THE ROLE OF KRAS GENE MUTATION TESTING IN COLORECTAL CANCER – A PREDICTIVE BIOMARKER OF RESPONSE TO EGFR INHIBITORS THERAPY
Autori:
Ivana Rako, Jasminka Jakić-Razumović, Domagoj Caban, Jadranka Sertić, Darko Katalinić, Hilda Golem, Stjepko Pleština
Sažetak
Aktivacija onkogena KRAS značajna je u kolorektalnoj karcinogenezi, a prisutnost KRAS-mutacije može se dokazati u više od 30% uzoraka kolorektalnog karcinoma (CRC). Među novijim lijekovima za liječenje metastatskog CRC-a jesu i pripravci koji sadržavaju protutijela na receptor za epidermalni čimbenik rasta (EGFR), cetuksimab i panitumumab. Nedavna istraživanja pokazuju da bolesnici s metastatskim CRC-om s mutacijama gena KRAS na 12. i 13. kodonu nemaju koristi od terapije inhibitorima EGFR-a. S ciljem određivanja statusa gena KRAS kao prediktivnog biomarkera testirana su 44 uzorka CRC-a na sedam poznatih mutacija gena KRAS. Nakon izdvajanja DNA iz tumorskog tkiva uklopljenog u parafinske blokove, prisutnost KRAS-mutacija određena je metodom PCR u stvarnom vremenu postupkom apsolutne kvantifikacije prvi put u Hrvatskoj, međunarodno certificiranom metodom. Mutacije su dokazane u 12 uzoraka tumora: pet bolesnika imalo je mutaciju Gly12Val (GGT>GTT), tri bolesnika Gly12Asp (GGT>GAT), dva bolesnika Gly13Asp (GGC>GAC) te po jedan bolesnik mutaciju Gly12Ser (GGT>AGT) i Gly12Cys (GGT>TGT). Naši nalazi pokazuju da je incidencija KRAS-mutacije u uzorcima bolesnika oboljelih od CRC-a 27%, što je podudarno s do sada objavljenim rezultatima u svijetu. Testiranje na KRAS-mutaciju prije primjene imunoterapije inhibitorima EGFR-a jedini je ispravni put u liječenju bolesnika s metastatskim CRC-om čime se poboljšava klinički ishod bolesti, a izbjegavaju se nepotrebne toksičnosti lijeka, nuspojave i financijski troškovi.
Summary
Activation of KRAS oncogene has been implicated in colorectal carcinogenesis. KRAS mutations can be detected in more than 30% of all patients with colorectal cancer (CRC). Most recently, regimens that include anti-epidermal growth factor receptor (EGFR) targeted antibodies, cetuximab and panitumumab, for metastatic CRC have been developed. Several recent studies have shown that patients with KRAS mutations in codons 12 and 13 in metastatic CRC do not benefit from anti-EGFR therapy. With the aim to determine KRAS status as predictive biomarker, 7 known mutations of KRAS gene in codons 12 or 13 on 44 CRC samples were tested. After DNA extraction from paraffin-embedded tumor tissue blocks, KRAS mutations were analysed using quantitative real-time PCR with internationally certified method, for the first time in Croatia. Mutations were detected in 12 tumor samples: five patients with Gly12Val (GGT>GTT), three with Gly12Asp (GGT>GAT), two patients with Gly13Asp (GGC>GAC), one patient with Gly12Ser (GGT>AGT) and one with Gly12Cys (GGT>TGT) mutation in tumor. Our data about KRAS mutational status in the sample of Croatian population diagnosed with CRC have shown that incidence of KRAS mutation is 27%, which is consistent with results already reported worldwide. The final result must be a proper selection of the correct therapy with EGFR inhibitors for the patients with CRC which is critical for improving clinical outcomes, unnecessary toxicities, side effects and financial cost.
