1931P - Hyaluronan (HA) accumulation in the tumor microenvironment (TME) is increased in colorectal cancer (CRC) and associated with consensus molecular subtypes (CMS) 4 molecular subtype

Abstract

BackgroundHA, a secreted large, megadalton glycosaminoglycan, is a major component of the extracellular matrix. Its accumulation in the TME increases interstitial pressure, induces vascular collapse and hypoperfusion, and may be a potential barrier to therapeutic access and immune infiltration. Enzymatic breakdown of HA by PEGPH20 alters the TME. PEGPH20 + chemotherapy or checkpoint inhibitor combinations are currently in clinical development. We examined the prevalence profile of HA in a large CRC cohort and report the relationship between HA accumulation and CRC molecular subtypes. MethodsHA accumulation was quantified in 115 CRC tumor samples using the Ventana Class I CDx HA assay, which scores the % of stromal HA at any intensity greater than background over the entire tumor tissue surface area. RNAseq transcriptome analysis was carried out and CMSs were determined, implemented by using the CMScaller R package. ResultsCRC samples had increased HA accumulation (HA score 20%-90%) compared with normal colon tissue (HA score 20%). HA localized predominantly to stroma in CRC samples and to lamina propria in normal colon tissue. Increased HA accumulation in CRC tumors was accompanied by increased desmoplastic stroma. We classified the 115 CRC tumors into 4 CMSs with distinct underlying biology and clinical outcomes (table). The CMS4 subtype, which has the worst prognosis, had significantly higher HA content compared with the other CMS subtypes as determined by Tukey’s honest significance test (p=0.0052 CMS4 vs CMS1; p<0.0001 CMS4 vs CMS2 and CMS3).Table: 1931PCMS Type and OutcomesTable: 1931PCMS TypePercent (Out of 115 Total SamplesBiological Characteristics and Clinical OutcomesCMS118%- Highly immunogenic - HypermutatedCMS 239%- Wingless/integrated (WNT)-β-catenin pathway activation - Good prognosisCMS314%- Metabolic cancer phenotypeCMS429%- Strong stromal gene signature - Worst prognosis ConclusionsHA accumulation is increased in CRC pts, suggesting PEGPH20 may be a promising therapeutic agent in this indication. There are potential links between HA accumulation, CRC disease biology, and clinical outcomes. Investigation of HA accumulation in association with additional molecular and clinical features of CRC is ongoing. Editorial acknowledgementElizabeth L. Pham of Halozyme Therapeutics, Inc. provided editorial support for this abstract. Legal entity responsible for the studyHalozyme Therapeutics, Inc. and Genentech, Inc. FundingHalozyme Therapeutics, Inc. and Genentech Inc. DisclosureB. Blouw: Shareholder / Stockholder / Stock options, Full / Part-time employment: Halozyme Therapeutics, Inc.. L. Ryner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, Inc.. R. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, Inc.. D. Taverna: Shareholder / Stockholder / Stock options, Full / Part-time employment: Halozyme Therapeutics, Inc.. Y. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, Inc.