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Poster display session

2992 - Circulating tumor (ct) DNA captures intrapatient heterogeneity in metastatic colorectal (mCRC) patients (pts) progressing to FOLFIRI+panitumumab

Date

09 Sep 2017

Session

Poster display session

Presenters

Joana Vidal

Citation

Annals of Oncology (2017) 28 (suppl_5): v158-v208. 10.1093/annonc/mdx393

Authors

J. Vidal1, J.M. Viéitez2, D. Paez3, C. Santos4, E. Falcó5, C. López López6, M. Valladares-Ayerbes7, L. Robles8, P. Garcia-Alfonso9, G. Duran Ogaya10, D. Azuara11, A. Dalmeses12, B. Bellosillo Paricio12, G. CAPELLA11, R. Salazar13, E. Aranda Aguilar14, C. Montagut1

Author affiliations

  • 1 Medical Oncology, Hospital del Mar, 08003 - Barcelona/ES
  • 2 Medical Oncology, Hospital Universitario Central de Asturias, 33011 - Oviedo/ES
  • 3 Medical Oncology, Hospital de la Santa Creu i Sant Pau, 8026 - Barcelona/ES
  • 4 Medical Oncology, Institut Català d'Oncologia Hospital Duran i Reynals, 08907 - Barcelona/ES
  • 5 Medical Oncology, Hospital Son Llatzer, Palma de Mallorca/ES
  • 6 Medical Oncology, Hospital Universitario Marqués de Valdecilla, Santander/ES
  • 7 Medical Oncology, Hospital Universitario a Coruña, 15006 - A Coruña/ES
  • 8 Medical Oncology, Hospital 12 de Octubre, Madrid/ES
  • 9 Medical Oncology, Hospital Universitario Gregorio Marañón, Madrid/ES
  • 10 Medical Oncology, Hospital Universitario Regional y Virgen de la Victoria, 29010 - Malaga/ES
  • 11 Translational Research Laboratory, Institut Català d'Oncologia Hospital Duran i Reynals-IDIBELL, 08907 - Barcelona/ES
  • 12 Molecular Biology Laboratory, Hospital del Mar, 08003 - Barcelona/ES
  • 13 Medical Oncology, Institut Català d'Oncologia Hospital Duran i Reynals-IDIBELL., 08907 - Barcelona/ES
  • 14 Medical Oncology, University Hospital Reina Sofia. CIBERONC Instituto de Salud Carlos III, 14004 - Cordoba/ES
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Resources

Abstract 2992

Background

CRC cells evade EGFR blockade by several mechanisms of acquired resistance, mainly mutations in RAS, EGFR ECD, HER2 and MET. ctDNA is shed into the bloodstream by tumor cells and can be effectively used to track tumor heterogeneity and to evaluate acquired mutations at tumor progression.

Methods

We included mCRC pts treated in a phase II study of FOLFIRI + panitumumab in irinotecan-refractory mCRC. ctDNA was collected at the end of treatment, processed with the Oncomine colon ctDNA Assay, and sequenced in the PGM Ion Torrent NGS System. The detectable cutoff mutation was 0.1%. Subclonal mutations were defined as mutations with mutant allele fraction (MAF) ≤ 50% of the greatest somatic MAF in the sample. Baseline mutations were analyzed in tumor tissue by dPCR.

Results

ctDNA from 16 pts was analyzed. Clinical characteristics of pts were 69% male; median age 61.5 years; 75% left vs 25% right colon. At least one mutation was detected in 94% of pts (15/16); median mutations per sample was 2.5 (range 1 -13). The frequency of detected mutations was: 13 TP53, 3 APC, 1 CTNNB1, 15 KRAS, 8 NRAS, 7 EGFR, 4 BRAF, 4 PIK3CA, 4 MAP2K1, 1 GNAS, 1SMAD4. While TP53, APC, PIK3CA and BRAF were most likely to be clonal, EGFR, MAP2K1, RAS were generally subclonal. All EGFR ECD mutations emerged in the left colon and all co-existed with RAS mutations plus at least one additional acquired mutation (median 6, range 3-11). RAS/BRAF mutations emerged in 100% and 66% of right and left colon respectively, and co-existed with other acquired mutations in 72% of cases (median 3, range 1-11) Best response was: PR 8 pts, SD 6 pts and PD 2. In both pts with PD only one acquired mutation was detected at progression (PIK3CA and KRAS respectively), and both mutations were detected in the matching pre-treatment tissue and plasma sample at low MAF. Pts follow-up is ongoing, correlation between mutational profile and response to treatment will be presented.

Conclusions

ctDNA analysis captured intrapatient heterogeneity that developed as a result of EGFR inhibition. All EGFR ECD mutations emerged in the left colon and always co-existed with several other mechanisms of acquired resistance, reflecting genomic complexity.

Clinical trial identification

NCT01704703

Legal entity responsible for the study

Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)

Funding

Public funding from the Spanish Ministry of Health, Social Policy and Equality. (Trial Ref: EC11-050)

Disclosure

J.M. Viéitez: Consultant or advisory relationship, research funding and honoraria: Amgen. M. Valladares-Ayerbes: Consultant or advisory relationship and honoraria: Roche, Amgen, Merck Serono. E. Aranda Aguilar: Honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche, Sanofi. All other authors have declared no conflicts of interest.

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