Newsletter #49–Aug./Sep. 1998
Hope and Hype Dominate ASCO Meeting
by Barbara A. Brenner
In May, 20,000 cancer specialists and numerous spin doctors from around the world gathered in Los Angeles for the annual conference of the American Society of Clinical Oncologists (ASCO). This is the largest oncology meeting in the world, and the topics covered not only all cancers, but also issues that ranged from screening to diagnosis, treatment and end-of-life care. The breast cancer news that issued from the meeting received far more media attention than it deserved, but, on several topics, there was important information -- some of it long awaited and encouraging -- to be gleaned out of the brouhaha generated by the ASCO media office.
HER2—Promise for Metastatic Disease
The May 18 headline in The San Francisco Chronicle —"Dramatic Success in Treating Breast Cancer Through Genes"—could well have been written by Genentech, the manufacturer of Herceptin. The facts presented at the ASCO meeting by the researchers are considerably less exciting, but nonetheless important.
Herceptin is designed to attack breast cancer through the HER2/neu protein. The protein is "overexpressed" (appears in higher-than-normal numbers) in some 30% of breast cancer cases. Herceptin is a monoclonal antibody designed to attach to the HER2/ neu protein of breast cancer cells and interfere with the cells' biological processes. Two studies reported at the ASCO meeting indicate that the treatment shows some benefit for some women who overexpress HER2/neu.1
One study looked at Herceptin as a stand-alone treatment for 213 women with metastatic disease who had had recurrences following chemotherapy, all of whom overexpressed HER2/neu.2 Based on a median time of nine months following treatment, the preliminary data indicate that somewhere between 31 (15%) and 44 (21%) of the women in the trial received some benefit from Herceptin. (The discrepancy in the numbers derives from a difference between what the investigators and what the independent Response Evaluation Committee (REC) believed to be evidence of response.) According to the REC, eight women had complete responses to Herceptin, and another 25 had partial responses. The median duration of the responses was 8.4 months; in other words, half the women who responded to Herceptin continued to benefit for more than 8.4 months, while half benefitted for less time.
For the women for whom Herceptin proved beneficial, the other good news was that it did so for the most part without the side effects normally associated with chemotherapy. While 40% of patients had symptoms including chills and fever with the first infusion of Herceptin, those symptoms did not recur with later treatments. The most significant adverse effect seen in this study was cardiac toxicity (damage to the heart), which occurred in nine patients (4%), all of whom had had treatment with an anthracycline (e.g., Adriamycin) or significant cardiac history before entering the study.
A second Herceptin study reported in Los Angeles involved the addition of the antibody to first line chemotherapy treatment for metastatic disease.3 This was a randomized trial in which the patients, all of whom had metastatic disease and overexpressed HER2/neu, received either Adriamycin/Cytoxan (A/C) or Taxol. Some patients in each group were also randomly assigned to receive Herceptin. The principal goal was to learn whether adding Herceptin to chemo regimes for these patients extended the amount of time that the women's conditions were stable.
At the time of the ASCO meeting, the study data had not been reviewed by an independent Response Evaluation Committee. Nonetheless, the conclusion of the investigators was that the addition of the monoclonal antibody to standard chemotherapy agents improved the response rate (defined as a 50% or greater measurable reduction in breast cancer) by at least 50% and increased the amount of time before breast cancer spread by approximately three months (from 4.6 months to 7.6 months). These results were seen in both the A/C and the Taxol arms of the study, though the improvement in response rate when Herceptin was added was greater for patients receiving Taxol treatment than for those receiving A/C treatment. As with the study of Herceptin alone, few side effects were seen from the monoclonal antibody. The most significant side effect was cardiac toxicity in patients receiving A/C plus Herceptin.
Both of these studies were funded by Genentech, the manufacturer of Herceptin. The drug is not yet available, except through the expanded access lottery established at the insistence of BCA and other advocacy organizations. Herceptin is before the FDA for fast-track approval.
Taxol May Increase Survival for Some
In a study likely to change treatment recommendations for women diagnosed with positive nodes, early results indicate that Taxol (paclitaxel) increases both disease-free and overall survival.4 The early results also indicate no advantage in either disease-free or overall survival from increased dosages of Adriamycin (doxorubicin).
The randomized trial enrolled 3,170 patients between 1994 and 1997, and the data were examined in a planned "first look" earlier this year. The researchers were surprised to find a relative four percent (90% compared to 86%) improvement in disease-free survival and a relative two percent (97% compared to 95%) improvement in overall survival for patients who received Taxol. While the NCI has cautioned against making treatment decisions based on these very early results, and it remains to be seen whether these advantages will hold up over time, it is expected that treatment recommendations will change based on the early results of the study.
Guidelines for Mastectomy Ignored
In 1992, the National Cancer Institute issued guidelines for when mastectomy should be done instead of lumpectomy followed by radiation (also known as breast conserving therapy, or BCT). Under these guidelines, the only factors indicating that a mastectomy should be chosen are: large tumor size, small breast size in comparison to tumor size, first or second trimester pregnancy, multiple lesions in various sites in the breast, or prior breast irradiation. Under these guidelines, approximately 75% of women with early-stage (non-metastatic) breast cancer are eligible for BCT. But, in a study of nearly 18,000 women treated for early-stage disease in 1994, only 44% had BCT.5
Despite the guidelines, factors such as clinical stage, histologic grade and age of the patient were all important factors in the choice between mastectomy and BCT, with later stage, higher grade, and greater age all associated with more frequent mastectomy.
