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Poster Display session 2

5602 - Clinical relevance of circulating tumor (ct)DNA genotyping for first line cetuximab-based treatment monitoring in metastatic colorectal cancer (mCRC): a prospective multicentric study

Date

29 Sep 2019

Session

Poster Display session 2

Topics

Tumour Site

Colon and Rectal Cancer

Presenters

JOANA Vidal Barrull

Citation

Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246

Authors

J. Vidal Barrull1, D. Casadevall2, M.C. Fernandez3, M. Castro-Henriques1, P. García-Alfonso4, B. Martin-Cullell5, V. Alonso-Orduna6, R.M. Rodríguez Alonso7, M. Benavides8, C. Santos Vivas9, E. Elez Fernández10, R. Garcia-Carbonero11, R. Ferreiro12, J.L. Manzano13, F. Losa14, R. Salazar15, J. Tabernero16, E. Aranda Aguilar17, B. Bellosillo3, C. Montagut Viladot1

Author affiliations

  • 1 Medical Oncology, Hospital del Mar, 08003 - Barcelona/ES
  • 2 Oncology, University Hospital del Mar, 8003 - Barcelona/ES
  • 3 Pathology Department, Hospital del Mar, 08003 - Barcelona/ES
  • 4 Servicio De Oncología Médica, General Universitario Gregorio Marañón, Madrid/ES
  • 5 Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 - Barcelona/ES
  • 6 Medical Oncology Service, Hospital Miguel Servet, 50009 - Zaragoza/ES
  • 7 Medical Oncology, IMIBIC, Reina Sofía Hospital, University of Córdoba, 14004 - Cordoba/ES
  • 8 Oncology, Universitario Regional Virgen de la Victoria, Malaga/ES
  • 9 Oncologia Radioterapica, Catalan Institute of Oncology. Hospital Druan y Reynals, 08908 - Barcelona/ES
  • 10 Department Servicio De Oncología Médica, 7Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 11 Medical Oncology, University Hospital 12 De Octubre, 28041 - Madrid/ES
  • 12 Medical Oncology, Hospital Universitario Ramón y Cajal, 28006 - Madrid/ES
  • 13 Oncology Medical, Hospital Universitario Germans Trias i Pujol, 08916 - Badalona/ES
  • 14 Medical Oncology Department, Hospital de Sant Joan Despí Moisès Broggi, 08970 - Barcelona/ES
  • 15 Medical Oncology, Institut Català d'Oncologia Hospital Duran i Reynals, 08907 - Barcelona/ES
  • 16 Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), 08001 - Barcelona/ES
  • 17 Oncology, University Hospital Reina Sofia, 14004 - Cordoba/ES

Resources

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Abstract 5602

Background

Genotyping of ctDNA characterizes the molecular profile and monitors tumor molecular dynamics, but the clinical applicability of next generation sequencing (NGS) DNA sequencing has not been assessed in a large prospective cohort of mCRC patients (pts).

Methods

mCRC pts with RAS wt tumors treated in first line with chemotherapy (CT) + cetuximab in 16 Spanish hospitals were included. Plasma samples were collected baseline (BL) and every 2 cycles until progression. ctDNA was isolated and sequenced with NGS platform Oncomine Colon cfDNA Assay which identifies hotspot mutations (mut) in AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, TP53 and APC. RAS ctDNA mut were also assessed by dPCR (BEAMing) at BL. Detection of any mut in plasma was considered as ctDNA+. Mut in BRAF/RAS/MAP2K1/PIK3CA were considered as anti-EGFR resistance.

Results

101 pts were enrolled (65.3% male; median age 64.5y; 77.6% left colon). RAS mut were detected in 11 pts BL by BEAMing. After quality assessment, 84 samples were sequenced by NGS BL and at least one mut was detected in 65 samples (77.3%; median 1, range 0-5) and 10 RAS mut were detected. Plasma samples from 47 pts were also analyzed after 4 cycles of treatment (C4) and mut were detected in 30 pts (63.8%; median 1, range 0-3). Median mutant allele fraction for paired samples was 24.9 at BL and 0.56 at C4 (p = 0.0045). Treatment clinical benefit (CB: PR, CR and SD ≥ 16weeks) was observed in 72 out of 85 pts. BL ctDNA+ or C4 ctDNA change were not associated with CB (p = 0.722). Assessment of RAS BL mut was not associated with CB (p = 0.243 by NGS and p = 0.712 by BEAMing), while the absence of RAS mut at C4 predicted treatment CB (93.2% vs. 6.8% RAS mut p = 0.02). Median PFS for all pts was 10.13 month. ctDNA+ at BL or C4 were not correlated with PFS (HR 0.8; p = 0.73). No differences in PFS were found in ctDNA RAS mut vs RAS wt BL (BEAMing+ HR = 1.2 p = 0.79 and NGS+ HR = 2.6 p = 0.052). Among all anti-EGFR resistant mut, only ctDNA RAS mut were detected at C4 (N = 4). Persistence or emergence of RAS mut at C4 were strongly associated with PFS (12.9m vs. 4.2. HR 8.8 p = 0.0003).

Conclusions

Early RAS ctDNA dynamics predicts benefit to first line CT+cetuximab in mCRC pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Grupo de Tratamiento de los Tumores Digestivos (TTD), Spain.

Funding

Merck-Serono.

Disclosure

J. Vidal Barrull: Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Amgen; Honoraria (self): Sysmex-Inostics. E. Elez Fernández: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi. F. Losa: Honoraria (self): Amgen; Honoraria (self): Merck-Serono. R. Salazar: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Guardant-Helth; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Ferrer; Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD. J. Tabernero: Honoraria (self), Advisory / Consultancy: Array Biopharma; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Molecular Partners; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Halio DX SAS. E. Aranda Aguilar: Honoraria (self): Celgene; Honoraria (self): Merck-Serono; Honoraria (self): Roche; Honoraria (self): Sanofi. B. Bellosillo: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Biocartis; Advisory / Consultancy: Novartis; Advisory / Consultancy: Thermofisher. C. Montagut Viladot: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Advisory / Consultancy: Sysmex-Inostics; Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Guardant-Helth; Advisory / Consultancy: Symphogen. All other authors have declared no conflicts of interest.

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