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139th National Cancer Advisory Board

primaries of the opposite breast 50 percent more than the tamoxifen treatment. Considering that tamoxifen had reduced that risk by 50 percent, the potential exists for a 70-75 percent reduction in primary invasive breast cancer compared with an untreated control group. Letrozole was capable of doing that in both the traditional adjuvant setting and the so-called extended adjuvant setting compared to placebo, but after 5 years of tamoxifen therapy. The P-4 proposal has already gone through peer review, and the hope is to initiate P-4 this calendar year.

In conclusion, Dr. Wickerham reminded everyone that the breast cancer stamp is one way to thank the women who have participated in the prevention trials. He acknowledged that the breast cancer prevention program of the NSABP owes its worldwide reputation to the thousands of women willing to enter its various prevention trials.

Questions and Answers

Dr. Runowicz asked for comment on the number of DCIS incidences that would have been expected on a placebo arm versus what was seen on the raloxifene arm alone, noting that she understood that raloxifene-mediated decrease was lower than that for tamoxifen. Dr. Wickerham replied that it would be necessary to refer to the P-1 trial and because the populations were somewhat different, it would be hard to say whether the few per thousand seen in the raloxifene group has no effect at all as in the expected population effect or a little bit lower. Dr. Chabner observed that, according to the Gail model, people above age 60 are at increased risk. He asked for an opinion on whether every woman without another factor that would proscribe its use should be on raloxifene to prevent breast cancer. Dr. Wickerham replied that the Gail score is used as a way to quantify risk within this clinical trial, but could conceivably be used as a tool to select individuals who may or may not be candidates when people become comfortable with it. He expressed the view that it is not an absolute criterion but simply a starting point in a reasonable risk benefit assessment that takes into account the Gail score but other things as well. Dr. Chabner pointed out that the estrogen receptor positivity findings represent an opportunity to try to understand tamoxifen resistance. Dr. Wickerham agreed and noted that NSABP already has begun to look at the molecular profile of the breast cancers that occurred in both trials while these women were on tamoxifen. One Pittsburgh group has begun that process to see whether a profile can be identified that would provide an insight into why resistance occurred.

Dr. Freedman asked about excluding patients where there was use of estrogenic substances in the past that might have influenced the progression, whether a history of that use was obtained, and whether the arms of the study were balanced. Dr. Wickerham replied that concurrent estrogen use was excluded. Women were permitted to enter the trial after a 3-month washout period of any of those products; all medications were characterized at the time of entry. In answer to the balance query, he observed that 20,000 people in the study would likely ensure a balance no matter what is examined. Dr. Meneses asked about overall adherence to the regimens. Dr. Wickerham explained that much time and effort was focused on adherence and compliance of both NSABP investigators or coordinators and the women coming into the trial. The goal was to make certain those coming into the trial knew what would be happening and the extent of the commitment they would be making. The original estimate for the STAR trial was that the level of noncompliance (i.e., dropping off medication but not out of the trial) would be 7.2 percent per year, but the actual level was lower. He stated that those figures are important because the sample size was defined based on those levels of assumptions; therefore, compliance was tracked carefully during the course of the study.

Dr. Kenneth Cowan, Director, Eppley Cancer Center, University of Nebraska Medical Center, commended the NSABP and NCI for spearheading these prevention efforts, noting that they provide evidence that an emphasis on prevention could lead to a significant health benefit in women and in other


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