Abstract P3-07-02: Developing a robust multidimensional molecular, pathological and radiological prognostic index (MPRPI) to evaluate the response to neoadjuvant chemotherapy (NACT) and predict clinical outcome of breast cancer (BC)
Authors: Abdel-Fatah Tarek M. a. , Chen Xin , Li Ruizhe , Giannotti Elisabetta , Auer Dorothee , Walker Jennifer , Lim Jun , Pockley A. Graham , Ball Graham , Rakhah Emad , Ellis Ian , Chan Arlene , Chan Stephen 
Published: March 2020

Abstract
Background: Recently neoadjuvant chemotherapy (NACT) is regarded as a potential standard approach whenever chemotherapy is indicated in principle and is considered as the preferred treatment approach for stage II/III triple-negative and HER2-positive BC. However, there is an urgent need to develop a more sensitive and robust test that can assess the response for NACT and guide the optimum adjuvant therapy. Aim: Our aim is to identify molecular, radiological and histopathologic criteria that could grade response to NACT and to develop a robust prognostic index that accurately predict clinical outcome of the subsequent adjuvant therapy. Method: Comprehensive histopathological and radiological assessment of consecutive series of 850 BC [T2-4, N0-3, M0] have been centrally carried out at the Nottingham University Hospital (NUH). Furthermore, the immunohistochemistry expression of Ki67 and SPAG5 proliferation biomarkers and the histological evaluation of tumour infiltration lymphocytes (TILs) had been examined in all patients while both volumetric and texture changes detected by magnetic resonance imaging (MRI) were available for 400 cases. Oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were assessed according to the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. The results were validated in an external cohort of 250 cases. The patient’s characteristics and treatment options are the same between the centres: (68%) has received anthracycline plus Taxane (AC+T) NACT and 32% of patients have received NACT Anthracycline only (AC). Neoadjuvant HER2 targeting agents (Trastuzumab) or (Trastuzumab + Petruzumab) had been prescribed to 16% of patients in addition to AC+T followed by adjuvant Trastuzumab (total=18 cycles). All pre-NACT ER+ patients were given at least 5 year of adjuvant endocrine therapy. The primary end point was disease free survival (DFS). The median follow up was 72 months. Results: Using multivariate Cox proportional hazards models with backward stepwise exclusion for DFS, we found the presence of TILs [(HR (95% CI): 0.68 (0.48-0.94; P=0.022], high SPAG5 expression in post-surgical tumour tissue [(HR (95% CI): 2.58 (1.19-5.63), p=0.017)], the reduction in the primary tumour volume measured by MRI (&gt;30%) [(HR(95% CI): 0.38 (0.16-0.89), p=0.026)], presence of Lymphovascular invasion [(HR(95% CI): 2.92 (1.33-6.40), p=0.008)], presence of chemotherapy induced fibrosis [(HR(95% CI): 0.41 (0.19-0.91), p=0.029)] and the high histological grade [(HR(95% CI): 2.62 (1.19-5.74), p=0.016)] showed statistical significant association with DFS. A prognostic index was calculated using the aforementioned factors after adjusting for both NACT and adjuvant therapy. The receiver-operating characteristic (ROC) curves indicated that this model is a good prognostic test [AUC = 0.854 (95% CI) = 0.777-.0.931; p= 0.00000001] and it outperformed residual cancer burden (RCB score) [AUC = 0. 711 (95% CI) = 0.612-.0.810; P= 0.0003]; and other NACT response grading systems including Miller-Payne system, Clinical-Pathologic Scoring System (CPS) and CPS-ER histological grade (CPS-EG) systems. Conclusion: A prognostic test with high sensitivity and specificity for assessing response to Neo-ACT has been developed and applying this test could guide the choice of the optimal adjuvant therapy.
Citation Format: Tarek M. a. Abdel-Fatah, Xin Chen, Ruizhe Li, Elisabetta Giannotti, Dorothee Auer, Jennifer Walker, Jun Lim, A. Graham Pockley, Graham Ball, Emad Rakhah, Ian Ellis, Arlene Chan, Stephen Chan. Developing a robust multidimensional molecular, pathological and radiological prognostic index (MPRPI) to evaluate the response to neoadjuvant chemotherapy (NACT) and predict clinical outcome of breast cancer (BC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-02.