Results from the first clinical trial to incorporate a gene expression assay—which may potentially facilitate clinical decisions in women with early-stage breast cancer—were recently published in the New England Journal of Medicine in July. The trial, known as the Trial Assigning Individualized Options for Treatment, or TAILORx, examined adjuvant therapy for early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
Q: First, can you describe the design of the study, the treatment arms, and how this 21-gene expression assay was incorporated into the trial?
DR. SPARANO: TAILORx is the largest cancer treatment trial ever conducted. It was sponsored by the National Cancer Institute, and the primary purpose of the trial was to integrate the 21-gene assay called Oncotype DX into the clinical decision-making process or paradigm for patients with early-stage breast cancer, based on what we knew at the time about the prognostic and predictive information that the assay told us. We designed the trial to address the questions that remained unanswered at that time, including the potential benefit of adjuvant chemotherapy and how to manage patients with a midrange recurrence score on the 21-gene panel assay.
The target population included patients with ER-positive, HER2-negative, axillary node–negative breast cancer. Together, this represents about 50% of all breast cancers and 8% of all cancers in the United States. Adjuvant chemotherapy is typically recommended for women who have ER-positive breast cancer with a tumor of at least 1 mm, according to a prior position statement issued by the National Institutes of Health in 2000. This was based on prior evidence indicating that even patients who had a relatively low risk of recurrence could potentially benefit from adjuvant chemotherapy. What we embarked upon in the trial was to take patients who met established clinical criteria for a recommendation, or who at least should be considered for adjuvant chemotherapy in accordance with National Comprehensive Cancer Network guidelines, and to either assign or randomize their treatment based on their Oncotype DX recurrence score. Patients who had a recurrence score of 10 or less (17%), which is considered low or very low, were assigned to endocrine therapy alone and followed. Those with a recurrence score of 26 or higher (15% to 20%), which is considered high, were assigned to chemotherapy plus endocrine therapy. The remaining two-thirds of patients who had a recurrence score between 11 and 25 were assigned to either chemotherapy plus endocrine therapy (standard arm) or endocrine therapy alone (experimental arm). The trial was designed to determine whether endocrine therapy alone was inferior or noninferior to chemotherapy plus endocrine therapy.
Q: What are the key results of this trial, and was anything particularly surprising?
DR. SPARANO: The key results were as follows: in 2015, we reported in the New England Journal of Medicine that patients with a low recurrence score (defined in the study as between 0 and 10) had a 1% risk of recurrence at 5 years with endocrine therapy alone. Obviously, this indicates that these patients would be unlikely to benefit from chemotherapy, and this information was integrated into the 8th edition of the American Joint Committee on Cancer staging and prognostic staging beginning in January of this year. Updated results from this most recent analysis indicated that at 9 years, there was about a 3% distant recurrence rate. Again, this confirms that chemotherapy is unlikely to benefit this population.
The second major finding, which involved the primary endpoint of invasive disease–free survival, was that endocrine therapy was not inferior to chemotherapy in patients who had an Oncotype DX recurrent score of 11 to 25, with very similar clinical outcomes at 5 years and 9 years. At 9 years, the rate of invasive disease–free survival was 83.3% in the endocrine therapy arm and 84.3% in the chemotherapy/endocrine therapy arm, which was not significantly different. There were also similar rates of local, regional, and distant recurrence at 9 years, so the study did meet its primary endpoint.
One of the findings that was of some surprise was that there was an interaction between age and potential chemotherapy benefit. For example, a woman age 50 or younger who had a recurrence score between 21 and 25 did derive some benefit from chemotherapy. Specifically, there was about a 7% difference in distant recurrence rates at 9 years for patients who received chemotherapy, so some benefit was seen in this age group in the 21-to-25 score group. In the overall group, however, there was no benefit, and, certainly, there was no benefit in women over the age of 50 who had a recurrence score of between 11 and 25.
Q: Are these trial results particularly practice-changing?
DR. SPARANO: I think practice has already changed since the introduction of this assay to clinical practice in 2004. There has definitely been a decline in the use of chemotherapy, largely in patients who had a recurrence score in the lower range of this study. For those who had a recurrence score in the middle range, which was the group that was randomized in this study, there was still some variability in chemotherapy use, but chemotherapy use had declined. What this study did, however, was provide much more definitive information about potential benefit or lack of benefit in patients who had a midrange recurrence score.
1. 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;379:111-21.