Prediction of Benefit From Adjuvant Treatment in Patients With Breast Cancer
Introduction
Breast cancer is increasingly diagnosed at earlier stages and is a disease with multiple subtypes, with differing prognostic and therapeutic implications. These two factors drive the need for determining appropriate therapy for patient subsets to avoid both undertreatment and overtreatment. Treatment guidelines based on clinical features partition women into low and high risk for recurrence1, 2 and recommend adjuvant chemotherapy for the majority of women. As per NCI guidelines, women with early-stage hormone receptor positive breast cancer and tumors > 1 cm have been recommended for chemotherapy1 while St. Gallen's criteria suggest chemotherapy for women with tumors > 2 cm.3 Eight-year follow-up from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 show that for estrogen receptor (ER)–positive, lymph node–negative tumors, the addition of first-generation chemotherapy regimens (cyclophosphamide, methotrexate, and fluorouracil [CMF] or methotrexate and fluorouracil) to tamoxifen provided a 7% absolute benefit in disease-free survival (DFS; P = .001).4 A subset analysis of tumors ≤ 1 cm in size showed an absolute benefit of 2% in relapse-free survival (RFS; P = .7). Additionally, women aged > 50 years did benefit as much as younger women. These findings indicate that many women are overtreated and do not benefit from chemotherapy. For breast cancer researchers, a primary concern is to identify patients for whom chemotherapy is not necessary.5 Fortunately, there have been significant developments in the field that provide the clinician and patient with a better understanding of the benefits of adjuvant therapy and guidelines are now incorporating these tools.6 Herein, we review the clinical tools that are commonly used as well as those under development and the clinical trials in which they are being further evaluated.
Section snippets
Clinical Parameters
Patient age, tumor size, grade, number of lymph nodes involved, the presence of ER and overexpression of HER2 protein are widely accepted clinical prognostic factors. The most comprehensive analyses of the benefits of adjuvant therapy have been conducted by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), which completes meta-analyses of phase III trials of adjuvant hormone and chemotherapy every 5 years. The EBCTCG typically analyzes data by age (< 50 years and > 50 years old),
Recurrence Score
The most widely used molecular profiling tool in use in the United States is the Recurrence Score (RS; commercially available as Oncotype DX®). This assay was developed based on findings from banked tumor specimens from a number of adjuvant treatment trials conducted by the NSABP enrolling subjects with ER-positive node-negative disease. This allowed retrospective evaluation of prospectively collected data. Using reverse transcriptase polymerase chain reaction (RT-PCR) on extracted RNA from
Clinical Trials Incorporating Tumor Subtyping
In general, there are 2 types of clinical trials using these new methodologies. In the first, molecular profiling is used to determine the benefit of chemotherapy in subgroups defined by molecular signature and will validate the use of these markers to determine therapy choices. In the second, a specific intervention is proposed in a molecularly defined population based on the hypothesis that the benefit of the drug will be predicted by the genetic signature.
Conclusion
Significant advances in molecular biology and the foresight to maintain tumor specimens in the clinical trial setting have led to major improvements in selecting appropriate candidates for adjuvant chemotherapy, in particular those with hormone receptor–positive, node-negative cancer. For hormone receptor–negative and more advanced disease, clinicians typically use adjuvant chemotherapy; however, treatment choices are expected to be better informed based on incorporation of molecular profiling
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2012, Personalized Medicine
- 1
Dr. Eng-Wong has no relevant relationships to disclose.
- 2
Dr. Isaacs has received research funding from Bayer Pharmaceuticals Corporation and has served as a member of the Speaker's Bureau for Abraxis BioScience, LLC; AstraZeneca; Genentech, Inc.; and GlaxoSmithKline.