A new National Cancer Institute clinical trial attempts to pinpoint early-stage breast cancer patients who will (and won’t) benefit from chemotherapy
by Lauren John
My mother, Anne Fleishman, is petite, blonde, and thin. I am tall, brunette, and a size 12. Whenever we go to a restaurant, my mother pushes the bread basket and butter far away from me. “You don’t need it,” she says.
Come dessert time, it happens again. I order rice pudding. “You don’t need it,” she says. When the waiter ignores her and asks if I want whipped cream on it, my mother tells him, “No!”
But I’m not the only one under observation. My cousin Judy is a size 2—even thinner than my mother. When Judy shows up for dinner, my mother offers her a homemade piece of apple cake. “Eat! Eat! You need it,” she says.
During my breast cancer chemotherapy ten years ago, all diet rules were suspended as my mother cooked for me and my husband, an act of love that we appreciate to this day. But in one crazy dream, no doubt induced by a host of chemo and antinausea drugs, as well as her fine home cooking, I pictured my mother walking through the chemo suite at Beth Israel Hospital in Boston, pushing IV poles toward some women and pulling them away from others. “You over there in the corner with the lovely turtleneck sweater, you’re looking healthy, your color is good, you don’t need the chemo,” she would say. “You, in the silk blouse sitting over there with the Martha Stewart magazine, you need to dress more warmly—and a little chemo couldn’t hurt.” My dream ended on a high note. Everyone in the chemo suite listened to my mother and got better, and celebrated with rice pudding and apple cake.
Clearly the Anne Fleishman protocol is a fantasy. But the problem she addressed is all too real. We can’t tell, just by looking at people, whether they are size 2 or size 12, who will benefit from chemotherapy and who will not.
The Sobering Statistics
According to the National Cancer Institute (NCI), breast cancer is the most frequently diagnosed cancer in women (after skin cancer), with an estimated 212,920 new cases of invasive breast cancer expected in the United States in 2006. Over one-half of these women will have estrogen-receptor-positive, lymph-node-negative breast cancer. For 80 to 85 percent of those women, the current standard treatment practice is surgical excision of the tumor, followed by radiation and hormonal therapy. Chemotherapy is also recommended for most women, but the proportion of women who actually benefit substantially from it is believed to be fairly small.
“A large number of…women are receiving toxic chemotherapy unnecessarily, and we need a means of identifying them,” said Jo Anne Zujewski, senior investigator in the Clinical Investigations Branch of NCI’s Cancer Therapy Evaluation Program.1
We also need better treatments than “toxic chemotherapy”—but first things first. This April, the NCI launched a Phase III clinical trial for early-stage breast cancer patients. The goal is to find better ways to customize their systemic (e.g., chemotherapy and/or hormonal) treatment. Women who enroll in the trial, known to patients and the media as TAILORx (the Trial Assigning Individualized Options for Treatment Rx), will supply tumor tissue that will be studied using a new genetic test (called Oncotype DX) that estimates their risk of recurrence. Once the recurrence risk is scored as high, medium, or low, their systemic treatments will be prescribed accordingly. The study will also create a tissue and specimen repository for use in future studies, including the development of, hopefully, even more accurate diagnostic tests.
The bottom line is that this clinical trial is “a test of a test,” explains Lea Ann Bernick, program manager of the Sutter Health Western Division Cancer Research Group.
“This is also a trial to improve standards of care…to better individualize what doctors are already telling patients to do based [on] their chance of recurrence,” she says. “Hopefully this study will give women…who fall into the gray or middle areas…another tool to use when making treatment decisions.”
Who are the women in the middle? “They are those who are at neither very high risk nor very low risk of recurrence,” she explains.
TAILORx aims to enroll approximately 11,000 early-stage breast cancer patients at 900 sites in the United States and Canada, and track their progress for ten years. As of August 2006, 40 women were enrolled nationwide, says Bernick. The Sutter Health Group is running the TAILORx trial at several San Francisco Bay Area medical centers, including Alta Bates Comprehensive Cancer Center in Berkeley, Mills Peninsula Medical Center in Burlingame, and the California Pacific Medical Center in San Francisco.
