Abstract 472P
Background
Worldwide, colorectal cancer (CRC) has the second highest mortality rate of all malignancies. Sequencing efforts on primary CRC (pCRC) have led to extensive knowledge about its genomic landscape. Because the molecular characteristics change over time and under treatment pressure, tumor characteristics of metastases can differ from those of the primary tumor. Therefore, better insight into the genomic alterations of metastatic CRC (mCRC) is key to improve treatment strategies.
Methods
We investigated whole genome sequencing (WGS) data of metastases of 429 CRC patients participating in the CPCT-02 study (NCT01855477). Based on prior treatment data, patients were divided into a group who did and a group who did not receive systemic treatment prior to the moment the biopsy was taken. Our sequencing data was compared to publicly available data from pCRC. In addition, observed molecular patterns were associated with pretreatment regimens and clinical outcome. The potential value of WGS analysis for current clinical practice was explored.
Results
Compared to pCRC we found that TP53, ZFP36L2, KRAS, and APC were more frequently mutated in mCRC whereas PIK3CA mutations were less frequent. Clear shifts in the relative contributions of mutational signatures were observed in mCRC compared to pCRC. We identified a subgroup of both pretreated and untreated mCRC samples characterized by signatures rarely found in pCRC (SBS9/39/41). Effects of prior treatment were observed in pretreated patients versus untreated patients on the total number of aberrations, mutational signatures, and CNVs. Based on their molecular landscape, 55% of the patients could qualify for on- or off-label FDA-approved targeted treatments. In addition to KRAS/NRAS and BRAF, mutations in FBXW7 were associated with poor response to EGFR-targeted treatments.
Conclusions
Differences in driver genes and mutational signatures were observed between mCRC and pCRC, and genomic effects of prior treatment were observed in pretreated mCRC patients versus untreated patients. In conclusion, this study provides an unprecedentedly comprehensive insight into the molecular landscape of mCRC and identifies clinically useful genomic features for future patient management.
Clinical trial identification
NCT01855477.
Editorial acknowledgement
Legal entity responsible for the study
Foundation CPCT.
Funding
Foundation CPCT and Hartwig Medical Foundation.
Disclosure
All authors have declared no conflicts of interest.