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NIH Conference Forms Platform for Future Practice Guidelines on Preoperative Therapy for Invasive Breast Cancer

2007; Wolters Kluwer; Volume: 29; Issue: 8 Linguagem: Inglês

10.1097/01.cot.0000269628.73662.fb

1548-4688

Peggy Eastman,

Breast Cancer Treatment Studies

BETHESDA, MD—Preoperative systemic therapy (neoadjuvant therapy) is increasingly being given to patients with invasive breast cancer, but there are as yet no standardized clinical practice guidelines for such therapy. So said speakers at a two-day conference at the National Institutes of Health here hosted by the National Cancer Institute. The meeting, which examined breast imaging as part of its overall focus on preoperative therapy, was held at a time when two different groups announced new data on the value of magnetic resonance imaging in breast cancer (see box). The purpose of the conference was not to set guidelines, but rather to establish a platform for developing those guidelines, and to set a research agenda. “Before you can have an edifice you need to build a foundation,” said Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs and the Norna S. Sarofin Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center. “This is not a meeting to define what is done in practice. None of us is expecting that answers are going to come out of this meeting; this is the start of a conversation,” he told OT, predicting that guidelines on preoperative systemic therapy for breast cancer may emerge in about a year. Until that time, he strongly urged breast cancer patients who have preoperative systemic therapy to do so in the context of a clinical trial. “We run the risk of doing more harm than good if we don't provide good recommendations,” said Antonio Wolff, MD, Associate Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University. “I think we have a responsibility to come up with some guidelines.” Eventual guidelines would be helpful, added Eric Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute, because, “the preoperative setting is not a license to practice creative oncology.” Dr. Winer added, “There is tremendous promise here, but we are not yet ready to change clinical practice in 2007.” Differing Practice Guidelines Without standardized national practice guidelines, oncologists are pursuing different practice patterns, said another speaker, Gabriel N. Hortobagyi, MD, Professor and Chairman of the Depart-ment of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center and President of the American Society of Clinical Oncology. “There are enthusiasts in this room, and there are skeptics,” he told OT. “Those of us who do it regularly like it very much; it's a very reasonable option and a preferable option.” Dr. Hortobagyi noted that preoperative systemic therapy is primarily for those whose tumors are two centimeters or larger or have palpable positive lymph nodes, since women whose breast cancers are diagnosed early when they are very tiny and who have no lymph node involvement may need only breast-conservation therapy followed by radiation. Advantages, Disadvantages Dr. Hortobagyi and others at the conference pointed out that preoperative therapy for breast cancer offers several advantages, including: ▪ The ability to reduce the size of the primary tumor and nodal metastases in more than 80% of patients, increasing the chances that a woman can have breast-conservation therapy. ▪ The opportunity to assess the response of the primary tumor to a specific chemotherapy regimen—allowing for change to another regimen if the patient responds minimally or not at all to the first chemotherapy regimen tried. “In the preoperative group some patients will have chemotherapy-resistant cells; that's important information to know,” Dr. Hortobagyi said. “It gives you some comfort up front; you can spare a non-responder a six-month regimen after surgery.” Donald Berry, PhD, Chair of the Department of Biostatistics and Applied Mathematics at M. D. Anderson, agreed, broadening these advantages to clinical trials: “The neoadjuvant setting gives you a good milieu to test an agent.” And, he added, “Let's get into the current century. Let's test more drugs and more drug combinations; neoadjuvant trials are efficient.” A disadvantage of preoperative therapy discussed at the meeting is the loss of complete pathological staging. Another is possible wound healing complications after surgery. Right Therapy to Right Person “We're trying to tailor the right therapy to the right person,” said Jo Anne Zujewski, MD, NCI's Head of Breast Cancer Therapeutics. “Molecular profiling using a neoadjuvant approach may be a way of tailoring therapy.” She agreed with Dr. Hortobagyi that not subjecting a patient to a chemotherapy regimen that does not work is just as important as providing an effective one. In breast cancer, “there is significant overtreatment today,” she said, and the judicious use of preoperative therapy based on a patient's molecular profile might be a way to cut down on that overtreatment. Preoperative systemic therapy for breast cancer has evolved over the last 10 to 15 years, speakers noted. “In order for surgeons to embrace preoperative chemotherapy, two things had to occur,” said Norman Wolmark, MD, Chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Professor and Chairman of Human Oncology at Drexel University School of Medicine, and Chairman of the Department of Human Oncology at Allegheny General Hospital. Those were (1) the retreat from radical mastectomy, which was fueled by NSABP data on survival after breast-conserving therapy; and (2) data on the efficacy of adjuvant chemotherapy in node-negative and node-positive breast cancer, which NSABP trials also provided. Of specific importance to the issue of preoperative therapy for breast cancer, said Dr. Wolmark, were the results of the NSABP B-18 trial, which was conducted to test whether chemotherapy prior to surgery would improve patient outcomes. That nine-year trial of more than 1,500 women with early-stage operable breast