Testing a Test
The test that will be tested in TAILORx is known as Oncotype DX, and it was developed by a private company, Genomic Health Inc. (www.genomichealth.com), which partnered with a network of cancer research professionals known as the National Surgical Adjuvant Breast and Bowel Project.2 This tumor tissue test (known technically as a diagnostic assay test) examines 21 different genes simultaneously in search of established patterns that indicate who might be at greatest risk for breast cancer recurrence.3
A number of recent studies indicate that this may be a promising, reliable indicator of breast cancer recurrence, the latest being an article published this year in the Journal of Clinical Oncology.4 The testing technique was also discussed as a way of predicting colon cancer recurrence at the 2006 meeting of the American Society of Clinical Oncology.5
All of the women eligible to participate in the study must be diagnosed with early-stage breast cancers. More specifically, the women who participate must be diagnosed with estrogen-or progesterone-positive, HER2/neu negative breast cancer that has not yet spread to the lymph nodes.6
“The good news is that this is a brand-new study, and there is lots of time for women to speak with their oncologists about it before enrolling,” she says. In fact, she adds, anyone interested in participating in the study has to be referred by their oncologist.
Who Gets What?
Under current treatment protocols most early-stage breast cancer patients who are estrogen- or progesterone-receptor-positive are advised to undergo a hormonal treatment, such as tamoxifen (which is taken in pill form). But depending on how their cancer cells “behave” during a battery of long-established laboratory tests, the results of which make up a pathology report, some women are advised to have both chemotherapy and hormonal treatment. Given that, by their very nature, early-stage breast cancers statistically have a lower rate of recurrence, there has always been the concern that patients may be overtreated. So, who gets what treatment in the TAILORx trial? Women with a high recurrence score will get chemo and adjuvant hormone therapy.
Those who have a low recurrence score will only get hormonal treatment. Those whose recurrence risk falls in between will be randomly assigned to receive adjuvant hormonal therapy with or without the chemo.
What kinds of hormones and what kinds of chemo drugs will be used? The specific drug and hormone regimens will take into consideration the overall health and menopausal status of the patients. Hormonal therapies will include tamoxifen and the aromatase inhibitors anastrozole, letrozole, and exemestane, while women who receive chemotherapy will receive one of several “gold standard” combinations.7
Should Everyone Get Something?
If you are thinking about participating in this trial, or just thinking about the clinical trial as a giant step forward in the way that the NCI thinks about and provides cancer treatment, consider this. Although some women will get chemo and some won’t, everyone in the trial will receive a hormonal therapy such as tamoxifen or an aromatase inhibitor. True, the hormonal therapies generally (but not always) have fewer debilitating side effects. But there is no control group in which early-stage breast cancer patients can opt out of both drug and hormone treatment, and simply be monitored through self-exam and mammography. Gwendolyn Holmes of St. Vincent’s Comprehensive Cancer Center in New York City believes that it would be “unethical” to have a control group that is not treated in some systematic way.
However, some breast cancer activists think that scientists should explore and compare how women with a low risk of breast cancer recurrence do both on and off systemic drug and hormone treatments. Might there be a breast cancer patient group with a low risk of recurrence that does best with no drug or hormone treatment at all? And is it really unethical to offer them this option?
As technology improves and larger banks of tumors are available for analysis in a prospective fashion, we will almost certainly perfect our ability to more precisely predict recurrence and tailor treatments. This will allow us to forgo unnecessary treatment in a large number of patients without denying treatment to patients who can most benefit from it.8
“When that day comes, we will shout from the rooftops,” said BCA executive director Barbara Brenner. “It’s a tragedy for far too many women that it has taken the medical community so long to focus on this important question. We anxiously await the results.”
1 NCI press release, “Personalized Treatment Trial for Breast Cancer Launched,” May 23, 2006. Available online at www.cancer.gov/newscenter/pressreleases/TAILORxRelease.
2 For more information on Oncoptype DX, read Barbara Brenner’s comments from the 2004 San Antonio Breast Cancer Symposium.
3 Online FAQ about Oncotyype DX available at www.genomichealth.com/oncotype/faq/pat.aspx.
4 Soonmyung Paik, et al., “Gene Expression and Benefit of Chemotherapy in Women with Node-Negative, Estrogen Receptor-Positive Breast Cancer,” J Clin Oncol, 2006; 24(23), August 10, 2006.
5 J.C. Chang, et al., “Gene Expression Profiles in Formalin-Fixed, Paraffin-Embedded (FFPE) Core Biopsies Predict Docetaxel Chemosensitivity,” Abstract No. 538, presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006.
6 More details about eligibility requirements and study centers across the United States are online atwww.cancer.gov/clinicaltrials/ECOG-PACCT-1.
7 NCI press release, “Personalized Treatment Trial for Breast Cancer Launched,” May 23, 2006. The press release states that, “women on the chemotherapy arm of the trial will receive one of several standard combination chemotherapy regimens considered to be the best available standard care today.”
8 Sandra M. Swain, “A Step in the Right Direction,” J Clin Oncol, 2006; 24(23), August 10, 2006. Available online at www.jco.org.