Abstract PL1: Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine
Authors: M Dowsett
Journal: Cancer Research (2022)

Abstract Genomic profiling has become mainstream for the management of early ER+ breast cancer and has become a favoured approach for research into pathways that govern prognosis and response and resistance to medical therapies.Management: Several commercial tests are available for the assessment of residual risk of recurrence of patients receiving hormonal therapies. We have compared several of these in postmenopausal patients treated with anastrozole or tamoxifen in the ATAC trial, including OncotypeDX (ODX), Prosigna (PAM50) and EndoPredict (EP). While PAM50 and EP provide estimates of risk that by design integrate tumour size and nodal status, estimates from ODX are also improved substantially by integration with clinicopathologic factors. The 3 tests include genes related to proliferation and to dependence on estrogen signalling with the ODX being dominated by the latter and PAM50 by the former. This may explain the better performance of the PAM50 than ODX at cessation of endocrine treatment after 5 years when the outcome for patients with high ER appears to worsen. While the tests have largely been validated in postmenopausal cases they are used in premenopausal cases as well. We found that while individual gene modules varied in expression across the menstrual cycle there was little systemic variability in the overall estimates of risk. Our recent work has indicated that mutations in TP53 add significant prognostic information to that from the commercial profiling tests.Research: We have conducted genomic analyses during presurgical therapy of ER+ breast cancer to determine the key pathways of endocrine resistance using change in Ki67 as the end-point of response. Very few tumours with low levels of ER by IHC (&amp;lt;10% positive cells) or rtPCR showed a Ki67 response. A group of the most widely studied genes in breast cancer including FOS and JUN show very marked increases in expression during surgical procedures and can lead to erroneous interpretation in the absence of controls. Considering intrinsic subtypes, tumours categorised as basal-like or HER2-enriched have little chance of Ki67 response; luminal B tumours showed a slightly lower chance of response. GSEA revealed that several hallmarks reflecting immune signalling were those most strongly associated poor Ki67 response with the interferon gamma and alpha and IL6-JAK-STAT3 signalling hallmarks being particularly involved. TME deconvolution indicated a broad involvement of many immune cell types. Other hallmarks of resistance included E2F target genes and hypoxia. Mutation of TP53 was strongly associated with Ki67 poor response. RNAseq profiling of patients treated with palbociclb as well as letrozole revealed high CCNE1 expression as associated with endocrine resistance. Citation Format: M Dowsett. Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PL1.