Abstract P1-15-21: The molecular characterisation of early and advanced breast cancer in a Middle-Eastern breast cancer cohort treated with neo/adjuvant anthracycline+/-taxane-based chemotherapy
Authors: Dawood S , Korbie D , Pheasant M , Kazim H , Al Hamadi A , Lloyd C , Dent R , Mainwaring PN 
Published: May 2019

Neoadjuvant therapy for breast cancer enables improved conservative operative approaches for breast cancer with similar survival. In addition, it may be used to define clinical as well as molecular systemic therapy sensitivity, aid molecular subtyping analysis of residual disease as well as incorporating potential mechanisms of resistance. Breast cancer in women in the Middle East is characterized by younger median age, more advanced stage at presentation and a higher proportion of patients with triple-negative disease. Recently, Symmans et al. published the results of neoadjuvant anthracycline+/-taxane-based chemotherapy demonstrating a strong association between residual cancer burden (RCB) and overall survival. In this and other cohorts e.g. TCGA, ICGC molecular data of pts from the Middle-East is under-represented.

Aim:

The aim of this project was to define the above parameters in a cohort of women treated with systemic therapy from June 2016 to October 2017 in a Middle Eastern breast cancer referral centre treated in the neo/adjuvant setting. In the neoadjuvant setting we are examining the association between primary biopsy and pathological response tissue (RCB criteria) integrating molecular pathology using massive parallel sequencing (MPS) analyses.

Methodology:

We designed a custom 1000 gene panel using Illumina IDT capture-based assay design and sequenced tumour samples to greater than 500X coverage. Sequencing analysis and variant calling were performed using Broad GAKT best practice; BWA, Mutect2, Oncotator pipeline.

Results:

We present a cohort of 57 pts with median age of 45(26-66), presenting with clinical stage I 2(4%), stageII 30(53%), stage III 25(44%) breast cancer for neoadjuvant (20) or adjuvant (37) anthracycline +/- taxane-based chemotherapy. Standard immunohistochemical (IHC) analysis revealed ER-pos PR-pos HER2-neg 38(67%) ER-pos PR-neg HER2-neg 2(4%) ER-neg PR-neg HER2-pos 3(5%), ER-pos PR-pos HER2-pos 5(9%), TNBC 9(16%). In the neoadjuvant cohort (20) pts, 7 were clinical stage II and 12 stage 3 at presentation. Anthracycline+/-taxane-based chemotherapy achieved pCR/RCB 0 7(35%), RCB I 3(15%), RBC II 4(20%), RCB III 6(30%). All Her2 positive patients received concurrent taxane-trastuzumab.

Implications:

Predictive molecular expression algorithms for response to systemic chemotherapy in the neoadjuvant setting have been published (Hatzis JAMA 2011; Masuda Clin Ca Res 2013).Molecular characterisation of RCB after neoadjuvant chemotherapy has looked at DNA mutations (Jiang PLOS Med 2016) and RNA expression (Lehmann J PLOS One 2016; Echavarria Clin Ca Res 2018). Integration of both provides insight into mechanisms of sensitivity and relapse using pathway analysis. We present genomic data on 20 of the neoadjuvant samples with sufficient quality DNA analysed using a custom designed 1000 gene panel using Illumina IDT capture-based assay design to greater than 500X coverage. The most commonly aberrant genes TP53, PIK3CA, GATA3, KMT2Dwere observed, with notable differences in PAX3, BRCA2, CHD2, FGFR4. Using integrated comprehensive tumour molecular comparisons pre- and post-treatment in the neoadjuvant patients and circulating tumour DNA analyses of the whole cohort will be presented.

Citation Format: Dawood S, Korbie D, Pheasant M, Kazim H, Al Hamadi A, Lloyd C, Dent R, Mainwaring PN. The molecular characterisation of early and advanced breast cancer in a Middle-Eastern breast cancer cohort treated with neo/adjuvant anthracycline+/-taxane-based chemotherapy [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 P1-15-21.