Can Some ER+/HER2+ Patients Be Safely Spared from Treatment with Chemotherapy plus Herceptin?

The ER+/HER2+ subtype accounts for up to 10% of all breast cancers and most are treated with surgery followed by adjuvant chemotherapy with Herceptin (trastuzumab) ± radiotherapy, then adjuvant endocrine therapy (ET) to reduce the risk of recurrence. However, not all ER+/HER2+ patients benefit from the addition of chemotherapy and Herceptin. In particular, given the significant side effects associated with chemotherapy, the risks may outweigh the benefits in some older patients and in those with comorbidities. Currently, there are no clinically validated tools to identify patients with ER+/HER2+ breast cancer whose risk of recurrence remains unchanged with the addition of chemotherapy plus Herceptin versus those who can be effectively managed with adjuvant ET alone.

Using levels of IL6ST, a biomarker for ET response, ER+/HER2+ patients who gain benefit from ET can be differentiated from those for whom ET alone is not sufficient to reduce the risk of recurrence. The aim of the study presented at SABCS 2019 was to evaluate whether ER+/HER2+ patients predicted to respond less well to ET alone using IL6ST levels, could gain additional benefit from chemotherapy plus Herceptin.1

Patients were divided into 3 cohorts: cohort A was comprised of 32 postmenopausal women with ER+/HER2+ breast cancer treated with neoadjuvant (3-6 months) and then adjuvant letrozole. Neoadjuvant clinical response was assessed by changes in tumor volume. Median follow-up was 7.5 years. Cohort B included 13 postmenopausal women with ER+/HER2+ breast cancer treated with surgery without neoadjuvant therapy. Cohort C included 117 postmenopausal women with ER+/HER2+ breast cancer from the National Cancer Institute Cancer Genome Atlas (TCGA) breast cancer data set.

In cohort A, 16 of 32 patients responded to ET alone with tumor volume reductions of >70% following neoadjuvant treatment. Innate resistance was apparent in 3 patients, whereas 13 patients acquired resistance after a period of response. Neoadjuvant clinical response was predicted with 92% accuracy using levels of IL6ST. Gene expression analysis in 17 patients showed increased MAPK and PI3K pathway activity. In the 16 patients who responded well to neoadjuvant ET, the recurrence rate was 0% at 5 and 10 years. Thus, levels of IL6ST could be used to significantly estimate recurrence-free survival for patients in cohort A.

Samples from cohorts B and C could be stratified into subgroups that mirrored the expression patterns with respect to ER, MAPK, and PI3K activity. IL6ST was also differentially expressed in these subgroups, with lower levels of IL6ST associated with active HER2 signaling and higher levels associated with active ER signaling.

These results suggest that IL6ST levels can differentiate patients with ER+/HER2+ breast cancer who respond well to ET alone and those with a poor clinical response who have a higher risk of recurrence. Nonresponders to ET have increased expression of PI3K and MAPK pathways, consistent with active HER2 signaling. Thus, there is a potential role for IL6ST in selecting ER+/HER2+ patients who benefit from HER2-targeted therapies in addition to ET.


1. Turnbull AK, et al. SABCS 2019. Abstract P1-18-07.

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