If a mean recurrence score of 11-25 is found in women with early hormone-receptor-positive HER2-negative breast carcinoma without axillary lymph nodes using a 21 gene expression test, adjuvant chemotherapy may be dispensed with. This was the conclusion of the Phase III TAILORx study presented by Joseph A. Sparano, Albert Einstein Cancer Center and Montefiore Health System, New York, at the plenary session of the 2018 ASCO Annual Meeting in Chicago on June 3, 2018, and published in parallel in the New England Journal of Medicine.
The 21 gene expression test (Oncotype DX) has been available for more than 10 years as a tool to assess the probable benefit of chemotherapy and the risk of remote recurrence in women with breast cancer that is hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative and lymph node negative within the first 10 years after diagnosis. The 21 gene expression test provides a recurrence score (RS) between 0 and 100. When the TAILORx study was planned, there were two prospective studies for the test, its prognostic value was proven in the B14 study with tamoxifen. Women with low RS below 18 who received adjuvant tamoxifen over 5 years had a very low risk of recurrence, after 10 years no distant metastases had occurred in 93.2%. The B20 study showed that the test is predictive. At high RS ≥ 31, the benefit of chemotherapy was high.
However, for the majority of women with a mid-range RS, the benefit of chemotherapy has so far been unclear. This was now investigated in the prospective TAILORx study, which included more than 10,253 women with HR+, HER2 and LK breast cancer aged between 18 and 75 years between April 2006 and October 2010. Of the 9,719 evaluable patients, 6,711 (69%) had an average RS of 11 to 25, 1,619 women (17%) had an RS ≤ 10 and 1,389 (14%) an RS ≥ 26.
Patients with RS 11-25 received randomized adjuvant endocrine therapy alone (n = 3,399, arm B) or endocrine therapy plus chemotherapy (n = 3,312, arm C). It was tested for non-inferiority of the two therapeutic regimes in the effect on invasive disease-free survival (IDFS). Women with RS 0-10 (n = 1,629) received endocrine therapy (arm A), patients with RS 26-100 (n = 1,389) received endocrine therapy plus chemotherapy (arm D).
The patients in the randomized part of the study (RS 11-25) were 55 years old in the median, 33 % were not older than 50 years. 74 % were assigned to the low-risk group and 26 % to the high-risk group according to clinical criteria. The most frequent chemotherapies were docetaxel/cyclophosphamide (56%) and regimes containing anthracycline (36%). Postmenopausal women usually received an aromatase inhibitor (91%), premenopausal women were treated with tamoxifen or tamoxifen followed by aromatase inhibitors, 13% were ovarian suppressed.
The primary endpoint was analyzed after 836 IDFS events after 7.5 years in the median in the ITT population. Endocrine therapy was not inferior to combination treatment in its effect on IDFS (hazard ratio 1.08, p = 0.26), thus the primary endpoint was reached. Both therapies were also equally effective in the effect on a remote relapse (HR 1.10, p = 0.48), on the relapse-free interval (HR 1.11, p = 0.33) and on overall survival (HR 0.99, p = 0.89). The 9-year event rates in the randomized arms B vs. C were similar for disease-free survival (83.3% vs. 84.3%), freedom from distant metastases (94.5% vs. 95.0%) and overall survival (93.9% vs. 93.8%). In arm A (RS to 10) 97% had no distant metastases after 9 years, in arm D (RS from 26) 13% had relapsed.
Non-preliminary exploratory analyses in the randomized groups revealed an interaction between age and RS. Younger women up to an age of 50 years and an RS of 16-25 had some benefit from chemotherapy.
Based on the results of the study, Sparano recommended that no chemotherapy be used in women:
"The hormone receptor-positive, HER2-negative, and LK-negative breast carcinoma are ready for de-escalation strategies to rationally reduce the use of chemotherapy," emphasized Lisa A. Carey, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, as a discussant of the study in the plenary session. "TAILORx confirms the excellent result without chemotherapy in very low RS and now supports the omission of chemotherapy in diseases without lymph node involvement with an RS up to 25" TAILORx has included patients with clinically low risk. It was unclear what was going on with patients in stages II and III. Carey also regretted that no such tests exist for women with HER2-positive or triple negative tumors.
1. Sparano JA et al. TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. 2018 ASCO Annual Meeting, Chicago, June 1-5, 2018, abstract LBA1. https://meetinglibrary.asco.org/record/161490/abstract.
2. Sparano JA et al. Adjuvant Chemotherapy Guided by a 21-gene expression assay in breast cancer. N Engl J Med published online on June 3, 2018, https://www.nejm.org/doi/full/10.1056/NEJMoa1804710.