How do you approach adjuvant therapy in patients who have a poor clinical response to neoadjuvant endocrine therapy?

Clinical response rates to neoadjuvant endocrine therapy vary from 40-60% in ER-enriched tumors. Pre and post-treatment PEPI score is shown to be prognostic. It is currently unknown what is best to do for women who do not respond well clinically, or for those who have a high ki67 and/or high PEPI score after neoadjuvant hormonal therapy.

Tumors that remain highly proliferative after neoadjuvant endocrine therapy have been shown to display upregulation of genes that are not necessarily downregulated by chemotherapy (Guerrero&Arteaga CCR March 26, 2018). This could imply chemotherapy resistance, and a targeted agent or even a CDK4/6 inhibitor may be a better approach, but these agents are not yet clinically available in this setting.

I recently had a case of a poor clinical response to neoadjuvant endocrine therapy on a trial with an AI plus a CDK4/6 inhibitor. I repeated ki67 on the resected tumor and it was high. I felt compelled to give adjuvant chemo, as a Mammaprint on the resected tumor came back high risk, and there was no adjuvant trial option available. I am curious what others are doing in this setting, however.

While there is little clinical trial experience to support this, I think that it is useful to differentiate between patients with indolent cancers that are unlikely to respond, clinically or pathologically, to either neoadjuvant endocrine therapy - even after 6 months of treatment - or neoadjuvant chemotherapy and those with more aggressive cancers that may progress on neoadjuavnt endocrine therapy. In the former group, which may be identified by a low Oncotype RS, low-risk Mammaprint, or a low Ki67, whether checked at baseline or after 2-4 weeks of endocrine therapy, I try to avoid giving chemotherapy even if they have a PEPI score > 0 (based on TN stage, not on ER or Ki67) at surgery. In the latter group, if I try them on neoadjuvant endocrine therapy (though with a high Oncotypoe on the diagnostic biopsy I usually go stright to chemo), I switch to chemo early if there is any evidence of disease progression or even lack of response by 6-12 weeks. The pCR rate to chemo in this group will be very low, but many will still achieve a clinical response, which may make them better candidates for less extensive surgery. Of course, if the patient is a candidate for the surgery she chooses upfront, she could also undergo surgery after failing neoadjuvant endocrine therapy, followed by adjuvant chemotherapy.