Tracing Treatment Strategies in Early-Stage HR+/HER2- Breast Cancer

Gretchen G. Kimmick, MD, MS, discusses the management of patients with early-stage hormone receptor–positive, HER2-negative breast cancer.

Gretchen G. Kimmick, MD, MS

The management of patients with early-stage hormone receptor (HR)—positive, HER2-negative breast cancer is changing, and in February 2019, the National Comprehensive Cancer Network guidelines were updated to reflect the increasing importance of a patient’s risk of recurrence in guiding treatment strategies.

The guidelines specify that a woman with a tumor >0.5 cm and an intermediate recurrence score <26 should be considered for adjuvant endocrine therapy alone, whereas the same woman with a recurrence score between 26 and 30 should be considered for either adjuvant endocrine therapy or adjuvant chemotherapy followed by endocrine therapy.

“Most of our decisions now are based on genomic profiles,” said Gretchen G. Kimmick, MD, MS, a medical oncologist at Duke Cancer Center, in a presentation during the 2019 OncLive® State of the Science Summit™ on Breast Cancer.

Of the available assays, the Oncotype DX 21-gene assay has generated excitement, said Kimmick. The test was evaluated in the phase III TAILORx trial in women with node-negative, estrogen receptor—positive breast cancer. In the trial, women with a recurrence score ≤10 and >25 received endocrine therapy alone or with chemotherapy, respectively. Notably, patients with a recurrence score between 11 and 25 were randomized to receive either endocrine therapy alone or endocrine therapy and chemotherapy.

At 5 years, 98.7% of patients with a recurrence score ≤10 remained free of recurrence (95% CI, 97.9%-99.2%).1 Kimmick noted that clinical risk should be evaluated at the 5-year mark to determine whether additional therapy is warranted.

At the 2018 ASCO Annual Meeting, 9-year follow-up data of the TAILORx trial demonstrated that endocrine therapy alone was noninferior to endocrine therapy plus chemotherapy in terms of invasive-disease free survival among women with a recurrence score between 11 and 25 (HR, 1.08; 95% CI, 0.94-1.24; P =.26).2

“This changed our practice,” said Kimmick. “Now, postmenopausal women with intermediate recurrence scores are getting endocrine therapy alone, unless they’re in the high-risk range.”

Notably, in the subgroup analysis, the data regarding the use of endocrine therapy alone in premenopausal women were less compelling. As such, investigators applied patients’ clinical risk to their genomic risk to better elucidate their risk of recurrence.

Age and menopausal status were found to be indicators of benefit to chemotherapy in an exploratory analysis of the trial, in which premenopausal women between the ages of 46 and 50 with recurrence scores between 16 and 25 derived a significant benefit from the addition of chemotherapy to endocrine therapy.3

“In women who are premenopausal and have an intermediate risk of recurrence and a high clinical risk, it’s reasonable to consider chemotherapy,” said Kimmick.

Data presented at the 2019 ASCO Annual Meeting also showed that high clinical risk among patients with low- and intermediate-risk recurrence scores conferred a worse prognosis with endocrine therapy alone. Moreover, women under the age of 50 with high clinical risk and recurrence scores between 16 and 20 benefitted from the addition of chemotherapy, whereas patients with a recurrence score between 21 and 25 benefitted from the addition of chemotherapy irrespective of clinical risk.

At the 2019 ESMO Congress, a TAILORx analysis of clinical outcomes was presented for patients with a high recurrence score of 26 to 100 who were treated with endocrine therapy plus chemotherapy, which were 14% (n = 1389) of the overall TAILORx population. Results showed that the estimated rates of freedom from distant recurrence of breast cancer were 93.0% (standard error [SE]+0.8%) at 5 years and 86.8% (SE&thinsp;+&thinsp;1.7%) at 9 years.4

For those who were treated with endocrine therapy alone, the estimated freedom rates at 5 and 9 years were 78.8% (SE&thinsp;±&thinsp;14.0%) and 65.4% (SE&thinsp;±&thinsp;10.4%), respectively, when estimating outcomes based on the chemotherapy effect observed in the HER2-negative cohort of the B20 trial.

