Wolmark's Passion for Evidence-Based Medicine Helped Transform Cancer Care

Norman Wolmark, MD

For many researchers, being involved in one landmark clinical trial is often enough to make for a storied and illustrious career. But being involved in more than one is something entirely different; over the course of his career, Norman Wolmark, MD, found himself in that rarefied air.

For women prior to 1971, the standard surgery for breast cancer was radical mastectomy, promoted by the Johns Hopkins University surgeon, William Stewart Halsted, during the last decade of the 19th century. He believed that metastasis did not occur through the bloodstream. At the time, adequate local removal of the cancer (ie, radical mastectomy) was thought to cure the patient—any new instance of cancer that appeared was treated as a new process.

Radical mastectomy involves the complete removal of the breast, chest wall muscle, and underarm lymph nodes. This method left many women disfigured. The result is severe scarring and pain, making patients hesitant to undergo the procedure. Other, less invasive, surgeries were also explored, but no randomized clinical trials had been initiated to find a definitive answer.

That changed when the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated trial B-04, which sought to resolve the controversy over the surgical management of breast cancer. The NSABP is a clinical trials cooperative group that has been supported since its inception by the National Cancer Institute (NCI); it is now part of the NRG Oncology Clinical Trials Group as a result of the NCI’s 2014 reorganization of the research network.

Wolmark was a key investigator, along with 2013 Giants of Cancer Care^® award recipient, Bernard Fisher, MD, the principal investigator. Wolmark says that Fisher “crystallized my thinking that underscored the fact that most medical decisions were driven by empiricism by the authoritarian tyranny of a small group of individuals who could influence the way a disease was treated for decades without any kind of scientific corroboration.”

Wolmark joined the group in 1973 and since then it has evolved “into the incubator for generating data-driven decisions for the treatment of breast cancer and oncology,” he says. “This has been an exciting, active environment.”

The findings from the study showed there was no significant difference in survival between women who underwent radical mastectomy and those treated with the less extensive total mastectomy in which the axillary nodes were not removed. This landmark study gave way to future breast-conserving procedures. Trial B-04 provided the rationale for B-06 in which 2163 women with invasive breast tumors that were 4 cm or less, with either negative or positive axillary lymph nodes (stage I and II breast cancer), were randomly assigned to 1 of 3 treatments: total mastectomy, lumpectomy, or lumpectomy followed by breast irradiation. B-06 results demonstrated that removing the tumor and the underarm lymph nodes plus adding radiation therapy was just as effective as a mastectomy and was far less disfiguring.

“Trial B-04 challenged the sanctity of the radical mastectomy,” Wolmark says. The subsequent trials “compared modified radical mastectomy with breast-preserving procedures, the results of which established breast-preserving surgeries as the standard of care in this setting,” he adds.

Wolmark’s research career at the NSABP also included trial designs that explored the role of adjuvant therapy in breast cancer.

Rare, Scintillating Moments

“I’ve certainly witnessed the era of chemotherapy in the adjuvant setting,” says Wolmark. In 1975, the NSABP published the first trial showing that L-phenylalanine mustard (L-PAM) administered for 2 years in women with histologically positive nodes prolonged disease-free survival, he said. In this trial, B-05, 380 women with node-positive breast cancer were randomly assigned to receive either L-PAM or placebo following primary breast cancer surgery. Results showed that postoperative adjuvant therapy could reduce the recurrence of the disease. Subsequent trials in patients with node-positive disease have studied combination and sequential chemotherapy. The foundation of those studies rests on B-05 and Wolmark’s involvement.Looking back over the course of his career, Wolmark doesn’t point to a specific moment when reviewing data from these clinical trials led to an immediate breakthrough. The evidence and conclusions were cultivated and collected and reviewed, similar to the pieces of a puzzle that are laid out in front of you and just begging to be put together to make a whole.

But there have been a number of rare, scintillating moments that are embedded in his memory.

“In 2005, we analyzed the data from the combined trials B-31, from NSABP, and N9831, from the North Central Cancer Treatment Group. It was the use of Herceptin [trastuzumab] in women with HER2-positive breast cancer,” Wolmark says.

