MS4-2: Preoperative Endocrine Therapy: New Approaches.
Authors: Smith I 
Published: June 2012

Abstract
Modern neoadjuvant endocrine therapy trials comparing aromatase inhibitors (AIs) with tamoxifen have shown that neoadjuvant AIs can downstage cancers and avoid mastectomy in around 50% of post menopausal women with large ER positive tumours, and are superior to tamoxifen in this respect.
The future potential of preoperative endocrine therapy is in the use of molecular biomarkers after starting treatment to predict outcome. This approach was pioneered in the IMPACT trial which showed that the reduction in tumour proliferation as measured by the biomarker KI67 comparing neoadjuvant anastrozole v tamoxifen v. the combination. was significantly greater for anastrozole than for the other 2 arms, predicting the same long-term outcome benefit in the equivalent adjuvant ATAC trial. The change in Ki67 with treatment could be used to predict potential benefit with other novel endocrine therapy approaches. Recently a similar neoadjuvant trial comparing anastrozole v letrozole v exemestane has shown no significant difference in Ki67 suppression between arms, predicting no long-term difference in clinical outcome with these agents.
Around 15% of patients with good initial tumour Ki67 suppression after 2 weeks of preoperative endocrine therapy show recovery of Ki67 by 12 weeks, providing early biomarker evidence of treatment resistance. Clinical outcome in these patients appears correspondingly worse. This provides an opportunity for biomarker led studies of agents targeting both innate and acquired resistance to endocrine therapy, defined by 2 week and 12 week Ki67 levels.. One such preoperative endocrine therapy trial with Ki67 as primary endpoint has already been carried out: patients were started on 2 weeks of preoperative anastrozole and then randomised to the addition or not of the tyrosine kinase inhibitor, gefitinib (IRESSA). This novel pre-operative endocrine therapy approach also allows the study of changes in other biomarkers and in gene expression as a means of elucidating underlying mechanisms of resistance
Finally the clinical potential of Ki67 after 2 weeks preoperative AI treatment is further demonstrated by the observation that higher 2 week values of Ki67 after treatment in the IMPACT trial predicted for a significantly worse recurrence-free survival. This raises the intriguing possibility that patients with ER positive breast cancer, including small cancers, could be treated with 2 weeks preoperative endocrine therapy before surgery and Ki67 levels at surgery be used to predict long-term outcome for the individual patient and in particular to identify those patients with a good prognosis who would not require chemotherapy. This hypothesis is being tested in the UK POETIC (Peri-Operative Endocrine Therapy for Individualised Care) trial which has so far accrued around 2,000 patients out of an overall target of 4,000. A similar approach in which Ki67, pathologic stage and ER at the end of a course of neoadjuvant endocrine therapy are combined to produce a Preoperative Endocrine Prognostic Index (PEPI) is being used to identify patients with such a low risk of relapse that adjuvant chemotherapy may not be necessary.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS4-2.