La terapia de reintroducción anti-EGFR guiada por biopsia líquida está ganando terreno como una opción potencial para pacientes con cáncer colorrectal metastásico refractario.
Sin embargo, es necesario identificar posibles biomarcadores para implementar la estratificación de los pacientes. El ensayo CAVE-2 GOIM investigó el papel de la reintroducción de cetuximab ± avelumab en pacientes con cáncer colorrectal metastásico (mCRC) RAS/BRAF de tipo salvaje (WT) y ADN tumoral circulante (ctDNA) (evaluado con el ensayo FoundationOne Liquid). Se realizó una correlación con el perfil molecular, la fracción tumoral de ctDNA (TF) y las características clinicopatológicas. En pacientes con tumores "negativos" en comparación con tumores "hiperseleccionados positivos", la tasa de respuesta general fue del 12% frente al 3%, la mediana de supervivencia libre de progresión (mPFS) fue de 5,6 meses (4,4-6,9) frente a 3,65 meses (2,8-4,8) (HR 0,61, IC del 95% 0,41-0,91; P = 0,0155), y la mediana de supervivencia general (mOS) fue de 14,5 meses (12,4-19,0) frente a 11,6 meses (8,5-15,6) (HR 0,61, IC del 95% 0,40-0,93; P = 0,023).
Por lo tanto, exploramos posibles biomarcadores en pacientes con tumores "hiperseleccionados negativos". De manera notable, entre los factores investigados en el análisis multivariado para la supervivencia libre de progresión y la supervivencia general, solo la TF de ctDNA conservó su significación. Para los pacientes con tumores hiperseleccionados negativos con TF de ctDNA ≥ 10 en comparación con los pacientes con TF de ctDNA < 10%, la mPFS fue de 4,8 meses (3,4-3,9) frente a 5,7 (4,4-6,9) (HR 1,74, IC del 95% 1,20-2,53; P = 0,00382) y la mOS fue de 11,0 meses (8,3-13,0) frente a 21,3 meses (HR 2,75, IC del 95% 1,79-4,23; P = 0,00000418). Estos datos sugieren que una mayor liberación de ctDNA podría refinar mejor la agresividad del cáncer y la carga metastásica que la carga tumoral.
En conjunto, estos resultados destacan el fuerte valor pronóstico de la TF de ctDNA y el posible papel en la personalización del tratamiento.
Liquid biopsy is gaining ground in the management of metastatic colorectal cancer (mCRC) to capture spatial heterogeneity, monitor response, identify potential mechanism/s of acquired resistance and identify minimal residual disease after curative loco-regional therapies [[1]]. Recently, it has been shown that biomarker-guided anti-epidermal growth factor receptor (EGFR) rechallenge therapy is a potential therapeutic option in patients with circulating tumor DNA (ctDNA) RAS/BRAF/EGFR-Extracellular domain (ECD) wild type (WT) metastatic colorectal cancer (mCRC) [[[2]], [[3]], [[4]]]. The rationale of this therapeutic strategy is that resistant cancer cells might progressively decay after discontinuation of EGFR monoclonal antibodies (mAbs), thus potentially restoring sensitivity to EGFR blockade [[5]].
Growing evidence support that a broader liquid biopsy-based molecular analysis could allow to identify patients without resistance alterations in genes other than RAS/BRAF/EGFR-ECD that could benefit from anti-EGFR therapies (namely “negative hyperselected” tumors) both in chemo-naïve population and in the refractory setting [[[6]], [[7]], [[8]], [[9]]]. However, confirmatory studies are required and even in this molecular selected population the identification of potential biomarkers represents an unmet need.
It has been previously shown that ctDNA tumor fraction (TF) might represent a potential prognostic factor in different tumor types, including mCRC [[10]]. However, validation in a prospective cohort is still lacking.
In this scenario we conducted a pre-planned exploratory analysis of patients enrolled in the CAVE-2 GOIM (Gruppo Oncologico dell’Italia Meridionale) trial to investigate potential biomarkers involved in anti-EGFR rechallenge therapy and explored the potential role of ctDNA TF [[11],[12]].
Material and methods
The CAVE-2 GOIM study is an academic randomized phase II trial that evaluated the role of cetuximab plus avelumab compared with cetuximab rechallenge therapy as later-line treatment in patients with molecular selected tumors. At baseline, liquid biopsy-based comprehensive genomic profiling (CGP) using the FoundationOne liquid (F1L) CDx assay was performed (https://www.foundationmedicine.com/test/foundationone-liquid-cdx) [[11],[12]] The test interrogates 324 genes: 309 genes are sequenced with complete exonic (coding) coverage, and selected intronic or non-coding regions are targeted in 15 of these genes. A subset of specific regions in 75 genes are captured with increased sensitivity. The F1L CDx assay allows to detect in selected genes base substitutions, insertions/deletions, copy number variations, amplifications, rearrangements, tumor mutational burden (TMB), microsatellite instability, and TF genomic signature.
Patients with microsatellite stable (MSS) tumors without RAS/BRAF clonal alterations were included. The primary endpoint is overall survival (OS). Secondary endpoints include progression free survival (PFS), objective response rate (ORR) and safety. Pre-planned translational analysis includes impact of tumor mutation burden and gene expression signatures on clinical outcomes. Here we present mature results with a longer follow-up. Then we explored potential factors involved in anti-EGFR rechallenge therapy in a multivariable model and assessed the role of ctDNA TF. The study protocol and full-inclusion and exclusion criteria have been previously reported [[13]].
Statistical analysis
Categorical variables were reported as frequency counts and proportions, whereas continuous variables were reported as medians and interquartile range (IQR). Molecular hyperselection was based on plasma ctDNA analysis of the following genes, which are involved in resistance to anti-EGFR monoclonal antibodies: KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, mutations PTEN deletion, and ERBB2 amplification (tumors without these pathogenic alterations are subsequently reported as negative hyperselected tumors). Based on previous findings a cut-off of 10 was used to differentiate tumors with high ctDNA burden (ctDNA TF ≥ 10) vs low ctDNA burden (ctDNA
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