BREAST CANCER ACTION - Return to Home Page - Breast Cancer ...

More documents

Recommendations

Info

10 February/March 2004 Breast Cancer Action Impressions From San Antonio continued from page 1 disappointing results of its Phase III trials in metastatic breast cancer patients last summer. In San Antonio, the company presented a subset analysis that, while not conclusive in itself, offers a possible direction for new trials. Patients with ER+ tumors receiving hormonal treatments while undergoing Theratope showed a trend (not a statistically significant difference) toward better time to disease progression and overall survival [Miles 36]. Determining which patients are most likely to respond can transform a drug failure into a success. The monoclonal antibody Herceptin would never have shown a benefit in breast cancer, Genentech researchers say, had they not been able to develop a test that predicted Herceptin response. To date, however, Genentech has been unable to devise such a test for its new drug Avastin ® , which targets VEGF, a gene responsible for angiogenesis (the growth of blood vessels that feed tumors). Straightforward tests for gene expression are not always useful, it seems. Many if not most of the new agents don’t show enough activity by themselves, at least not in a general patient population. So, for rational combinations to be designed, much more must be learned about the complex signaling pathways within cancer cells, crosstalk between genes, and messages from outside the cancer cell that govern cell proliferation and cell death (apoptosis). Although it is now “hot,” the genomic research paradigm is not the only avenue worthy of exploration. Which cancer cells researchers target may be important, as Max Wicha, of the University of Michigan, suggested in a plenary talk in San Antonio [Wicha P1]. His research elegantly demonstrates that tumor stem cells, the original cells from which all other cancer cells differentiate, may turn out to be of crucial importance in explaining drug resistance and the incurability of many cancers. Pointing to the notable success in curing metastatic testicular cancer, Wicha suggested that therapies designed to target only stem cells may be much more effective. Mining the Past to Predict the Future: Is It Possible? With the introduction of microarray and related technologies a few years ago, where the entire genetic fingerprint of a cancer (or the most relevant genes) could be analyzed on a single chip, the door seemed to swing wide to precise individualization of treatment. A single test would have the power to predict the risk of recurrence, and then to tell a woman with breast cancer exactly which treatments she needed—or whether she needed no further treatment after surgery, an even more powerful revelation for the majority of newly diagnosed women whose breast cancers are actually cured by surgery alone. The concept was mind-boggling. Imagine no more overtreatment or undertreatment. No more one-size-fits-all. And for many if not most of us, there would be the certainty of knowing we were cured. Such were the hopes. So far, the possibilities have proven to be just that—possibilities. Determining which patients are most likely to respond can transform a drug failure into a success. The study poised to be this year’s breakthrough news involved the use of the multi-gene RT-PCR test to predict recurrence, a new 21-gene microarray developed by Genomic Health. This test is derived from a combination of genes known to govern primarily cell proliferation and hormonal regulation in tumor cells. The revolutionary premise here is that this test is done on standard diagnostic pathology specimens, namely, archived, paraffin-embedded tumor tissue. If this is proven useful, researchers will be able for the first time to correlate archived tumor tissue with known patient outcomes from studies initiated and completed years ago, avoiding lengthy and costly “prospective” clinical trials. The validation study for RT-PCR was done through the National Surgical Adjuvant Breast and Bowel Project, one of the cancer cooperative groups responsible for many important clinical trials. Researchers hoped to predict who was most and least likely to have a recurrence, based on tumor tissue alone. Using samples of the tissue of 668 nodenegative breast cancer patients with ER+ tumors who were treated with tamoxifen during the 1980s, the study authors said that they were able to predict outcome better than any single prognostic factor, apart from tumor grade. The “low risk” group they identified had a risk of recurrence of 6.8 percent at 10 years, while the “high risk” group had a recurrence rate of 30.5 percent [Paik 16]. Genomic Health, who will be marketing this test as Oncotype DX early in 2004 for a minimum of $3,000, claims that it will help women with node-negative ER+ tumors taking tamoxifen (as most such patients do) select treatment more wisely. But even if the test is confirmed in other studies, how much will it really help the individual woman? How will the results be confounded if Arimidex ® is widely accepted as standard of care, rather than tamoxifen? Is a 6.8 percent risk of recurrence low enough for a woman to feel comfortable refusing tamoxifen? Wouldn’t a woman in the highest risk group be considering chemotherapy anyway? Today, oncologists combine factors when considering prognosis, including tumor size, involved lymph nodes, tumor grade, etc. Several complex algorithms that feed recent data from clinical trials into a computer program are freely available to assist in this task, such as Adjuvant at www. adjuvantonline.com. So, it’s unclear what this test will add to the picture, even if its results are widely confirmed. And speaking of confirmation, another study presented at the conference, using the same test in a similar population, some of whom who did not receive tamoxifen, was conducted at M.D. Anderson Cancer Center. This study failed to show any predictive value for recurrence [Esteva 17]. So, much more work is clearly needed. A fundamental question to be asked here, according to statistician Donald Berry of the M.D. Anderson Cancer Center, is whether these incredibly complex analyses of genetic expression are likely to ever provide reliable, reproducible results, given the multiplicity of potential data points, the difficulties with uniform data collection and pathology, and a variety of other statistical and methodological issues that make interpretation of tests like this fraught with problems. ◆ Musa Mayer is a 14-year survivor and the author of four books including, most recently, After Breast Cancer: Answers to the Questions You’re Afraid to Ask (O’Reilly, 2003). She provides information and support for women with metastatic breast cancer daily at www.bclist.org and www.bcmets.org. THE NEXT SAN ANTONIO BREAST CANCER SYMPOSIUM WILL BE DECEMBER 8–11, 2004…
Breast Cancer Action February/March 2004 11 From the Executive Director continued from page 2 can establish that some early change during the treatment process (the “surrogate endpoint”) indicates that a woman will have longer disease-free survival (DFS), more time to progression (TTP), or better chances of overall survival (OS), then you can move more quickly with smaller trials to complete evaluation of the treatment without waiting the many years it takes to establish DFS or OS themselves. But this logic only works if, in fact, the interim change correlates to the ultimate goals that you’re trying to achieve. What those goals are, of course, will be different depending on the stage of disease being treated. Overall survival is important to everyone who’s ever had a diagnosis, while TTP will be of greater concern to women living with metastatic breast cancer. But, whatever the goal of the therapy, the “surrogate” has to work as a stand-in. And there’s the rub. 1 Several of the early (and theoretically “hot”) presentations at this meeting used the surrogate endpoint of Ki67 expression as evidence for DFS and, ultimately, OS. Ki67 is one of a number of genes that control cell proliferation. If a tumor expresses a lot of Ki67, the theory is that this will lead to more cell proliferation, and ultimately new or growing tumors. Basing their work on this theory, researchers are using Ki67 reduction as a surrogate endpoint in drug analysis. But after the presentation of two different studies that relied upon this surrogate endpoint, a member of the audience asked whether Ki67 had been validated as a marker for clinical outcome. And, lo and behold, it turns out that, in the words of the researcher who was asked, the evidence that Ki67 is a good predictor of recurrence is “very sketchy.” For that matter, there is no standard for measuring Ki67, and therefore no way to consistently evaluate its increase or decrease. And no studies were cited showing that changes in Ki67, in fact, correlate to an improved (or to a worse) outcome in patients. Yet, despite this lack of a validated surrogate endpoint, researchers pointed to suppression of Ki67 as evidence that anastrozole (Arimidex ® ) alone may be more effective than tamoxifen (Nolvadex ® ) alone or tamoxifen and anastrozole combined in the neoadjuvant setting for postmenopausal ER+ women [Dowsett, 2]. This conclusion was reached even though the trial showed no statistical difference between anastrozole and tamoxifen in terms of clinical response in this very short (two-week) study involving 330 patients. The same nonvalidated endpoint was used to evaluate the short-term effects of gefitinib (Iressa®) on ductal carcinoma in situ (Abstract 14). I was surprised—in fact, appalled—that anyone would test a drug as unproven as Iressa in a group of patients with non-life-threatening disease. 