By Jeffrey T. Jensen, MD, MPH, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and Microchips.
SYNOPSIS: Use of a gene-expression assay to predict prognosis may reduce the need for adjuvant chemotherapy in some women with early stage invasive breast cancer.
SOURCE: Sparano JA, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 2015;373:2005-2014.
This paper reports initial results from the Trial Assigning Individualized Options for Treatment (TAILORx) study, a prospectively conducted clinical trial designed to evaluate the clinical usefulness of the 21-gene assay (Oncotype DX Recurrence Score, Genomic Health) in low-risk women with hormone-receptor–positive, HER2-negative, axillary node–negative invasive breast cancer. Subjects had to meet National Comprehensive Cancer Network guidelines for adjuvant chemotherapy; a primary tumor size of 1.1-5.0 cm in greatest dimension (or 0.6-1.0 cm for high-grade tumors); an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (no or mild symptoms); and normal hematologic, bone marrow, hepatic, renal, pulmonary, and cardiac function. The clinical trial was sponsored by the National Cancer Institute (NCI), and patients were recruited from NCI-supported research centers. Eligible patients at these sites received counseling about the study, and consenting subjects agreed to have their breast cancer treatment determined by results of a genetic test, the Oncotype DX Recurrence Score. The score (0 to 100) was calculated using a reverse-transcriptase–polymerase chain-reaction 21-gene assay performed on RNA extracted from the formalin-fixed paraffin-embedded tissue from each patient. Subjects with a score of < 10 received endocrine therapy (tamoxifen and/or aromatase-inhibitor) alone, those with a score of > 25 received chemotherapy plus endocrine therapy, and those with a midrange score of 11-25 were randomly assigned to receive either chemotherapy plus endocrine therapy or endocrine therapy alone. The primary trial endpoint was a time-to-event analysis of the rate of survival free from invasive cancer. This paper presented only the results from the cohort with low-risk scores (0-10) assigned to receive endocrine therapy only.
Of the 10,253 women eligible for the study, 1629 (15.9%) had a low-risk score (< 10) and received endocrine therapy only. At 5 years, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4-94.9), and the rate of overall survival was 98.0% (95% CI, 97.1-98.6), but most of the events were due to a second primary cancer and deaths from causes unrelated to the primary breast cancer. In other words, use of the genetic tests safely eliminated the need for chemotherapy in 16% of women with early-stage breast cancer.
COMMENTARY
With the diagnosis of a true invasive breast cancer, the use of highly aggressive therapies seems justified, even when the overall benefit looks marginal and the morbidity of treatment can compromise quality of life. The use of advanced molecular techniques could improve results by identifying the heterogeneity of prognoses associated with an individual diagnosis. While the promise of personalized medicine is vast, these diagnostics must undergo prospective validation.
Sparano et al evaluated whether a molecular biology approach could determine which women would benefit from adjunctive chemotherapy. The proprietary test evaluates the expression patterns of 21 breast cancer-associated genes to calculate a risk score of low, intermediate, and high risk for recurrence based on earlier retrospective evaluations outcomes associated with these patterns.1-4 The test, OncotypeDx, is currently approved on the basis of these retrospective evaluations. Although the prospective validation of a test to screen low-risk women unlikely to benefit from chemotherapy is an important step forward, there are several limitations to this study. The test was marketed based on results from the retrospective studies that suggest the addition of chemotherapy provides little benefit to women with low-risk scores. Women with high-risk scores represent a poor prognosis group that benefits the most from chemotherapy. Whether women with tumors of intermediate scores benefit from aggressive chemotherapy is the subject of the prospective randomized, clinical trial currently in progress. Since women with intermediate gene scores represented 67% of the study population, results of the randomized, clinical trial will be extremely important.
Unfortunately, the test is already in clinical use with a cutoff point for low risk of 18 rather than the 10 reported in this paper, so these results cannot be considered a validation of the higher cutoff point in the approved test. Still, 16% of the approximately 10,000 node-negative, hormone-receptor–positive breast cancer patients enrolled in the study had a score of < 11, and the prospective results confirmed that this is a good prognosis group that can avoid chemotherapy. Let’s hope that the randomized, clinical trial supports expanding this simplified treatment for women with intermediate scores. Until then, clinicians should be cautious about the predictive power of this test for women with high gene scores.
More work is needed to develop low-cost diagnostics to improve cancer diagnosis and personalized therapies. The title of Clifford Hudis’s accompanying editorial in the same issue of the journal gets it right: “Biology Before Anatomy in Early Breast Cancer — Precisely the Point.”5 Companies developing these approaches will make a lot of money, but advanced diagnostics will hopefully save money and lives by reducing the use of expensive, toxic, and ineffective chemotherapy protocols. Making cancer therapy “smart” will require the joint effort of scientists, clinicians, and regulators to prevent false and misleading claims.
REFERENCES
- Albain KS, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: A retrospective analysis of a randomised trial. Lancet Oncol 2010;11:55-65.
- Brufsky AM. Predictive and prognostic value of the 21-gene recurrence score in hormone receptor-positive, node-positive breast cancer. Am J Clin Oncol 2014;37:404-410.
- Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-2826.
- Paik S. Methods for gene expression profiling in clinical trials of adjuvant breast cancer therapy. Clin Cancer Res 2006;12(3 Pt 2):1019s-1023s.
- Hudis CA. Biology before anatomy in early breast cancer — Precisely the point. N Engl J Med 2015;373:2079-2080.
Use of a gene-expression assay to predict prognosis may reduce the need for adjuvant chemotherapy in some women with early stage invasive breast cancer.
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