Wolmark Critiques Adjuvant Tamoxifen Guideline in Keynote Address

Norman Wolmark, MD

In May 2014, ASCO issued guidelines recommending the administration of adjuvant tamoxifen for 10 years in women with stage I-III hormone receptor (HR)-positive breast cancer, based on data from the collection of 5 clinical trials. This recent issuance, along with other recommendations and guidelines, served as the backdrop for the keynote address, titled “Past as Prelude: Further Dilemmas in Hormonal Treatment of Early Breast Cancer, delivered by Norman Wolmark, MD, during the Chemotherapy Foundation Symposium on Wednesday, November 5.

I think it's very worthwhile reviewing the dilemmas we now face in the adjuvant therapy of breast cancer, particularly from the trials that have emerged in the last two years, said Wolmark, a professor and chairman of the Department of Human Oncology at the Allegheny University of Health Sciences and serves as chairman and principal investigator of the National Surgical Adjuvant Breast and Bowel Project (NSABP). This dilemma has become exacerbated. The ovary is an enigma—how are we going to address it?

The ASCO guideline was based on findings from the large aTTom and ATLAS phase III trials, among others. In the aTTom study, women continuing tamoxifen for 10 years had a 25% lower recurrence rate and a 23% lower breast cancer mortality rate compared with those who stopped at 5 years. In the large ATLAS trial, there was a 2.8% reduction in mortality risk for continuing treatment with tamoxifen and the rate of recurrence for those receiving tamoxifen for 10 years was 25% less compared with those receiving just 5 years of treatment.

The past NCI guidelines were established in 1995 and were distributed to every oncologist at every US hospital. They were based on results from the NSABP protocol B-14, which evaluated the administration of adjuvant tamoxifen for 5 years versus 10 years in patients with HR-positive breast cancer. This study suggested that more than 5 years of adjuvant treatment was not warranted in routine clinical practice in this patient population. This set us back a decade. A solid decade, Wolmark said In reference to earlier guidelines on the use of adjuvant tamoxifen. “We had not realized that there was a rebound benefit when you stopped the tamoxifen and at a 7-year preplanned interim analysis, 5 years was better than 10. And we stopped the trial because it crossed futility limits. What a mistake. The ATLAS and aTTom trials were unencumbered by interim analysis—they plotted on and went forward, so good for them.

Looking ahead to 2015, new guidelines about AIs and GnRH agonists are on the way, said Wolmark. Additionally, further emphasis on molecular profiling should be incorporated.

You would think we would have learned from the past, said Wolmark, referring to the May 2014 ASCO guidelines. Do the guidelines apply to every patient, in this age of molecular genomics? If the data are incontrovertible and absolutely definitive, then by all means go ahead and formulate guidelines. But if the guidelines don't take into account genomic profiling, you may miss your mark. You run the risk of paying an enormous price and setting back the art by at least a decade.”

Invoking the memory of Ezra Greenspan, MD, founder of the symposium, he wondered, What would he have thought of the consensus guidelines issued by ASCO? Would he have been in equipoise with it? I think not. He was not prone towards hyperbole. Ezra Greenspan encouraged dialogue. He encouraged discussion. He encouraged scientific discourse, he said.

“To make that ASCO statement without taking into account genomic profiling is far too encompassing. ASCO felt the need to publish before we had the full set of information,” Wolmark said. “Ezra’s admonitions are pertinent today as they were 3 decades ago: assess the data, analyze the permutations and combinations, factor in modern advances and then speak. Otherwise, hold your peace.”

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