Guidelines Updated for Use of Tumor Markers in Breast Cancer

November 13, 2007 — The American Society of Clinical Oncology (ASCO) has updated its recommendations for use of tumor markers in prevention, screening, treatment, and surveillance of breast cancer. The revised guidelines were published in the October 22 Early Release Article issue of the Journal of Clinical Oncology, after approval by the ASCO Board of Directors Executive Committee on July 12, 2007.

In 1996, ASCO first published evidence-based clinical practice guidelines regarding the use of tumor markers in breast cancer. An Update Committee of the original Expert Panel updates these guidelines at intervals, with the last update regarding tumor markers in breast cancer published in 2000.

"For the 2007 update, the Panel expanded the scope of the guidelines to include a broader range of markers in breast cancer," write Lyndsay Harris, MD, from the Yale Cancer Center, Yale University in New Haven, Connecticut, and colleagues from ASCO. "In addition, the impact of genomic technologies was considered in the Update. While molecular subtyping is still in its infancy, and subgroups are not well defined, the use of multiparameter technologies in clinical practice has considerable potential."

Using computerized literature searches of MEDLINE and the Cochrane Collaboration Library, the Update Committee reviewed and analyzed data published since 1999, particularly focusing on available systematic reviews and meta-analyses of published studies on tumor markers. Recommendations were based on significant health outcomes, namely overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness.

Of 13 categories of breast tumor markers considered, 6 were new to these guidelines. The categories recommended for use in practice, based on evidence of clinical use, were CA 15-3, CA 27.29, carcinoembryonic antigen (CEA), estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and certain multiparameter assays for gene expression. However, not all applications for these markers were supported.

Categories for which available evidence was insufficient to support routine use in clinical practice was DNA/ploidy by flow cytometry, p53, cathepsin D, cyclin E, proteomics, certain multiparameter assays, detection of bone marrow micrometastases, and circulating tumor cells (CTCs).

Specific changes from the 2000 guidelines are as follows:

• ER and PgR should be measured on every primary invasive breast cancer and may be measured on metastatic lesions if the results would affect treatment planning. Steroid hormone receptor status should be used to identify patients most likely to benefit from endocrine therapies. In patients with ductal carcinoma in situ (DCIS) who are candidates for hormonal therapy, data are insufficient to recommend routinely measuring ER and PgR.
• Immunohistochemically based markers of proliferation are new to the guidelines. Present data are insufficient to recommend measuring markers of proliferation to assign patients to prognostic groups. These include Ki67, cyclin D, cyclin E, p27, p21, thymidine kinase, and topoisomerase II.
• To guide selection of trastuzumab in the adjuvant or metastatic setting, HER2 expression or amplification should be evaluated in every primary invasive breast cancer, either at the time of diagnosis or at the time of recurrence.
• HER2 may be useful to predict response to specific chemotherapeutic agents. Based on level II evidence, overexpression of HER2 (3+ by protein or > 2.0 fluorescent in situ hybridization [FISH] ratio by gene amplification) identifies patients who may benefit more from anthracycline-based adjuvant therapy. Assuming there are no contraindications to anthracycline therapy, and that chemotherapy is being considered for a patient with HER2-positive breast cancer, it is recommended that an anthracycline be strongly considered. In the context of trastuzumab therapy, there is level I evidence that a regimen without anthracycline may produce similar outcomes. The Update Committee does not currently recommend that HER2 be used to guide use of taxane chemotherapy in the adjuvant setting.
• uPA and PAI-1 as a marker for breast cancer is a new topic to the guidelines. In patients with newly diagnosed, node-negative breast cancer, uPA and PAI-1 measured by enzyme-linked immunosorbent assays (ELISAs) on 300 mg or more of fresh or frozen breast cancer tissue may be used to determine prognosis. Especially in hormone receptor–positive women who will receive adjuvant endocrine therapy, low levels of both markers are associated with a sufficiently low risk for recurrence that chemotherapy will only confer minimal additional benefit. Compared with observation alone, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based adjuvant chemotherapy offers substantial benefit in patients with high risk for recurrence, based on high levels of uPA and PAI-1.
• Cyclin E fragments as markers for breast cancer is a new topic to the guidelines. Currently available data are insufficient to recommend use of whole-length or fragment measurements of cyclin E to manage patients with breast cancer.
• Proteomic analysis for breast cancer is new to the guidelines; present data are insufficient to support use of proteomic patterns to manage breast cancer.
• Multiparameter analysis of gene expression for breast cancer is new to the guidelines. The Oncotype DX assay (Genomic Health Inc, Redwood City, California) can be used to predict the risk for recurrence in newly diagnosed patients with node-negative, estrogen-receptor–positive breast cancer who are treated with tamoxifen. Oncotype DX may help identify patients who should most benefit from adjuvant tamoxifen and who may not require adjuvant chemotherapy. Patients with high recurrence scores seem to benefit relatively more from adjuvant chemotherapy with (C)MF than from tamoxifen.
• Bone marrow micrometastases as markers for breast cancer are a new topic to the guidelines. Currently available evidence is insufficient to recommend evaluation of bone marrow micrometastases for management of patients with breast cancer.
• CTC assays as markers for breast cancer is a new topic to the guidelines. CTCs should not be used to diagnose breast cancer or to guide any treatment decisions in patients with breast cancer. The recently Food and Drug Administration–cleared CellSearch Assaytest (Veridex, Warren, New Jersey) for CTC cannot be recommended in patients with metastatic breast cancer.

"It is important to emphasize that guidelines and technology assessments cannot always account for individual variation among patients," the guidelines authors conclude. "They are not intended to supplant physician judgment with respect to particular patients or special clinical situations, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result."

Some of the guidelines authors have disclosed various financial relationships with Adjuvant Inc, LabCorp, Veridex, Fujiribo Diagnostics Inc, Genomic Health, Abraxis, American Biosciences, AvariaDx, Cytogen Corp, Monogram Bioscience, Pfizer, Precision Therapeutics Inc, Rudential Financial, QuatRx Pharm, Siemens Medical Solutions Diagnostics, StemCapture, Ciphengen, Tanox, Third Nerve LLC, Health Discovery Corp, Genenech, AstraZeneca, Immunicon, GlaxoSmithKline, Wyeth Ayerts-Genetics Institute, and Novartis.