Prognostic and predictive value of circulating tumor cells (CTC) phenotypes in CRS-HIPEC patients with colorectal and appendiceal peritoneal carcinomatosis: Insights from a phase II randomized trial.

Abstract

e15065 Background: CTCs are a minimally invasive biomarkers in metastatic colorectal/appendiceal cancer, however, standard assays relying on epithelial CTC (CTC EpCAM) enumeration to predict disease recurrence often fail as CTC EpCAM do not fully represent dynamic heterogenous tumor environment and the epithelial-mesenchymal transition. We quantified CTC EpCAM and mesenchymal CTCs (CTC FAPα) using serial processing and calculated a mesenchymal-to-epithelial CTC ratio (FAPα /EpCAM, Φ) which was an early predictor of the disease progression in PDAC. We evaluated Φ as a predictive biomarker of cancer recurrence in colorectal/ appendiceal peritoneal carcinomatosis. Methods: A correlative study was performed within a Phase II RCT comparing mitomycin-C vs. melphalan CRS-HIPEC for colorectal/ appendiceal peritoneal carcinomatosis. We calculated the Φ ratio at pre-op (prior to CRS-HIPEC on Day 0) and post-op intervals. Longitudinal collections were analyzed to evaluate phenotypic trends prior to radiographic cancer recurrence. Results: 67 pts underwent CTC correlative study. For pre-op (Day 0) Φ, 39 were evaluated after excluding pts with no CTC. Recurrence occurred in 29/39 pts with a mean time to recurrence of 11.8 months, for these pts pre-op mean Φ was 1.58 (median 0.69) was not statistically different from Φ for patients without recurrence (mean 1.26; median 0.53). For post-op MRD analysis, we included 31 pts whose CTC were collected between Month 1 to 3. 23 pts recurred with a mean time to recurrence of 14.9 m, with post-op mean Φ was 1.33 (median 0.79) was not statistically different from Φ for patients without recurrence (mean 1.96; median 1.83). For 11 recurred patients for which longitudinal CTC collections was within 3 months of the later collection, Φ increased in 7/11 (63.6%) and decreased in 4/11 (36.4%). With measurable baseline Φ, the median % increase prior to recurrence was +192.4% (mean +259.2%, range +37.5% to +622.2%). Paired CEA was available in 9/11, with concordant directionality in 4/9 (44.4%). Conclusions: Single-timepoint CTC Φ ratio (pre-op or post-op MRD) did not significantly predict long-term recurrence likely due to the prolonged mean time to recurrence. However, frequent longitudinal evaluation of Φ as a part of MRD/surveillance testing did predict disease recurrence for 63.6% of pts at an earlier timepoint compared to standard imaging. The low concordance with CEA suggests that CTC phenotypic shifting offers superior surveillance value in peritoneal carcinomatosis undergoing CRS-HIPEC. Clinical trial information: 03073694 . Measure Pre-op Φ Recurrence Pre-op Φ No Recurrence Post-op Φ Recurrence Post-op Φ No Recurrence N 29 10 23 8 Age (Yrs) 58.62 61.7 57.4 61 FAP/EPCAM (Mean/Median) 1.58, 0.69 1.26, 0.53 1.33, 0.79 1.96, 1.83 Mean months to recurrence 11.8 14.9