Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer

For post-menopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI = 0) after 16-18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy.