Endocrine Therapy Response Status Is Necessary for Treatment Planning in HR+/HER2– Early Breast Cancer

Beyond genomic testing, endocrine therapy response should be used to determine whether patients with hormone receptor (HR)–positive, HER2-negative, N0-1 early breast cancer, according to results of the phase 3 ADAPTcycle trial (NCT04055493) that were presented during the 2023 San Antonio Breast Cancer Symposium.¹

“Endocrine therapy response should be considered in addition to gene expression testing for routine decision-making regarding chemotherapy use in hormone receptor-positive, HER2-negative, N0-1, early breast cancer, to maximize the number of patients in whom chemotherapy can be spared,” Oleg Gluz, MD, of the West German Study Group, said in a presentation in the findings.

Further, according to the findings, the optimal course of endocrine therapy should be 2 to 4 weeks of aromatase inhibitor in postmenopausal patients and 4 weeks of a Gonadotropin hormone-releasing hormone (GnRH) and aromatase inhibitors in premenopausal patients. The GnRH and the aromatase inhibitors should be started simultaneously.

The data also showed that adding ovarian function suppression (OFS) to tamoxifen (TAM) or aromatase inhibitors significantly increased the likelihood of response in premenopausal patients. The rates of responses were similar to those seen with postmenopausal patients previously treated with an aromatase inhibitor.

The findings suggest that when treated with optimal endocrine therapy, both pre- and postmenopausal patients have similar levels of endocrine therapy sensitivity, according to Gluz.

Key Findings

By looking at the screening cohort of theWSG ADAPTcycle trial, investigators determined the likelihood of response to endocrine therapy in a large group of patients with hormone receptor-positive, HER2-, N0-1, early breast cancer (N = 4334).

The odds ratio associated with TAM was 0.19 (95% CI, 0.14-0.24; P < .001). With an aromatase inhibitor alone, the OR was 1.00. However, when OFS was added to TAM, the odds ratio became 0.62 (95% CI, 0.42-0.93; P = .020) and when OFS was added to an aromatase inhibitor, the odds ratio became 2.00 (95% CI, 1.33-2.99; P = .001).

Investigators also looked at the likelihood of endocrine response by a variety of baseline characteristics. The odds ratio associated with being 50 years or younger was 1.00. The odds ratio associated with being 50 years or older was 1.71 (95% CI, 1.32-2.22; P < .001).

The odds ratio for recurrence score was 0.58 (95% CI, 0.53-0.64; P < .001). For those with endocrine responses at baseline, the associated odds ratio was 0.62 (95% CI, 0.56-0.67; P < .001), and the odds ratio associated with estrogen receptor was 1.10 (95% CI, 95% CI, 1.03-1.18; P = .004).

“If you looked on the multivariable analysis for endocrine response as an endpoint, we have observed that treatment, age, recurrence score, and baseline Ki67, and estrogen receptor expression by immunohistochemistry…. all these factors were independently associated with endocrine responses in this cohort and provide further information.”

Endocrine Responders

In the population of patients whose Ki67 scores were less than 10% at baseline, the rate of response in the 50 years or younger population was 34.7% (n = 277) with TAM alone, 55.7% (n = 142) with TAM and OFS, and 76.4% (n = 240) with an aromatase inhibitor plus OFS.

Among the 50 years or older cohort, the response rate was 43.8% (n = 159) with TAM, 76.4% with aromatase inhibitors (n = 1892), and 82.5% (n = 104) with endocrine therapy plus OFS.

In the ADAPT trial, the response rate with TAM had been 40.1% in the premenopausal population of endocrine responders, and the rate of responses with an aromatase inhibitor alone in the postmenopausal population had been 81.5%. These findings from the larger population, therefore, confirmed the likelihood of these response rates.

Furthermore, as Gluz pointed out, adding the OFS hiked up the response rates in both populations.

“If ovarian suppression was added to [the] younger patient’s [treatment] in that short period of time before the surgery, the endocrine response rates brought was up to 77% in patients treated by aromatase inhibitors in this younger group,” he said, “[Response] levels which were [also] observed in older patients.”

Patients With High Recurrence Score

Among patients who were 50 years or younger and whose recurrence scores were between 0 and 25, the response rates were 44.0% (n = 201) with TAM alone, 68.1% (n = 81) with TAM and OFS, and 81.8% (n = 126) with an aromatase inhibitor plus OFS.

