Abstract
BackgroundKRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS).MethodsPatients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients’ individual data were collected from patients’ records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan–Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests.ResultsA total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors.ConclusionsIn our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might “fill the gap” in response rates that was seen in our study.
Highlights
Kirsten Rat Sarcoma viral oncogene homologue (KRAS) mutations in metastatic colorectal cancer define a subset of tumors that have primary resistance to anti-epidermal growth factor receptor (EGFR)-based therapy
Similar results were retrospectively observed in all trials where anti-EGFR were used for metastatic colorectal cancer (mCRC) patients: because of this fact, KRAS and Neuroblastoma RAS Viral oncogene homologue (NRAS) wild-type status is mandatory for treatment with either Panitumumab or Cetuximab in patients with mCRC
All KRAS variants are used as to identify those tumors who have primary resistance to anti-EGFR treatment: pooled analysis of patients enrolled in registrative trials of both Cetuximab and Panitumumab [14] showed that different KRAS variants might be associated with changes in treatment outcome among patients treated with chemotherapy combinations + antiEGFR
Summary
KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Retrospective studies conducted in anti-EGFR monotherapy trials have shown that Kirsten Rat Sarcoma viral oncogene homologue (KRAS) mutations confer resistance to anti-EGFRbased therapy [1, 2]. These initial reports were confirmed in CRYSTAL [3] and PRIME [4] trials where KRAS mutated status was associated with resistance to anti-EGFR drugs even when combined with standard first-line palliative chemotherapy. While it is well documented that KRAS mutations confer resistance to anti-EGFR treatment, data focused on different clinical behavior of specific KRAS mutations are, lacking. G12D mutation is the most frequent along with G12V, G12C mutations are rarely seen, and G12R becomes relatively frequent (while G12R is rarely seen in NSCLC and almost nonexistent in mCRC) [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
