you to put three zeros after the decimal place."
We said, "Why?"
They said, "That’s our policy."
We said, "How many have you seen like this?"
They said, "We’ve never seen one."
But--of course--their policy prevailed. Why? Because they are authoritarian.
So that is proof of principal.
The Oncotype DX [Genomic Health's molecular diagnostic test for breast cancer] was developed in a meticulous, obsessive manner. And it was validated in an appropriate and blinded manner, where the link between the outcome and the data set existed with one honest broker. This broker was the only link between the data and the outcome parameters.
The beauty of the Oncotype DX -- aside from the fact that it gives you unblinded information -- is that it is practical.