Adjuvant Endocrine Therapy Noninferior to Chemoendocrine Therapy for Intermediate Risk Breast Cancer

Joseph A. Sparano, MD

Adjuvant endocrine therapy alone is sufficient for patients with hormone receptor (HR)—positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate risk of distant recurrence compared with endocrine therapy in combination with chemotherapy. Results of the phase III TAILORx trial presented during the 2018 ASCO Annual Meeting showed that adjuvant endocrine therapy achieved noninferiority to chemoendocrine therapy.¹

The results, which were also published in theNew England Journal of Medicine,²are expected to save thousands of women from overtreatment with chemotherapy. The noninferiority of endocrine therapy alone compared with endocrine therapy plus chemotherapy (HR, 1.08; 95% CI, 0.94-1.24; P= .26) met the trial’s primary endpoint.

“These are very important data because this is the most common form of breast cancer in the United States and developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO expert Harold A. Burstein, MD, PhD, of the Dana-Farber Cancer Institute following the presentation. “What the data provided here today from this massive NCI-sponsored trial show is that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”

Estrogen receptor (ER)—positive, HER2-negative, node-negative breast cancer is one of the most common types of breast cancer, accounting for up to 50% of breast cancers, noted lead study author Joseph A. Sparano, MD, the associate director for clinical research at the Albert Einstein Cancer Center. Up to 30% of patients with these tumors typically have a recurrence by 10 years. Although adjuvant chemotherapy is recommended for these patients, the benefit is typically small, on the order of 3% to 5%.

The 21-tumor gene expression assay, Oncotype DX Breast Recurrence Score, helps to predict the need for chemotherapy based on patient scores from 0 to 100. Patients with a score of 26 to 100 benefit from the use of added chemotherapy to endocrine therapy, while those with a low risk of recurrence (0-10) derive minimal to no benefit from added chemotherapy. The benefit of added chemotherapy has been uncertain for patients with intermediate risk (11-25).³

TAILORx is a phase III randomized, prospective, noninferiority trial that included women with ER-positive, HER2-negative, node-negative breast cancer who met criteria for adjuvant chemotherapy. Between April 2006 and October 2010, 10,273 women were registered for the study.

“[This is] the largest adjuvant breast cancer trial ever performed. It was performed in 6 countries, 4 continents, over 1100 sites…and includes a total of 30 co-authors,” said Sparano, who also serves as the vice chair of the ECOG-ACRIN Research Group, which designed and conducted the study.

The women were divided into different arms based on their recurrence score. Those with a low recurrence score of 0 to 10 (n = 1629 evaluable patients) were included in arm A and received endocrine therapy alone. Women with a high recurrence score of 26 to 100 (n = 1389 evaluable patients) were enrolled in arm D to receive endocrine therapy in combination with standard adjuvant chemotherapy.

Of 6711 evaluable women with an intermediate recurrence score of 11 to 25, 3399 were randomized to receive endocrine therapy alone, and 3312 were randomized to the standard treatment arm to receive endocrine therapy plus chemotherapy. Randomization was based on stratification factors of menopausal status, planned chemotherapy, planned radiation, and recurrence score groupings of 11 to 15, 16 to 20, and 21 to 25.

Sparano added that the mid-range recurrence score randomized arms were originally based on a recurrence score of 18 to 30 that was later changed to 11 to 25 to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for undertreatment.

Importantly, Sparano highlighted that the trial was a prospective study reflecting current standards for modern chemotherapy and endocrine therapy. Burstein added after the presentation that prior studies employing the 21-gene recurrence score test were based on older standards of chemotherapy. These findings helped to validate the role of adjuvant endocrine therapy with or without chemotherapy in the setting of modern chemotherapy regimens.

The median age of the participants was 55 years with 33% being aged 50 or younger. More than half of the patients (57%) had intermediate-grade disease and 63% had a 1-2 cm tumor.

At 9 years, patients with intermediate recurrence scores receiving endocrine therapy and chemotherapy in combination with endocrine therapy showed similar invasive-free survival rates (83.3% vs 84.3%). Distant recurrence-free interval (94.5% vs 95.0% with chemoendocrine therapy), recurrence-free interval (92.2% vs 92.9%, respectively), and overall survival (93.9% vs 93.8%) rates were similar between the 2 intermediate score arms at 9 years.

In the low recurrence score arm, there was a 3% distant recurrence rate with endocrine therapy alone, and patients in the high recurrence score arm had a 13% rate of distant recurrence with added chemotherapy.

An exploratory analysis of patients in the 2 mid-range recurrence score arms considered factors that may determine which patients would benefit from added chemotherapy. Although there was no significant interaction between menopause, tumor size, or grade with recurrence score, there was an interaction between age and recurrence score.

In women 50 years or younger with a recurrence score of 16 to 20, there were 2% fewer distant recurrences, and 7% fewer in those with a recurrence score of 21 to 25.

“The younger women who had a recurrence score of 16 to 25 had some chemo benefit,” Sparano explained. “This was information that could drive some younger women who have a recurrence score in this range to accept chemotherapy.”

The TAILORx trial once again confirmed that with the use of the recurrence score, patients of any age with a low recurrence score (0-10) would be recommended for endocrine therapy alone (16% of patients), and all women with a recurrence score of 26 to 100 (17%) would be recommended for added chemotherapy.

For women over 50 years with a recurrence score of 11 to 25 (45%), their scores would suggest that they should be spared from chemotherapy, as well as patients 50 years or younger who have a recurrence score of 11 to 15 (8%).

“In terms of the big picture of the impact on care, application of this test in clinical practice to this population would be estimated to spare chemotherapy in about 70% and to select chemotherapy in about 30% on average,” Sparano explained. Burstein added that “there will be discussion for the small group of women who are less than age 50 who have intermediate-range recurrence scores on the order of 20 to 25 as to whether they need chemotherapy or whether using an alternative endocrine approach, such as ovarian suppression, might accomplish the same goals.”

“The goal of this study was not just to use less treatment, the goal was to tailor treatment…with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their treatment. So, this is an extraordinary day for breast cancer doctors and for women who have breast cancer, it allows us to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” added Burstein.

References

1. Sparano JA, Gray RJ, Wood WC, 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.J Clin Oncol.2018;36(suppl; abstr LBA1).
2. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer [published online June 3, 2018].N Engl J Med.doi: 10.1056/NEJMoa1804710.
3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.J Clin Oncol.2006;24(23):3726-3734. doi: 10.1200/JCO.2005.04.7985.