Wolmark recalls that the data were presented at the American Society of Clinical Oncology meeting in Orlando, Florida, during a special education session because the analysis occurred after the deadline for a late-breaking abstract.

Greatest Contribution

“As Edward H. Romond, MD, the lead investigator, presented the data, I turned around to look at the audience and a significant portion had tears in their eyes. We all stood back and admired the Kaplan-Meier curves. That’s an illustration of the impact of the data when comparing the use of Herceptin in the treated group with the placebo group. This was a change in the standard of care and introduced the use of targeted agents as a new paradigm, not only for breast cancer, but for all oncology.”Interestingly, Wolmark doesn’t think his greatest contribution to the field involved the pristine evolution of science. “It was far more mundane,” he says. “But I think it led to some lasting benefits, based on the subsequent clinical trials that were performed afterwards.Wolmark was named the NSABP’s new chairman in 1994. If he thought his first year was going to go smoothly, the congressional hearings in April of that year would dash any preconceived notions. That was the year that the NSABP came under fire by the subcommittee for the House of Representatives Committee for Energy and Commerce, which was chaired by then-Representative John Dingell, Jr.

One of the investigators in the network of study sites in Canada had falsified data in a trial. The NSABP had been slow to correct the public record, and it had continued to use data from the same site, with the negligent investigators as coauthors, in subsequent studies. This prompted an extensive congressional investigation of the NSABP, its leaders, and the NCI’s oversight and corrective measures.

“All NSABP clinical trials at the time were halted during that period,” says Wolmark. “It was a significant possibility that the group would be parceled off to other entities, including the prevention trials that were ongoing at the time.”

He and the officers of the NSABP spent the better part of the year on Capitol Hill, lobbying various members of Congress to keep the NSABP an integral entity. “We came perilously close to being dissolved,” Wolmark says. Although there were oversights that had occurred at the Canadian site, it was also apparent from the analysis that the inclusion of data from the ineligible patients did not materially affect the conclusions of the study.

Upbringing and a Word of Warning

The efforts by Wolmark and his colleagues at NSABP eventually succeeded. “I think our interventions allowed the NSABP to continue doing the work that it’s known for.” If their efforts failed, “the whole cascade of subsequent trials, including the Herceptin trial, would not have occurred or, at least, the NSABP would not have been part of it, had I not spent the year on the hill,” he says.Wolmark grew up in Montreal, Canada, the son of immigrant parents of modest backgrounds. He says they viewed Canada and the United States as providing a unique opportunity for everyone. “If you applied yourself, if you were diligent, if you had a little bit of intelligence, then you would succeed.” Doing something for your fellow man was instilled in him unequivocally and it is what guided his choice to pursue medicine, rather than biochemistry, when his interests turned to graduate learning at McGill University. “I received my acceptance letters from medical school and graduate school on the same day. But I realized that I could make a meaningful impact by pursuing medicine and it could be done with critical relevance.”

Despite being a father of 2 adult children and a grandfather to 5 children who keep him busy, Wolmark is still very involved with NSABP operations, serving as chairman and principal investigator at the NASBP Foundation, which is based on the campus of Allegheny General Hospital in Pittsburgh, Pennsylvania. He still has a clinical practice at the Allegheny Health Network and performs surgeries—although not to the same extent as in the past. He recalls that when he finished his fellowship at Memorial Sloan Kettering (MSK) Cancer Center in 1979, breast cancer was not yet an established specialty in the oncology field; it gradually evolved over time. “My residency experience interdigitated well because of the emphasis in breast cancer at the NSABP, and it influenced my clinical career,” he says.

Ever the champion of evidence-based medicine, Wolmark is concerned about the resurgence of anecdotalism, noting that he is “always wary of the individual who is armed with a retrospective case series whose intention it is to influence the standard of care.”

It is the antithesis of the NSABP.

“We’re seeing smaller and smaller subsets and clinical trials that are not rigidly performed, and that’s a dangerous thing,” Wolmark continues. “We’re also seeing the rise of discounting data from clinical trials, especially the rise in [preventive] bilateral mastectomies, despite the recommendations made by physicians who have reviewed the data.”

He points to a recent study from MSK that asked patients what influenced their decisions about their care. “Sadly, it wasn’t the work of the NSABP, but what was read on social media. And that’s another form of tyranny.”