Prognostički i prediktivni značaj lokalizacije i karakteristika primarnog tumora u lečenju metastatskog kolorektalnog karcinoma kod pacijenata bez mutacije KRAS gena

Abstract

Uvod: Kolorektalni karcinom (KRK) predstavlja globalni problem, obzirom na njegovu učestalost. Lečenje pacijenata koji boluju od metastatskog kolokrektalnog karicnoma (mKRK) je veoma složen proces. Dokazano je da pored patohistoloških i molekularnih karakteristika, lokalizacija primarnog tumora (LPT) takođe utiče na ukupno preživljavanje. Iako se smatra jednim organom, segmenti debelog creva se međusobno razlikuju, kako u histološkom, fiziološkom, tako i u molekularnom smislu. Poznato je da određen procenat pacijenata sa RAS/RAF nemutiranim tipom tumora, ipak ne reaguje na anti EGFR terapiju. Razlozi mogu da budu posledica primarne ili sekundarne rezistencije, ali i prekomerne ekspersije HER 2 receptora kod pacijenata sa mKRK. Ovom studijom želeli smo da istaknemo važnost LPT kao prognostičkog i prediktivnog markera, kao i da ispitamo značaj prekomerne HER2 ekspresije kod pacijenata sa mKRK. Materijal i metode: Studija je bila retrospektivno -prospektivna, obuhvatila je ukupno 181 pacijenta sa metastatskim KRAS nemutiranim kolorektalnim karicnomom,. 101 pacijent je imao tumor levog kolona, 80 pacijenata je imalo tumor desnog kolona. Analizirane su patohistološke i molekularne karakteristike tumora ( KRAS, HER 2) koje su korelilrane u odnosu na lokalizaciju primarnog tumora. Takođe je ispitivan efekat terapije anti EGFR antitelima pomoću progression free survival (PFS) i overall survival (OS), u odnosu ma loklaizaciju primarnog tumora, kao i u odnosu na prekomernu ekspresiju HER 2 receptora kod pacijenata sa KRAS nemutiranim mKRK. Rezultati: 101 pacijent (55,8%) je imao KRAS nemutirani KRK lokalizovan u levom kolonu(KLK), 80 (44,2%) je imao tumor lokalizovan u desnom kolonu(KDK). Medijana ukupnog preživljavanja OS kod pacijenata sa KLK je statistički značajno bolja (43 vs. 33month,Mantel-Cox p = 0,005; Breslow p = 0,001). Medijana PFS kod pacijenata sa KLK je statistički značajno bolja nego kod pacijenata sa primarnim tumorom lokalizovanim na desnoj (6 vs. 3 month, Mantel-Cox p < 0,001; Breslow p < 0,001). Multivarijantnom analizom, dobijeni su nezavisni prediktori kumulativnog preživljavanja (OS) kod pacijenata sa KRK: mucinozni adenokarcinom (p < 0,001; HR 2,69; 95% CI 1,59-4,56), desna lokalizacija (p = 0,022; HR 1,46; 95% CI 1,06-2,01)), prisustvo perineuralne invazije (p = 0,034; HR 1,43; 95% CI 1,03-1,98) i prisutnost tumora na resekcionom rubu (p =0,049; HR 1,68; 95% CI, 1,02-2,81). Cox regresionom analizom, metodom Conditional Forward, dobijeni su nezavisni prediktori kumulativnog preživljavanja bez progresije bolesti (PFS) kod pacijenata sa karcinomom kolona: mucinozni adenokarcinom (p = 0,001; HR 2,53; 95% CI 1,49-4,29) i desna lokalizacija (p = 0,004; HR 1,60; 95% CI 1,16-2,21). U grupi pacijenata sa KLK, Cox regresionom analizom, metodom Conditional Forward, dobijen je samo jedan nezavisni prediktor kumulativnog preživljavanja (OS) i to je prisustvo perineuralne invazije (p = 0,038; HR 1,60; 95% CI 1,03-2,48). U grupi pacijenata sa KDK, Cox regresionom analizom, metodom Conditional Forward, dobijen je samo jedan nezavisni prediktor kumulativnog preživljavanja (OS) i to je mucinozni adenokarcinom (p = 0,038; HR 3,12; 95% CI 1,72-5,66). OS pacijenata sa HER2 pozitivnim nalazom 3+ je lošije u odnosu na pacijente sa HER 2 negativnim nalazom (0, 1+, 2+) (p = 0,339). PSF pacijenta sa HER2 pozitivnim nalazom je statistički značajno lošije (p < 0,001) u odnosu na pacijente sa HER 2 negativnim nalazom (i pored izuzetno malog broja pacijenata sa HER2 pozitivnim nalazom). Zaključak: Lokalizacija primarnog tumora je važan prognostički i prediktivni marker u lečenju pacijenata sa KRAS nemutiranim mKRK. Pacijenti sa KDK imaju statistički značajno kraće ukupno preživljavanje i vreme do progresije bolesti na anti EGFR terapiju. Uloga prekomerne ekspresije HER2 receptora, kod KRAS nemutiranog mKRK, zahteva dodatna ispitivanja, iako smo zabeležili nizak procenat prekomerne ekspredije HER 2 receptora, ti pacijenti su imali kraće ukupno preživljavanje i vreme do progresije bolesti na anti EGFR terapiju.

