Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil – results from the QUASAR trial of colorectal cancer

Introduction: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC. Materials and methods: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses. Results: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy. Discussion: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted.