Prognostic value of microsatellite instability and p53 expression in metastatic colorectal cancer treated with oxaliplatin and fluoropyrimidine-based chemotherapy

Abstract

Purpose: The aim of this study was to evaluate the prognostic value of MSI-H and p53 overexpression in metastatic colorectal cancer (mCRC) treated with oxaliplatin and fluoropyrimidine-based first line chemotherapy.

Methods: Tumour samples were retrospectively obtained from 229 patients from a prospective randomised phase III trial of the AIO colorectal study group, comparing CAPOX and FUFOX in mCRC. Immunohistochemistry of p53 and MMR proteins as well as microsatellite analysis were performed.

Results: The incidence of MSI-H and p53 overexpression was 7.9 % and 65.4 %, respectively. MSI-H status was not correlated with ORR, PFS and OS. We observed a trend to lower DCR for MSI-H tumours (65 % vs. 85 %, p = 0.055). p53 overexpression was not correlated with DCR, ORR and PFS. The median OS of patients with tumors with p53 overexpression was significantly longer compared to tumors withhout p53 overexpression (19.6 vs. 15.8 months; p = 0.05). The post-progression survival (PPS) of p53-positive patients undergoing 2nd and/or 3rd line chemotherapy with irinotecan and/or cetuximab was significantly longer compared to p53-negative patients.

Conclusion: MSI-H tumours tend to have lower disease control rates when treated with an oxaliplatin/fluoropyrmidin combination. mCRC patients with p53 overexpression undergoing an irinotecan containing second- or third-line chemotherapy after oxaliplatin failure have a significantly longer post-progression survival compared to patients without p53 overexpression. To validate the clinical impact of p53 in patients with mCRC treated with irinotecan- and/or cetuximab further studies are needed.

Zusammenfassung

Studie: Evaluation des prognostischen Wertes von MSI-H und p53-Überexpression bei metastasierten kolorektalen Karzinomen (mKRK), die mit oxaliplatin- und fluoropyrimidin-basierter Erstlinienchemotherapie behandelt wurden.

Methodik: Retrospektiv wurden Tumorgewebeproben von 229 Patienten einer prospektiven randomisierten Phase-III-Studie der kolorektalen Studiengruppe der AIO, welche CAPOX gegen FUFOX bei mKRK verglich, analysiert. Ein immunhistochemischer Nachweis einer p53-Überexpression bzw. der MMR-Proteine sowie Mikrosatellitenanalysen wurden durchgeführt.

Ergebnisse: Die Inzidenz von MSI-H und p53-Überexpression lag bei 7,9 % bzw. 65,4 %. Der MSH-I-Status korrelierte nicht mit der ORR, dem PFS oder OS. Ein Trend unter MSI-H-Tumoren zu einer geringeren DCR war festzustellen (65 % vs. 85 %). Eine p53-Überexpression korrelierte nicht mit der DCR, ORR, oder dem PFS. Das mediane OS der Patienten mit p53-überexprimierten Tumoren war signifikant länger verglichen mit Tumoren ohne p53-Überexprimierung (19,6 vs. 15,8 Monate; p= 0,05). Das PFS der p53 überexprimierenden Patienten unter der Zweit- und Drittlinienchemotherapie mit Irinotecan und/oder Cetuximab war signifikant länger als bei Patienten ohne p53-Überexpression.

Diskussion: MSI-H Tumoren zeigten unter einer Kombinationstherapie aus Oxaliplatin/Fluoropyrimidin tendenziell eine schlechtere DCR. p53 überexprimierte mKRK unter einer irinotecanhaltigen Zweit- bzw. Drittlinienchemotherapie nach Oxaliplatinversagen hatten ein signifikant längeres PFS im Vergleich zu nicht p53 überexprimierenden Tumoren. Um die klinische Bedeutung dieser Beobachtung zu valuieren, werden weitere Studien benötigt.

Schlüsselwörter

metastasierters kolorektales Karzinom - Mikrosatelliteninstabilität - p53 - Oxaliplatin - Prognose

Key words

metastatic colorectal cancer - microsatellite instability - p53 - oxaliplatin - prognosis

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