cancer randomized patients to receive four cycles of doxorubicin/cyclophosphamide (AC) either before or after breast cancer surgery. The B-18 trial showed that survival was about the same in the two groups. “It really doesn't matter whether we give chemotherapy preoperatively or postoperatively in terms of disease-free survival,” said Dr. Wolmark, a member of OT's Editorial Board. However, “one sees a trend that favors the preoperative group,” especially in women under age 50. A similar randomized prospective European trial of nearly 700 patients conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed nearly the same results as the NSABP B-18 trial. Still to be answered is whether women who have systemic therapy before surgery instead of after are at greater risk for local recurrence, a subject debated at the NIH conference. Opportunity to Move State of the Art Forward Based on these results and those of other clinical trials, “I think we have a marvelous opportunity to move the state of the art forward,” Dr. Wolmark said. And, he noted, “I think we will be harshly criticized if we don't.” Others agreed. “We would like to see more of our patients have breast-conserving therapy after preoperative treatment,” said Harold J. Burstein, MD, PhD, Instructor in the Department of Medicine at Harvard Medical School and Dana-Farber Cancer Institute. “Today, we have more agents to bring into this setting.” ‘General Points’ In the absence of clinical practice guidelines for preoperative therapy in invasive breast cancer, the following general points (summarized at the end of the two-day conference) emerged: ▪ Preoperative systemic therapy should be done only if there is a well-trained, multidisciplinary team. Dr. Gabriel Hortobagyi stressed this point in an interview: “You do need a well-oiled team,” he said. “Once that team is established it works like a dream.” That team should consist of all those involved in care of the breast cancer patient, including the primary oncologist, surgeon, plastic surgeon if there is to be any reconstruction, pathologist, radiation oncologist and breast imager. “We need to be a team here,” agreed Julie R. Gralow, MD, Associate Professor of Medical Oncology at the University of Washington. ▪ There needs to be a commonly accepted and used terminology related to preoperative therapy for breast cancer. Dr. Jo Anne Zujewski said that an effort is currently underway to standardize the terminology for endpoints in this field. ▪ Patients who are candidates for preoperative therapy need a careful, clear explanation of why it might be their best option. “Patients have a varied knowledge of their disease,” said Mary Lou Smith, JD, Co-Founder of the Research Advocacy Network. “The patient is on an emotional roller coaster. The natural human reaction is, ‘Get it out!’ When we talk to people, they've never heard of waiting for surgery.” ▪ The optimal chemotherapy regimen in the preoperative setting is the same one that would be optimal in the postoperative setting. ▪ Breast imaging with ultrasound and mammography is the standard way of tracking the efficacy of preoperative therapy. Driving the use of MRI as an emerging technology for monitoring the response to preoperative therapy is its staging accuracy. ▪ Preoperative therapy with anti-angiogenesis agents is a promising target now under investigation in clinical trials. ▪ The timing of sentinel node biopsy remains controversial. ▪ Pathologic complete response after chemotherapy is not adequate when used as a single surrogate marker. ▪ Preoperative hormonal therapy is a reasonable approach for a postmenopausal woman who is not a candidate for chemotherapy. ▪ The timing of surgery, in the absence of disease progression, should occur after a predetermined course of preoperative therapy. ▪ Data from clinical trials are needed to resolve unanswered questions related to preoperative systemic therapy for invasive breast cancer. Breast MRI Gets Boost from Two Groups The American Cancer Society's new recommendations on the use of magnetic resonance imaging for women at high risk of breast cancer advise that those women have annual screening using MRI in addition to mammography. Based on data from an ACS-convened expert panel, the Society recommends that women should have annual MRI screening in addition to mammography if they: ▪ Have a BRCA1 or BRCA2 mutation. ▪ Have a first-degree relative with a BRCA1 or BRCA2 mutation and are untested. ▪ Have a lifetime risk of breast cancer of 20% to 25% or more using standard risk-assessment models. ▪ Received radiation to the chest between ages 10 and 30 (such as during treatment for Hodgkin disease); and carry or have a first-degree relative who carries a genetic mutation in the TP53 or PTEN genes (Li-Fraumeni syndrome and Cowden and Bannayan-Riley-Ruvalcaba syndromes). In addition to the new ACS recommendations, an NCI-funded study from the American College of Radiology Imaging Network (ACRIN) found that MRI can detect cancers in the opposite breast of women newly diagnosed with breast cancer (NEJM 2007;356:1295–1303). “One in 10 women diagnosed with cancer in one breast will develop the disease in the opposite breast. Having a better technique to find these cancers as early as possible will increase the chances of successful treatment,” NIH Director Elias A. Zerhouni, MD, said in an NCI news release about the study. In the ACRIN study of 1,007 women from 25 centers with a recent diagnosis of cancer in one breast (969 of whom completed the study)—first author was Constance D. Lehman, MD, PhD, of the University of Washington Medical Center, Seattle Cancer Care Alliance—30 contralateral breast cancers were detected by MRI. All of the women in whom these contralateral tumors were diagnosed had had a negative mammogram and negative clinical breast examination of the opposite breast within 90 days before having MRI. NCI Director John E. Niederhuber, MD, said in the news release that the findings can be used to help women more confidently opt out of a double mastectomy—if MRI of the opposite breast is negative.