2 The trial showed a trend—but not statistically significant results—of Ki67 reduction from Iressa. Based on trend data of a nonvalidated endpoint, the researcher concluded that EGFR inhibitors such as Iressa should be studied in ERnegative DCIS. He also noted that, while drugs like Iressa may not work alone, they may work in combination with other compounds. How many drugs are healthy people going to have to take in the brave new world of cancer chemoprevention? And what will the long-term effects be? These questions weren’t answered at San Antonio. They weren’t even asked. In fact, the great thing missing in most of the presentations I heard at San Antonio was information about what the drugs under study meant for women’s lives. Given how little we know about surrogate endpoints and their relationship to patient outcomes, will patients really do better on the new drugs than on the old ones, taking into account not only the breast cancer outcome but also the other effects of the drug? Many of the studies presented at San Antonio either did not consider the clinical impacts of the treatments, or minimized them. In a presentation I missed, researchers showed that docetaxel (Taxotere ® ) gave women with metastatic disease almost three more months of life than paclitaxel (Taxol ® ). I was entering the lecture hall as the talk was ending, but a breast surgeon from San Francisco who was on her way out whispered in my ear that these patients were trading three additional months of life against extraordinary bone pain. Apparently, this trade-off wasn’t discussed in the presentation or the questions afterwards. Someone—everyone—needs to remind the presenters at this meeting that what matters to patients is what these drugs do for them and to them, in both the short and the long run. Yet the breast cancer advocates at this meeting—120 registered out of the more than 6,000 people in attendance—were remarkably silent during the question-andanswer portions of the presentations I heard. I think we need to have more activists at the Community Organizer Kendra Klein shares BCA’s perspective with a visitor to our booth at the San Antonio conference. San Antonio meeting to make sure that the concerns of women living with and at risk for breast cancer don’t get drowned out by the marketing hype that drives so many of the presentations. ◆ If you’re interested in joining BCA at the 2004 San Antonio Breast Cancer Symposium, contact Kendra Klein at 415/243-9301 or kklein@ bcaction.org. 1.The medical journals are filled with stories of surrogate endpoints that didn’t work out. Best known in breast cancer is probably the use of “tumor response rates” in evaluating high-dose chemotherapy/autologous bone marrow transplant treatment. The tumor response rates did not, as it turned out, predict accurately for either overall survival or time to progression of disease. But we didn’t learn this before many, many women had had this often devastating treatment. See “Preliminary Results for NCI Show HDC Offers Little Benefit,” BCA Newsletter #54 (June/July 1999), viewable online at http://www.bcaction.org/Pages/SearchablePages/ 1999Newsletters/Newsletter054A.html. 2.I was astonished to see this study because I recalled the presentation at San Antonio in 2002 about Iressa in the metastatic setting (which was a failure—see “Changing Goals for Iressa,” BCA Newsletter #76, viewable online at http:// www.bcaction.org/Pages/SearchablePages/2003N ewsletters/Newsletter076I.html). I also know the controversy that arose over the FDA’s approval of Iressa for lung cancer despite lack of evidence of efficacy. At the 2003 conference, the presenter of the Iressa studies acknowledged that the latest studies are geared toward “chemoprevention,” not treatment. …HOW MANY ACTIVISTS WILL BE THERE?
Page 1 and 2: BREAST CANCER ACTION Newsletter #80
Page 3 and 4: Breast Cancer Action February/March
Page 5 and 6: Breast Cancer Action February/March
Page 7 and 8: February/March 2004 7 Photo: Gwen R
Page 9: Breast Cancer Action February/March

BREAST CANCER ACTION - Return to Home Page - Breast Cancer ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?