Patients with primary CRC and lymph node metastases and those at high risk for metachronous CLM (stage II/III) have been treated with adjuvant chemotherapy, including oxaliplatin in recent years.3,7,8
Nevertheless, some of these patients will develop CLM, which can be successfully treated if they can be completely resected with histologically negative margins.24,25
In this study, we analyzed DFS and OS rates after resection of metachronous CLM according to adjuvant chemotherapy type for the primary tumor. After controlling for primary and metastatic disease stage, the primary risk factor associated with poor outcome was treatment with adjuvant FOLFOX after resection of CRC. These findings suggest that the type of adjuvant therapy given after colon resection impacts the tumor biology of the subsequent metastases. To validate this hypothesis, we analyzed somatic gene mutations in CLM. We found a higher rate of mutations in FOLFOX-treated patients, with KRAS
mutational status being entirely responsible for this difference.
Prior to the oxaliplatin-era, published series reporting on patients who developed metachronous CLM indicated 46% to 62% 3-year DFS and 64% to 75% 3-year OS rates.9,26,27
Our retrospective analysis of prospectively collected CLM patient data demonstrated that the natural history of the subset of metachronous CLM from stage III CRC may have changed after the introduction of oxaliplatin-based chemotherapy. Patients with metachronous CLM treated with 5-FU experienced longer survivals (3-year DFS 38% and OS 70%) than those treated with FOLFOX (3-year DFS 18% and OS 58%). Clinical trials indicate that the use of FOLFOX after primary resection prevents or delays CLM in a larger number of patients than does 5-FU alone,7,8
but it may at the same time contribute to the selection of patients with a more aggressive form of metastatic disease—that is, resistant to oxaliplatin and responsible for a poorer OS and DFS after resection of metachronous CLM.
Two prospective randomized studies on adjuvant chemotherapy in stage II and III colon cancer patients have demonstrated that patients who recur after adjuvant FOLFOX have shorter OS than patients who recur after randomization to adjuvant 5-FU.8,28
In the MOSAIC trial, the median time from relapse to death was 21 months for the FOLFOX group and 24 months for the 5-FU group.8
This has been previously attributed to the lower efficacy of oxaliplatin regimens upon retreatment of previously FOLFOX-treated patients. According to this hypothesis, these patients have fewer effective chemotherapy regimens and a resulting lower OS. However, our data supports the alternate suggestion that FOLFOX-resistant colon cancer has a different biology than 5-FU–resistant tumors. Preclinical studies suggest that oxaliplatin resistant cell lines develop epithelial-to-mesenchymal transition, characterized by a migratory and proinva-sive phenotype.29,30
As DFS after hepatectomy is dictated by unrecognized microscopic disease outside of the visible metastases, such migratory behavior may contribute to the higher recurrence rates after FOLFOX.
mutation in primary tumors represents a modest prognostic marker for metastatic CRC patients in some, but not all, clinical series. However, it is clearly associated with resistance to epidermal growth factor receptor inhibitors.31–34
mutation in CLM has also been shown to be associated with lower survival and accelerated disease progression in patients with resected CLM in an era predating FOLFOX chemotherapy.35
The same study reported a low rate of KRAS
mutations (16%), similar to our study, after resection of metachronous CLM. KRAS
mutation analysis was additionally used in 2 previous studies to assess the minimum surgical margins in resected CLM.36,37
mutation has recently been associated with higher rates of lung metastases, a common location of recurrence for patients with resected CLM.32
The current study is the first to characterize KRAS
mutation in patients undergoing curative liver resection for metachronous CLM in the era of adjuvant FOLFOX chemotherapy for CRC; the higher rate of KRAS
mutation in patients treated with FOLFOX underscores the association between modern chemotherapy and the long-term selection of worse tumor biology.
This study is limited by its retrospective nature. The selection of adjuvant chemotherapy regimens in routine patient care is based on many clinical and pathologic factors not fully captured by multivariate analysis; however, the degree of magnitude of the observed effect and the inclusion of multiple prognostic variables argues against this. A prospective study to confirm our findings may not be feasible because chemotherapy with FOLFOX for lymph-node positive CRC is currently the standard of care on the basis of randomized trials.3,7,8
Efforts to replicate this finding from completed randomized adjuvant studies are ongoing. Our study is also limited by the fact that somatic gene mutation profiling using Sequenom MassArray technology could only be performed in a subset of 129 patients. However, this high-throughput technology enabled the testing of 159 different mutations on 33 different genes, allowing evaluation of genes and pathway interactions that could not be evaluated with a single gene study. Another possible limitation of this study is the absence of KRAS
status evaluation of the primary tumor. Thus, it was not possible to determine whether a discordance in mutation rates existed between patients who did and did not receive oxaliplatin after resection of the primary. However, numerous studies of KRAS
mutational status in primary and metastatic disease sites have shown high concordance rates, ranging from 84% to 100%38–44
, whereas only one study, in 21 patients, reported a low concordance rate of 52%.45
In conclusion, this study suggests that oxaliplatin-based adjuvant therapy may provide a selection pressure favoring a chemotherapy-resistant subset enriched for KRAS
mutations while on balance preventing liver recurrences in patients with KRAS
wild-type tumors. This change may be responsible for the early recurrence and lower OS observed after resection of metachronous CLM. The selection of patients with chemotherapy-resistant CLM and predestined worse prognosis represents a new challenge for hepatobiliary surgeons in an era that is characterized by multimodal therapy of CLM and the increasing use of perioperative chemotherapy with molecular profiling.16,46,47