Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer
| Autor: | 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 authorshipjoint corresponding authorship |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
EGFR BLOCKADE Colorectal cancer medicine.medical_treatment COLON CANCER Bioinformatics medicine.disease_cause Metastasis Targeted therapy 03 medical and health sciences 0302 clinical medicine medicine Panitumumab Trametinib Cetuximab MUTATIONS business.industry MEK inhibitor medicine.disease Oncology DRUG RESISTANCE EGFR BLOCKADE INTRATUMOR HETEROGENEITY COLON CANCER EVOLUTION MUTATIONS CETUXIMAB EVOLUTION CETUXIMAB 3. Good health DRUG RESISTANCE 030104 developmental biology Oncology INTRATUMOR HETEROGENEITY 030220 oncology & carcinogenesis Cancer research KRAS business medicine.drug |
| Zdroj: | Cancer Discovery. 6:147-153 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-15-1283 |
| Popis: | 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 MEK1K57T 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 KRASQ61H 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. Cancer Discov; 6(2); 147–53. ©2015 AACR. See related commentary by Hiley and Swanton, p. 122. This article is highlighted in the In This Issue feature, p. 109 |
| Databáze: | OpenAIRE |
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