Introduction: Colorectal cancer (CRC) represents a global issue, taking into consideration its frequency. Treating of patients with metastatic colorectal cancer (mCRC) is a very complex process. It has been proven that, in addition to pathohistological and molecular characteristics, the localization of the primary tumour (LPT) also affects the overall survival. Although considered a single organ, segments of the colon differ from each other, histologically, physiologically, and molecularly. It is known that a certain percentage of patients with RAS / RAF wild type (wt) tumour type, however, does not respond to anti-EGFR therapy. The reasons may be a consequence of primary or secondary resistance, but also excessive expression of HER2 receptors in patients with mCRC. With this study, we wanted to highlight the importance of LPT as a prognostic and predictive marker, as well as to examine the importance of overexpression of HER2 in patients with mCRC. Methods: This research included 181 patients with KRAS wild type mCRC, who received anti EGFR therapy at the Oncology Institute of Vojvodina. 101 patients had a tumour of the left colon, 80 patients had a tumour of the right colon. The research analysed pathohistological and molecular characteristics of the tumour (KRAS, HER2) that were correlated with respect to the localization of the primary tumour. It also investigated the effect of anti-EGFR antibody therapy using progression-free survival (PFS) and overall survival (OS), in relation to the localization of the primary tumour, as well as in relation to HER2-receptor overexpression in patients with KRAS wt mCRC. Results:K RAS wt KLK was present in 101 patients (55.8%), KDK in 80 (44.2%). The median OS in patients with KLK was statistically significantly better (43 vs. 33 months, Mantel-Cox p= 0.005; Breslow p = 0.001). Median (PFS) with KLK was statistically significantly better than in patients with primary tumour localized on the right side (6 vs. 3 months, Mantel-Cox p <0.001; Breslow p < 0.001). Multivariate analysis of independent predictors of cumulative survival (OS) of patients with colorectal carcinoma: mucinous adenocarcinoma (p <0.001; HR 2.69; 95% CI 1.59-4.56), right localization (p = 0.022; HR 1.46; 95% CI 1.06-2.01), presence of perineural invasions (p = 0.034; HR 1.43; 95% CI 1.03-1.98) and the presence of tumours at the resection margin (p = 0.049; HR 1.6; 95% CI 1.02-2.81). Cox regression analysis, Conditional Forward method obtained independent predictors of cumulative progression-free survival (PFS) of patients with colon cancer: mucinous adenocarcinoma (p = 0.001; HR 2.53; 95% CI 1.49-4.29) and right localization (p = 0.004; HR 1.60; 95% CI 1.16-2.21). In the group of patients with KLK, Cox regression analysis, Conditional Forward metho, obtained only one independent predictor of cumulative survival (OS) and that is the presence of perineural invasion (p = 0.038; HR 1.60; 95% CI 1.03-2,48). In the group of patients with KDK, Cox regression analysis, Conditional Forward method, obtained only one independent predictor of cumulative survival (OS) and that is mucinous adenocarcinoma (p = 0.038; HR 3.12; 95% CI 1.72-5.66). The OS of patients with HER2 positive result 3+ is worse than that of patients with HER2 negative result (0,1+, 2 +) (p = 0.339). The PFS of patients with HER2 positive results was statistically significantly worse (p <0.001) compared to patients with HER2 negative results (despite the extremely small number of patients with HER2 positive results). Conclusion: Localization of the primary tumour is an important prognostic and predictive marker in the treatment of patients with wildtype mCRC with anti-EGFR antibodies. Patients with KDK have a statistically significantly shorter time to disease progression to anti-EGFR therapy and overall survival. The role of HER2 receptor overexpression in wild-type mCRC requires further examination, although we noted a low percentage of HER2 receptor overexpression in wt mCRC; these patients also had a shorter time to disease progression to anti-EGFR therapy and overall survival.