2-5 July 2025 / Barcelona
ESMO GI Congress 2025
GONO studies presented during 2025 ESMO GI Congress:
- PARERE Study – By Dr. Paolo Ciracì
- ctDNA in liver-limited mCRC – By Dr. Vittorio Studiale
PARERE Study
At the ESMO Gastrointestinal Cancers Congress 2025 in Barcelona, Dr. Paolo Ciracì presented the molecular results of the randomized phase II PARERE study on behalf of GONO investigators.
PARERE was designed to evaluate the role of the liquid biopsy-guided anti-EGFR retreatment in the late-line setting of patients with RAS/BRAF wild-type, chemorefractory metastatic colorectal cancer, with the aim of defining its optimal placement in their therapeutic route.
Between December 2020 and December 2024, a total of 428 patients across 40 Italian oncology units underwent molecular screening to assess the absence of RAS and/or BRAFV600E mutations in their circulating tumor DNA (ctDNA). Only patients with centrally confirmed ctDNA wild-type were eligible for randomization to receive the anti-EGFR panitumumab followed by regorafenib (a standard of care late-line therapeutic option) versus the reverse sequence.
Notably, liquid biopsy identified RAS and BRAF ctDNA mutations in over one-third of patients who would have been otherwise deemed clinically eligible for anti-EGFR re-treatment.
After a median follow-up of 23.5 months, among the 213 randomized patients, re-treatment with panitumumab was associated with higher objective response rate, disease control rate and longer progression-free survival, as compared to regorafenib, regardless of the study sequence.
Approximately 9% of randomized patients harboured additional mutations potentially mediating resistance to anti-EGFR monoclonal antibodies – beyond RAS and BRAFV600E – in their ctDNA. In this subgroup of patients, no difference was found when they were re-treated with panitumumab or regorafenib, while the benefit from anti-EGFR re-treatment was more evident in those that were negatively hyper-selected.
Furthermore, no clinical features were able to predict the benefit from anti-EGFR re-treatment, except for an anti-EGFR interval longer than 6 months.
ctDNA in liver-limited mCRC
Circulating tumor DNA dynamics predict clinical recurrence in liver-limited metastatic colorectal cancer patients resected after first-line systemic treatment
During the 2025 edition of the ESMO Gastrointestinal Cancers Congress held in Barcelona, Spain, Dr. Vittorio Studiale presented the results of a collaborative project between GONO investigators and Tempus AI (Chicago, US) in a Poster Presentation. This work explored the dynamics of circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC) patients with liver-limited disease who underwent resection following first-line systemic treatment.
Despite liver resection offering a long-term survival benefit to a subset of these patients, most of them unfortunately relapse within two years. Currently, we lack robust clinico-pathological characteristics to reliably predict early recurrence after liver metastasectomy, which could help avoid potentially futile resections following first-line chemotherapy. This knowledge gap presented an ideal opportunity to assess the prognostic value of ctDNA dynamics at the pre-surgical timepoint, especially since existing literature on the topic primarily focuses on patients resected upfront.
We selected 116 patients from three Italian academic centers, all of whom had initially unresectable, liver-limited disease and underwent resection after upfront chemotherapy. Plasma samples were collected at baseline (T0), pre-surgery (TPrS), and post-surgery (TPoS). These samples were then analyzed using the Tempus xM MRD assay (xM), a tumor-naïve ctDNA-based MRD assay that integrates methylation and genomic variant classifiers to provide a binary MRD call.
Our key findings highlight the strong prognostic value of ctDNA. Patients with MRD detection after surgery experienced significantly shorter relapse-free survival (RFS) compared to those who were ctDNA negative (median RFS >24 months versus 5.5 months respectively, HR 6.7, p<0.001). Furthermore, ctDNA clearance between TPrS and TPoS also correlated positively with RFS. Patients who remained persistently ctDNA negative or converted to negative showed longer RFS (16.3 and >24 months, respectively) than those who were persistently ctDNA positive or converted to positive after surgery (5.3 and 5.9 months, respectively). Most notably, the dynamics of ctDNA in terms of variant allele fraction (VAF) reduction between T0 and TPrS proved particularly insightful. Patients exhibiting a VAF reduction of ≥50% achieved a significantly longer RFS compared to those with <50% reduction or an increase in VAF (median RFS 18.8 versus 9.8 months, HR 2.21, p = 0.012).
These results not only reaffirm the known strong prognostic value of ctDNA in the post-surgical setting, but also emphasize the potential role of pre-surgical ctDNA analysis. The dynamic changes in VAF between baseline and pre-surgery might emerge as a novel biomarker to inform multidisciplinary treatment decisions for these patients, offering additional prognostic information prior to resection. To further validate these findings and facilitate their integration into clinical practice, future prospective studies and validation in larger cohorts are warranted.
