TY - JOUR
T1 - Tumor heterogeneity and Lesion-Specific response to targeted therapy in colorectal cancer
AU - Russo, Mariangela
AU - Siravegna, Giulia
AU - Blaszkowsky, Lawrence S.
AU - Corti, Giorgio
AU - Crisafulli, Giovanni
AU - Ahronian, Leanne G.
AU - Mussolin, Benedetta
AU - Kwak, Eunice L.
AU - Buscarino, Michela
AU - Lazzari, Luca
AU - Valtorta, Emanuele
AU - Truini, Mauro
AU - Jessop, Nicholas A.
AU - Robinson, Hayley E.
AU - Hong, Theodore S.
AU - Mino-Kenudson, Mari
AU - Di Nicolantonio, Federica
AU - Thabet, Ashraf
AU - Sartore-Bianchi, Andrea
AU - Siena, Salvatore
AU - Iafrate, John
AU - Bardelli, Alberto
AU - Corcoran, Ryan B.
N1 - M. Russo non risulta correttamente affiliata in questa pubblicazione.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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-specifi c responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profi les allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.
AB - 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-specifi c responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profi les 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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U2 - 10.1158/2159-8290.CD-15-1283
DO - 10.1158/2159-8290.CD-15-1283
M3 - Article
AN - SCOPUS:84957063275
VL - 6
SP - 147
EP - 153
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 2
ER -