How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient’s progressing liver metastasis following prolonged response to cetuximab revealed a MEK1 K57T mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS Q61H mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient. SIGNIFICANCE: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.

Tumor heterogeneity and Lesion-Specific response to targeted therapy in colorectal cancer

RUSSO, MARIANGELA
Co-first
;
SIRAVEGNA, GIULIA;CRISAFULLI, GIOVANNI;LAZZARI, LUCA;DI NICOLANTONIO, Federica;BARDELLI, Alberto
Co-last
;
2016

Abstract

How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient’s progressing liver metastasis following prolonged response to cetuximab revealed a MEK1 K57T mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS Q61H mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient. SIGNIFICANCE: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.
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2
147
153
http://cancerdiscovery.aacrjournals.org/content/6/2/147.full.pdf
Oncology, DRUG RESISTANCE, EGFR BLOCKADE, INTRATUMOR HETEROGENEITY, COLON CANCER, EVOLUTION, MUTATIONS, CETUXIMAB
Russo, Mariangela; Siravegna, Giulia; Blaszkowsky, Lawrence S.; Corti, Giorgio; Crisafulli, Giovanni; Ahronian, Leanne G.; Mussolin, Benedetta; Kwak, Eunice L.; Buscarino, Michela; Lazzari, Luca; Valtorta, Emanuele; Truini, Mauro; Jessop, Nicholas A.; Robinson, Hayley E.; Hong, Theodore S.; Mino-Kenudson, Mari; Di Nicolantonio, Federica; Thabet, Ashraf; Sartore-Bianchi, Andrea; Siena, Salvatore; Iafrate, John; Bardelli, Alberto; ^*; Corcoran, Ryan B.; ^*; ^ joint co-last authorship; *joint corresponding authorship
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1573141
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