Bone-preserving agents, such as zoledronic acid, have also come into play for postmenopausal women, as they can help decrease the risk of disease recurrence and improve overall survival, added Kimmick.

Several studies have evaluated the benefit of extending adjuvant endocrine therapy in an attempt to further reduce the risk of recurrence. In the GIM4 trial, postmenopausal women who received 2 to 3 years of adjuvant tamoxifen were randomized 1:1 to receive either an additional 2 to 3 years or 5 years of letrozole.

The additional 5 years of endocrine therapy conferred a significant improvement in disease-free survival (adjusted HR, 0.815; 95% CI, 0.66-1.01),5 said Kimmick.

Using the Breast Cancer Index (BCI), investigators demonstrated that patients in the Trans-aTTom trial with a high BCI were more likely to benefit from extended treatment with an aromatase inhibitor. Patients who were BCI-high experienced an absolute benefit of 10.2% with 10 years of extended tamoxifen (P = .027).6 Because the gene expression-based signature is not yet commercially available, clinical judgement is still the standard way to assess whether patients should continue therapy, she added.

Although extended endocrine therapy has been shown to decrease patients’ risk of recurrence, compliance rates tend to drop off as time goes on, said Kimmick. As such, the SOLE trial was designed to see whether treatment breaks could be implemented without sacrificing efficacy. In the trial, postmenopausal women with HR-positive, node-positive disease who had completed 4 to 6 years of adjuvant endocrine therapy were randomized to receive an additional 5 years of continuous letrozole (n = 2426) or 5 years of intermittent letrozole (n = 2425).

The breast cancer-free interval (BCFI) and distant recurrence-free interval (DCFI) were fairly similar, said Kimmick. Specifically, at 5 years, the BCFI was 91.2% and 90.9% in the continuous and intermittent arms, respectively, while the respective DCFI was 93.2% and 92.5%.7

“For women who have trouble tolerating [endocrine therapy], they can consider the intermittent schedule,” said Kimmick.

In the early stages of evaluation are CDK4/6 inhibitors, said Kimmick, which have shown significant benefit in the metastatic setting and may offer a strategy to overcome resistance to endocrine therapy in the early-stage setting. Those studies are pending, Kimmick concluded.


  1. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014. doi: 10.1056/NEJMoa1510764.
  2. Sparano Jam Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.
  3. Sparano JA, Gray RJ, Makower DF, et al. Impact of clinical risk category on prognosis and prediction of chemotherapy benefit in early breast cancer (EBC) by age and the 21-gene recurrence score (RS) in TAILORx. J Clin Oncol. 2019;37(15 suppl; abstr 503). doi: 10.1200/JCO.2019.37.15_suppl.503.
  4. Sparano J, Gray RJ, Makower D, et al. Clinical outcomes by chemotherapy regimen in patients with RS 26-100 in TAILORx. Ann Oncol. 2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.
  5. Del Mastro L, Mansutti M, Bisagni G, et al. Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: a randomized, phase III study of Gruppo Italiano Mammella (GIM). J Clin Oncol. 2019;37(15 suppl; abstr 504). doi: 10.1200/JCO.2019.37.15_suppl.504.
  6. Bartlett J, Sgroi D, Treuner K, et al. Trans-aTTom: Breast Cancer Index for prediction of endocrine benefit and late distant recurrence (DR) in patients with HR+ breast cancer treated in the adjuvant tamoxifen—to offer more? (aTTom) trial. J Clin Oncol. 2019;37(15 suppl; abstr 505). doi: 10.1200/JCO.2019.37.15_suppl.505.
  7. Colleoni M, Luo W, Karlsson P, et al. SOLE (Study of Letrozole Extension): a phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC). J Clin Oncol. 2017;35(15 suppl; abstr 503). doi: 10.1200/JCO.2017.35.15_suppl.503.