More From TAILORx: Adding Clinical Risk to Genomic Testing Can Guide Therapy Choices in Breast Cancer

The follow-up to the landmark TAILORx trial shows that adding a clinical risk evaluation of the breast cancer tumor may have prognostic value; the authors' recommendations are drawn from other studies.

The 21-gene assay, Oncotype DX, which a year ago was found to help many women with a common type of breast cancer avoid chemotherapy, may be best used alongside an assessment of tumor size and stage, according to investigators of the TAILORx trial, who on Monday offered a follow-up to their landmark findings.

But these new results, presented at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, and published in the New England Journal of Medicine,1 appear with an editorial that explores why they come a year after the original results. Precision medicine, the commentators say, is sometimes “messier” than the name suggests.2

Last year’s practice-changing results were a headline of ASCO: chemotherapy with endocrine therapy after surgery offered no benefit for 70% of women with hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer.

This time, Joseph A. Sparano, MD, of the Albert Einstein College of Medicine, and his coauthors used the same data to show that adding “clinical risk” to the equation—tumor size and histologic grade—offers additional prognostic value, “that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.”

However, the recommendations from these new results are drawn from other studies, not from the data themselves.

Reviewing TAILORx

The Oncotype DX assay provides a recurrence score of 0-100, with higher scores indicting worse prognosis. TAILORx enrolled 10,273 women with early cancer to learn more about the risks for patients with this type of cancer, and specifically the risks for women with scores in the middle range—11 to 25. Based on results from earlier trials, those with scores of 0-10 received endocrine therapy only; those with scores above 26 received endocrine therapy and chemotherapy. Those in the middle range were randomized to receive either chemotherapy and endocrine therapy or endocrine therapy alone. Patients were followed for 9 years.3

Results reported in June 2018 showed that while most women in this range did not need chemotherapy, some women would still benefit from it: those age 50 or younger with a recurrence score of 16 to 25.

Adding Clinical Risk

The investigators used a binary classification system from the MINDACT trial (Microarray in Node-Negative Disease May Avoid Chemotherapy), which divided patients into high or low risk based on tumor size and histologic grade. The investigators report that the “integration of genomic and clinical information may provide a more accurate estimate of prognosis for individual patients than could be provided by either the genomic or clinical information alone.”

Notably, the analysis found predictive information about recurrence, but not benefits of chemotherapy. Results showed:

  • For women with recurrence scores of 11-25 who received endocrine therapy only, the hazard ratio (HR) comparing high clinical risk to low clinical risk was 2.73; 95% confidence interval (CI), 1.93-3.87.
  • For women with recurrence scores of 11-25 who received chemotherapy and endocrine therapy, the HR for high versus low risk was 2.41; 95% CI, 1.66-3.48.
  • For women with recurrence scores of 26 or higher, the HR for high versus low risk, who all had both chemotherapy and endocrine therapy, the HR was 3.17; 95% CI, 1.94-5.19.

Among women who were age 50 years or younger who had endocrine therapy alone, the investigators wrote, “the estimated rate of distant recurrence at 9 years was less than 5%,” with a low recurrence score, regardless of clinical risk.

The risk rose above 10% among younger women who had an intermediate recurrence score and high clinical risk.

Aromatase Inhibitor May Be an Option

So, what to do for these patients? Sparano, et al, note that some of chemotherapy’s ability to reduce death rates in younger women is attributed to its ability to induce menopause; while offering plenty of caution, they suggest that for some younger women, adding an aromatase inhibitor to tamoxifen may be in order.

They write, “Given the incremental benefits observed with ovarian suppression plus tamoxifen or an aromatase inhibitor, as compared with tamoxifen alone in premenopausal women, and the low percentage of premenopausal women who received ovarian suppression in TAILORx, it is possible that similar incremental benefits observed in younger women who received chemotherapy and had a recurrence score of 16 to 25 could be achieved with ovarian suppression and an aromatase inhibitor, as observed in other trials.”

Unlike the clarity of last year’s findings, the authors of the editorial say this time the TAILORx team must rely on interpretations. David J. Hunter, MBBS, and David L. Longo, MD, write that the investigators “speculate on the basis of previous studies that adding ovarian suppression and an aromatase inhibitor might give a reduction in risk equivalent to that observed using adjuvant chemotherapy.”

“The promise of ‘precision’ medicine has collided with the rather messier world of using all available evidence to try to make educated guesses to improve patient outcomes. How could this be?” Hunter and Longo ask.

The answer, they say, comes from the need to reuse data from large studies like TAILORx, because such studies are too expensive to repeat every time there is a question—and the one asked in this new study will apply to many women. The commentators commend the TAILORx investigators for taking on the questions they have asked, and note, “Distinguishing between results that warrant a change in practice and those do not will not a ‘precise’ process.”


1. Sparano JA, Gray RJ, Ravdin PM, et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer [published online June 3, 2019]. N Engl J Med. doi:10.1056/NEJMoa1904819.

2. Hunter DJ, Longo DL. The precision of evidence needed to practice “precision medicine.” [published online June 3, 2019]. N Engl J Med. doi:10.1056/NEJMe1906088.

3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111-121. doi:10.1056/NEJM0a1804710.