Abstract PL2: Neoadjuvant Endocrine Therapy: The Times They are A-Changing

Neoadjuvant endocrine therapy (NET) in hormone-receptor positive breast cancers (HR+ BC) has been, in general, under-utilized, mostly because the majority of HR+ BC are diagnosed as stage I or II, and undergo surgical management as their first strategic step. However, NET is a suitable therapeutic choice for HR+ BC in cases where downsizing of the tumor is necessary (i.e. achievement of breast conservation). A seminal clinical trial comparing NET with neoadjuvant chemotherapy (NAC) in post-menopausal patients with HR+ BC revealed that the rates of overall response and breast conservation surgery were almost identical. NET also allows clinicians to infer prognosis based on simple pathologic characteristics: several clinical trials, including the phase III POETIC clinical trial (n=4486) showed that low Ki67 (less than 10%) at baseline and after 2 weeks had excellent long term outcome, whereas Ki67 larger than 10% at baseline and after 2 weeks had significantly worse long term outcome. Additionally, the Preoperative Endocrine Prognostic Index (PEPI), which is based on pathologic tumor size, node status, Ki67 level and ER status (Allred score) at the time of surgery, post NET, can accurately predict long term outcome. Interestingly, the early (about 2 weeks) Ki67 levels post NET has consistently predicted results of several phase III adjuvant or metastatic endocrine therapy trials (IMPACT - ATAC; Z1031 - MA-27) even in combination with targeted agents (LORELEI - SANDPIPER; NET + everolimus - BOLERO-2). Results of the ALTERNATE (A011106), a NET comparing AI with fulvestrant in post-menopausal patients with stage II and III HR+ BC is eagerly awaited, as it is bound to mimic the results of phase II and III trials comparing fulvestrant and AI in HR+ MBC (FIRST, FALCON, FACT, SWOG0226). Ultimately, these tools help clinicians decide if the addition of chemotherapy is necessary or not in patients with HR+ BC. Finally, NEC is an excellent tool in providing insights into the biologic basis of endocrine therapy efficacy (biomarkers of response and mechanisms of resistance studied in the post-treatment residual cancer). NET incorporating targeted therapies such as PI3K pathway inhibitors have yielded somewhat disappointing results compared to endocrine therapy alone (LORELEI, Neo-ORB), considering that PIK3CA mutations are the most common genomic alterations seen in HR+ BC. However, several ongoing trials of NET with CDK4/6 inhibitors were recently completed or are ongoing (NeoPalAna, NeoMONARCH, PALLET, PELOPS), and these trials may be instrumental not only in predicting the success of the large phase III adjuvant endocrine therapy with or without CDK4/6 inhibitors clinical trials. Ultimately, relatively small NET clinical trials could help with the design of more intelligent large clinical trials, providing the opportunity of residual tissue availability as a platform of discovery for biomarkers of sensitivity and resistance, an excellent platform for the development of investigational drugs and triaging of novel combinations. Citation Format: Mayer I. Neoadjuvant Endocrine Therapy: The Times They are A-Changing [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PL2.