Validation of Genetic Assay Means Certain Breast Cancer Patients Don’t Need Chemotherapy

By Jame Abraham, MD

Results of a large prospective clinical trialvalidate the use of a genetic test to help advise women with certain breast cancers whether they can forego chemotherapy after surgery. Certain patients who would otherwise be recommended for chemotherapy on the basis of clinicopathologic features may be safely spared this adjuvant treatment, researchers concluded.

The prospective validation study of this 21-gene assay was performed in patients with hormone-receptor-positive, HER2-negative, axillary-node negative breast cancer who had a low risk of recurrence after surgery based on clinicopathologic features, but who nevertheless met established clinical guidelines for the recommendation or consideration of adjuvant chemotherapy.

More than 100,000 women in the U.S. received a diagnosis of estrogen-receptor-positive breast cancer associated with negative axillary lymph nodes in 2014. Although approximately 85 percent could be recurrence-free at 10 years with adjuvant endocrine therapy alone, many are prescribed chemotherapy as well.

Adjuvant chemotherapy amounts to overtreatment in low-risk patients

Adding chemotherapy leads to a relative reduction in the risk of recurrence of approximately 30 percent on average, which translates into an absolute benefit in the rate of freedom from recurrence of up to 5 percentage points. Many patients with estrogen-receptor-positive breast cancer would therefore be overtreated with chemotherapy on the basis of clinicopathologic features, since most would have been adequately treated with endocrine therapy alone, according to study results, published in November 2015 in the New England Journal of Medicine.

This study found that the test, Oncotype DX Recurrence Score (Genomic Health Inc., Redwood City, California), available since 2004, could accurately estimate a woman’s risk of developing breast cancer after having surgery to remove her tumor and accurately inform decision-making regarding adjuvant chemotherapy.
Sponsored by the National Cancer Institute, the Trial Assigning Individualized Options for Treatment (TAILORx) included 10,253 women ages 18 to 75 with early-stage breast cancer not metastatic to the lymph nodes who met National Comprehensive Cancer Network guidelines for the recommendation of adjuvant chemotherapy.

Researchers set score ranges lower than those previously defined

All participants underwent Oncotype DX testing, a reverse-transcriptase-polymerase-chain-reaction 21-gene assay performed on RNA at a Genomic Health laboratory. The recurrence scores ranged from 0 to 100, with higher scores indicating a greater risk of recurrence. Patients with a score of 0 to 10 were assigned to receive endocrine therapy alone. The recurrence-score ranges used in the study were lower than those previously defined as low:

• Low: <10 (versus <18 in previous definition)
• Intermediate 11 to 25 (versus previous, 18 to 30)
• High >26 (versus >31)

Of the 10,253 participants:

• 1,626 (15.9 percent) were in the low-risk group
• 6,897 (67.3 percent) had mid-range risk
• 1,730 (16.9 percent) were at high risk

At five years, the rate of invasive disease-free survival in the low-risk group was 93.8 percent, and the rate of freedom from recurrence of breast cancer at a distant site was 99.3 percent. The rate of overall survival at five years was 98 percent.

In patients who were found to have a low risk of recurrence on the basis of genetic-assay results, and who were thus assigned to receive endocrine therapy alone, the risk of the recurrence of breast cancer at a distant site was less than 1 percent, and the risk of any recurrence was less than 2 percent at five years.

Use of assay supported

Study authors support the use of the 21-gene assay to spare the use of chemotherapy in patients who otherwise would be recommended to receive it based on clinicopathologic features.

Study results on outcomes for the 6,897 patients with mid-range scores randomly assigned to receive either hormone therapy alone or hormone therapy and chemotherapy have not yet been finalized.

This is a very important study that helps us determine which patients may benefit from adjuvant chemotherapy, and will help many patients avoid the unpleasant short-term sequelae of chemotherapy and its potential serious long-term effects.
Dr. Abraham is Director of the Breast Oncology Program at Taussig Cancer Institute and Co-Director of Cleveland Clinic’s Comprehensive Breast Cancer Program.