Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer.
Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer.
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DOI：
10.1158/2159-8290.cd-15-1283
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发表时间：
2016-02
期刊：
影响因子：
28.2
通讯作者：
Corcoran RB
中科院分区：
文献类型：
--
作者：
Russo M;Siravegna G;Blaszkowsky LS;Corti G;Crisafulli G;Ahronian LG;Mussolin B;Kwak EL;Buscarino M;Lazzari L;Valtorta E;Truini M;Jessop NA;Robinson HE;Hong TS;Mino-Kenudson M;Di Nicolantonio F;Thabet A;Sartore-Bianchi A;Siena S;Iafrate AJ;Bardelli A;Corcoran RB
与靶向药物获得性耐药相关的基因组异质性如何影响对后续治疗的反应尚不清楚。我们研究了结直肠癌中的 EGFR 阻断，以评估组织和液体活检是否可以与放射成像相结合，以监测个体致癌改变对病变特异性反应的影响。对西妥昔单抗长期反应后患者进展性肝转移的活检显示，K57T MEK1 突变是一种新的获得性耐药机制。使用帕尼单抗和 MEK 抑制剂曲美替尼治疗后，该病变消退。在 ctDNA 中，突变 MEK1 水平随着治疗而下降，但之前未被识别的 KRAS Q61H 突变也被发现，尽管接受治疗，但该突变仍有所增加。后来在一个单独的无反应转移瘤中发现了同样的 KRAS 突变。总之，肿瘤活检和连续 ctDNA 监测的并行分析表明，对后续靶向治疗的病灶特异性放射学反应可能是由同一患者的不同肿瘤病灶内产生的不同耐药机制驱动的。
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 radiological 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 K57T MEK1 mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In 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 non-responding 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.