Prospective Validation of a 21-Gene Expression Assay (OncotypeDX) in Breast Cancer

Published - Written by Andrea Merrill

Prospective Validation of a 21-Gene Expression Assay in Breast CancerImagine it is 1970. You are a 50-something year old woman and your doctor has just palpated a 1 cm mass in your left breast.  What are your options for treatment?  Unfortunately, radical mastectomy, introduced by Dr. William Halsted in 1894, remained the standard of care at that time.  Breast cancer treatment as it was in 1970, just 45 years ago, would be unrecognizable today.

Over the ensuing decade, a growing body of literature began to question this radical approach, with promising results for more limited operations such as simple mastectomy and lumpectomy. Further advances in chemotherapy and radiation therapy allowed for more limited surgery, creating the systemic, multidisciplinary approaches used today. Additionally, with new discoveries of genetic mutations specific to breast cancer, therapies are becoming more targeted and individualized. What might be suitable for one woman with a 1 cm breast cancer may not be adequate in another whose tumor has a different genetic profile.

While we have come very far in breast cancer treatment, we continue to ask ourselves, what more can we do to treat and prevent breast cancer recurrences? How much treatment is too much? How can we identify those who will benefit from less treatment?  Although previous studies have recommended chemotherapy for the majority of women with localized breast cancer regardless of node or hormonal status, about 85% of these women would be recurrence-free with endocrine therapy alone.

Enter the OncotypeDx Recurrence Score®, a 21-gene multiparameter assay designed to stratify risk of recurrence in women who otherwise would be recommended by current guidelines to undergo adjuvant chemotherapy. The TAILORx trial in this week’s NEJM now reports the results of the first prospective clinical trial utilizing the OncotypeDx Recurrence Score® to assess the benefit of chemotherapy by recurrence score. The results of the initial study were published in NEJM in 2004

The clinical trial enrolled women ages 18-75 with estrogen receptor (ER) positive, HER2/neu negative, node negative invasive breast cancers either greater than 1cm or 0.6 to 1 cm with intermediate to high histologic grade. All women with low risk recurrence scores 0-10 (on the 0-100 OncotypeDX scale) were assigned to receive 5 years of adjuvant endocrine therapy alone after surgery.

Of the 10,253 eligible patients, 1629 (~16%) had OncotypeDX risk scores of 0-10.  Overall, event rate was low after 5 years of follow-up. Rate of invasive disease-free survival was 93.8%, freedom from recurrence of breast cancer at a distant site was 99.3%, rate of freedom from recurrence was 98.7% and rate of overall survival was 98%.  Multivariate analysis did not reveal an effect of age, tumor size, or type of surgery on rate of recurrence or survival. Histologic grade did show an association with risk of recurrence, but recurrence rates remained low.

This study provides prospective validation for using the OncotypeDX Recurrence Score® to spare patients from chemotherapy who would otherwise be recommended to receive it. However, this low-risk group of ER positive, HER2/neu negative, node negative patients with the lowest scores (0-10) represents only 16% of all those in the original study cohort. Additionally, the OncotypeDX score was designed to assess 5-year risk, and it is known that late recurrence after 5 years accounts for about half of all distant recurrences in this group.

Regardless of its limitations, “it is one more step toward precision” says Dr. Clifford A. Hudis in the accompanying editorial. He adds, “This multigene assay is unlikely to be the only test that can provide a prediction of chemotherapy benefit. A less expensive and broadly distributed test would be valuable globally. For now, however, this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive tests to select patients who should not receive chemotherapy.”

NEJM Deputy Editor Dr. Dan Longo concurs: “The benefits from adjuvant chemotherapy have always been accrued by a minority of the breast cancer patients receiving it. We have accepted giving toxicities to many patients to benefit a few. With advances in assessing risks based on tumor genotype, it is now possible to reduce the fraction of patients treated with adjuvant chemotherapy who are unlikely to benefit from it. ”

Results from the other arms of the OncotypeDX clinical trial should hopefully provide more guidance for those at intermediate and high risk of recurrence, with potential to restrict the use of chemotherapy to those most likely to benefit from it. Clearly we have come a long way from Halsted’s day of the radical mastectomy but still have far to go.

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