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	Editor’s Note
	The Process Works

Every September, breast cancer aficionados — hoping to obtain an early peek at the next “hot story” in clinical research — eagerly anticipate the arrival of the San Antonio Breast Cancer Symposium agenda. By the time my copy appeared, Rick Kaderman, our vice president of Scientific Affairs, had already placed a very prominent highlight mark on the session scheduled for 9:00 AM, Thursday, December 12. The profoundly intriguing title of the presentation to be delivered by Marc Citron was “Superiority of dose-dense over conventional scheduling and equivalence of sequential vs. combination adjuvant chemotherapy for node-positive breast cancer (CALGB 9741, INT C9741).”

Like Rick, I was very eager to learn more about the results of this study, but I was also well aware that the abstract for this tantalizing report would not be available until shortly before the meeting. In late October, I ran into Cliff Hudis, one of the authors of the paper and a frequent guest on our series. I thought this might be my opportunity to obtain an inside track on some of the details of the data. However, no amount of cajoling would loosen Cliff’s lips. How much of an advantage would the dose-dense approach convey? Would there be an overall survival benefit? As I pondered these and other questions, my curiosity was piqued even more by Cliff’s broad smile and strong encouragement to attend the session. I sensed that this might be the chemotherapeutic equivalent to last year’s ATAC trial results, which permanently changed the adjuvant endocrine therapy landscape.

Knowing that any discussion with CALGB investigators would be embargoed until the abstract was posted on the San Antonio website shortly before the meeting, I arranged a November interview with the individual whose perspective on this trial most aroused my interest. Larry Norton has spent the last 25 years espousing a mathematical approach to the war on cancer, and his fervor and commitment to the Norton-Simon hypothesis has always evoked my admiration, particularly since, until now, there has been little phase III clinical trial confirmation of this principle.

In a 1994 interview for this series, Larry predicted that his mathematical model would someday be tested in a large-scale, randomized breast cancer trial. It was quite clear at that point that he expected the results to confirm his long-held speculation that inhibiting tumor regrowth between chemotherapy treatment cycles played a key role in the effectiveness of a chemotherapeutic regimen. CALGB 9741 was launched in 1997. The trial had a crisp, highly targeted, two-by-two factorial design (Figure 1) and because the agents and doses in the three arms were identical, the study addressed Norton’s dose-dense theory head on.

I was a bit nervous when I arrived at Larry’s cozy corner office at Memorial Sloan Kettering on November 18, as I was not 100 percent certain that the abstract had already been released. We both immediately logged on to the San Antonio website and, thankfully, the abstract was there in all its glory — a 26 percent relative reduction in relapse rate and 31 percent relative reduction in mortality with the dose-dense strategy. These findings were particularly noteworthy because of the reduced toxicity in these randomization arms. While Larry quipped “This is one of the first regimens where there’s nothing not to love about it, “ he was also typically cautious in predicting how the data would impact patient care and the design of future clinical trials.

A few weeks later, Marc Citron presented these historic findings to a packed San Antonio lecture hall. I interviewed Dr Citron later that day, and his thoughtful views will be presented in our next issue of Breast Cancer Update. As part of our annual San Antonio Breast Cancer Symposium “interview blitz,” I also chatted with 14 other researchers at all hours of the day and night during the meeting. Like last year’s ATAC extravaganza, there were a multitude of opinions. However, there was a uniform perspective among these researchers that the CALGB findings provide important proof of a principle that, at the very least, will now require routine discussion of the results with patients contemplating adjuvant chemotherapy.

One of the most rewarding aspects of producing the Breast Cancer Update series has been the opportunity to participate in documenting the evolution of clinical research. While large phase III adjuvant trials like CALGB 9741 and ATAC have been at the focal point of progress in reducing breast cancer mortality, these studies have, at times, also been quite maddening in their very gradual evolution.

When I interviewed Michael Baum last year about ATAC, he commented on the frequent “periods of uncertainty in the evolution of science and medicine.” Many of the questions posed by investigators last year about ATAC were answered at this year’s meeting, where 14 more months of follow-up demonstrated that the disease-free survival curves of the anastrozole and tamoxifen arms are continuing to diverge Figure 2). Most of the researchers I interviewed now agree with the viewpoint Gabe Hortobagyi has been expressing since the first presentation of ATAC — anastrozole is a rational, and in many cases, preferable endocrine approach for postmenopausal women with ER-positive breast cancer. It will be interesting to see whether clinicians repeat the ATAC experience and have a similarly cautious initial response to the CALGB data, particularly since a survival benefit is being reported with the dose-dense strategy.

Twenty-five years ago, a group of 100 researchers gathered for the first San Antonio Breast Cancer Symposium. That same year, at the National Cancer Institute, the remitting course of a patient with Hodgkin’s disease treated with MOPP caused a light bulb to go off” in Larry Norton’s head. The carefully planned scientific process that followed this observation culminated in a startling presentation that has not only provided a new treatment option for women, but has also confirmed that the clinical trial process truly works.

—Neil Love, MD

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