Among patients who were 50 years or younger and whose recurrence scores was between 26 and 100, the response rates were 15.8% (n = 35) with TAM alone, 40.8% (n = 29) with TAM and OFS, and 66.7% (n = 54) with an aromatase inhibitor plus OFS.

Among patients who were older than 50 years and whose recurrence scores were 0 and 25, the response rates were 57.1% (n = 141) with TAM alone, and 87.9% (n = 1247) with an aromatase inhibitor alone.

Among patients who were older than 50 years and whose recurrence scores were between 26 and 100, the response rates were 18.2% (n = 14) with TAM alone and 55.6% (n = 399) with an aromatase inhibitor alone.

“As expected, patients with higher recurrence score levels had less endocrine response rates,” Gluz said. “But, if adequate endocrine treatment was [added], in the younger patients, we observed up to 67% endocrine responder [rates] in cases with higher recurrence scores and 55% of patients with [high] recurrent scores [achieved] endocrine response in our postmenopausal patients.”

The Premenopausal Population

Among patients who were 40 years or younger and whose recurrence scores was between 0 and 25, the response rates were 49.4% (n = 41) with TAM alone, 70.6% (n = 24) with TAM and OFS, and 93.5% (n = 29) with an aromatase inhibitor plus OFS.

Among patients who were younger than 40 years and whose recurrence scores were between 26 and 100, the response rates were 11.9% (n = 7) with TAM alone, 39.3% (n = 1) with TAM and OFS, and 69.0% (n = 20) with an aromatase inhibitor plus OFS.

“In this population, we observed very substantial endocrine response rates—up to 94% in patients with recurrence scores up to 25 if OFS was done [in addition to aromatase inhibitors], and up to 70%, endocrine response rates in cases of recurrence scores over 25,” Gluz emphasized.

Findings in Context

Previously, findings from the WSG ADAPT HR+/HER2- trial showcased “excellent” 5-year patient outcomes. Specifically, the 5-year distant disease-free survival (dDFS) rate associated with adjuvant endocrine therapy alone was 97% among a population of patients who were 50 years or younger, had N0-1 hormone receptor-positive/HER2- early breast cancer, had a recurrence score equal to or less than 25, and who had achieved a response to endocrine therapy after short preoperative endocrine therapy.

Since then, emerging data from other prospective trials have suggested that adjuvant chemotherapy plus endocrine therapy may be more effective in younger populations vs endocrine therapy alone, but not in postmenopausal patients. Investigators have theorized why this is—positing that distinct tumor biology in pre- vs postmenopausal patients, chemotherapy induced amenorrhea, or the use of tamoxifen alone without ovarian suppression could be responsible. Yet the answer remains unknown.

These findings seek to better define the benefit of endocrine therapy and the likelihood of responses according to age and other stratification factors. Findings were based on the screening cohort of the WSG ADAPTcycle trial.

Methodology

Investigators had screened 5293 German women with intermediate- to -high-risk hormone receptor-positive, HER2-negative, early breast cancer between July 2019 and June of 2023. Among this sample, there were 4334 women with all the available characteristics to be evaluated for this study.

Ultimately, 1684 patients were randomly assigned to receive either (neo)adjuvant endocrine therapy plus 2 years of ribociclib (Kisqali) or (neo)adjuvant chemotherapy with standard endocrine therapy as part of the ADAPTcycle trial. However, the findings presented at the 2023 Symposium are focused on the larger pool of 4334 women who had been screened.

Of note, this sample included 1423 patients endocrine therapy responders (63%), of which 659 (48.2%) were 50 years or younger, and 2155 (72.7%) were older than 50 years.

An endocrine response was defined as Ki67 below or equal to 10% after 2 to 4 weeks of preoperative endocrine treatment. Ki67 was assessed by 2 pathologists. Responders were assessed in subgroups according to endocrine therapy received, their age, and their recurrence score.

The median overall endocrine therapy response was 9.9 (min/max, 3.7-12.5). In the younger population, the median response, specifically, was 9.2 (min/max, 4.6-11.9) and in the older population, it was 10.3 (min/max, 3.7-12.5).

Final Takeaways

Gluz concluded by stating that the results from the screening group confirmed the findings previously reported in the ADEPTcycle trial. He noted that this study is the first to show prospective data on Ki67 in premenopausal patients with all available endocrine therapy options.

Further follow-up from the ADAPTcycle will determine the impact of endocrine therapy response, with and without ovarian function suppression, on survival outcomes.

Reference

Gluz O, Christgen M, Nitz U. et al. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): results from the multicenter ADAPTcycle trial.Presented at: San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Abstract LBO1-05