PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients

被引:333
作者
Perrone, F. [1 ]
Lampis, A. [1 ]
Orsenigo, M. [1 ]
Di Bartolomeo, M. [2 ,3 ]
Gevorgyan, A. [2 ,3 ]
Losa, M. [1 ]
Frattini, M.
Riva, C. [1 ]
Andreola, S. [1 ]
Bajetta, E. [2 ,3 ]
Bertario, L. [4 ]
Leo, E. [5 ]
Pierotti, M. A.
Pilotti, S. [1 ]
机构
[1] Fdn IRCCS Ist Nazl Tumori, Dept Pathol, I-20133 Milan, Italy
[2] Fdn IRCCS Ist Nazl Tumori, Med Oncol Unit 2, I-20133 Milan, Italy
[3] Inst Pathol, Lab Mol Diagnost, Locarno, Switzerland
[4] Fdn IRCCS Ist Nazl Tumori, Prevent Predict Med Unit, I-20133 Milan, Italy
[5] Fdn IRCCS Ist Nazl Tumori, Colorectal Surg Unit, I-20133 Milan, Italy
关键词
GROWTH-FACTOR RECEPTOR; GENE COPY NUMBER; MUTATION STATUS; SHOWS ACTIVITY; BRAF GENE; EXPRESSION; KRAS; CARCINOMA; PREDICTS; EGFR;
D O I
10.1093/annonc/mdn541
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.
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收藏
页码:84 / 90
页数:7
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