On the basis of their analysis, the investigators concluded that the low rate of BCT resulted from a failure to understand the NCI guidelines and a persistent belief, despite contrary data from randomized trials, that age, prognosis and tumor type are irrelevant selection criteria for BCT.
Premature Claims for Raloxifene
The USA Today headline captured the hype quite nicely: "Could Daily Drug Dose Stop Breast Cancer?" (5/19/98). The paper quoted one of the country's most prominent oncologists, Larry Norton of Memorial Sloan-Kettering Cancer Center, as "forsee[ing] a day in the near future when all post-menopausal women, and some premenopausal women, will be taking something to prevent breast cancer." The ridiculous headline and Norton's preposterous statement were based on two-and-a-half-year findings from a seven-year study, which is not designed to test whether the drug "prevents" breast cancer. According to the abstract, the hypothesis being tested is whether women on raloxifene have a lower risk of fractures.6
All of the women participating in the trial that was reported on at the ASCO meeting have osteoporosis. Osteoporosis results from a deficiency of estrogen and, accordingly, is likely to put those with the disease at lower risk of breast cancer than the rest of the population. And, in any event, raloxifene has been studied for only two years, certainly not long enough to know what its benefits or risks are.
Raloxifene, marketed by Eli Lilly under the name Evista, is approved by the FDA for prevention of osteoporosis. The drug has not been approved for breast cancer prevention or any other use connected to breast cancer. Yet, the investigators, whose work is funded by Eli Lilly, tout the drug's ability to prevent breast cancer and did so for many months before the ASCO meeting.
These premature claims about the breast cancer "benefit" of raloxifene appear to be part of a campaign by Eli Lilly to market it aggressively to menopausal women who hesitate to take hormone replacement therapy because of a fear of breast cancer. The experience with tamoxifen in women with breast cancer—where use beyond five years increased risk of recurrence—is a telling example of why drugs need to be examined over a long period of time.7 In addition, in laboratory studies, raloxifene, which is a chemical cousin to tamoxifen, increased the incidence of ovarian cancer in mice and rats. This risk was not cited at the ASCO meeting.
The NCI, which acted so precipitously in ending the trial of tamoxifen in healthy, high-risk women (see 'Prevention Pill'—More Harm Than Good? BCA Newsletter #48, June/July 1998, p. 1), will undertake a trial comparing tamoxifen to raloxifene, again in healthy women. A five-year study is promised, but, based on the tamoxifen trial, don't hold your breath.
An Activist's Perspective on ASCO
The 20,000 cancer doctors who attended the ASCO conference came because they wanted to learn what new developments might be important in their practices. For doctors who treat breast cancer, the learning process consisted of one-paragraph abstracts of each of the 340 breast cancer studies, five- to ten-minute presentations on a select few of these studies and five minutes for questions posed from the floor to the studies' presenters. As a woman treated by doctors who attend this meeting, I can only hope and pray that somehow, somewhere, they obtain more information before making treatment recommendations.
In fact, I hope that at some point my doctors have the same chance that the media representatives at the ASCO meeting had. For while the doctors were listening to very brief presentations on very important issues in cancer, the media representatives attended media briefings that were at least an hour long and at which they were free to quiz study investigators at length. I for one would be happier if ASCO would give the media briefings to my doctors, and limit the media to reading the hard data contained in the far-too-brief abstracts.
1 The Herceptin data reported at ASCO were developed in Phase III trials and were presented to the FDA in early May as part of the process of approval for marketing the drug. See "Genentech Expands HER2 Lottery," BCA Newsletter #46, February/March 1998.
2 M.A. Cobleigh et al., "Efficacy and Safety of Herceptin as a Single Agent in 222 Women with HER2 Overexpression Who Relapsed Following Chemotherapy for Metastatic Breast Cancer," Abstract No. 376, Program Proceedings, American Society of Clinical Oncology, 34th Annual Meeting, May 16-19, 1998. Nine of the women enrolled in the trial never received Herceptin.
3 D. Slamon, et al., "Addition of Herceptin to First Line Chemotherapy for HER2 Overexpression Metastatic Breast Cancer Markedly Increases Anticancer Activity: A Randomized Multinational Controlled Phase III Trial," Abstract No. 377, Program Proceedings, American Society of Clinical Oncology.
4 I.C. Henderson, et al., "Improved Disease-Free and Overall Survival From the Addition of Sequential Paclitaxel But Not From the Escalation of Doxorubicin Dose Level in Adjuvant Chemotherapy of Patients with Node-Positive Primary Breast Cancer," Abstract No. 390A, Program Proceedings, ASCO.
5 M. Morrow, "Factors Responsible for the Underutilization of Breast Conserving Therapy," Abstract No. 379, Program Proceedings, ASCO.
6 S.R. Cummings, "Raloxifene Reduces the Risk of Breast Cancer and May Decrease The Risk of Endometrial Cancer in Post-Menopausal Women. Two-Year Findings from the Multiple Outcomes of Raloxifen Evaluation (MORE) Trial," Abstract No. 3, Program Proceedings, ASCO.
7 See also Pearson, C., "Raloxifene: Is It Really a Replacement for Hormone Replacement Therapy?" The Network News, National Women's Health Network, March/April 1998.