Objectives To examine the effect of microsatellite instability (MSI) on the outcome of fluoropyrimidine and oxaliplatin containing first-line chemotherapy in metastatic colorectal cancer (mCRC).
Methods Patients with mCRC and treated with fluoropyrimidine/oxaliplatin first-line chemotherapy were included in our study. Demographic data, tumour characteristics, chemotherapy regimens, treatment responses and progression-free survival (PFS) were collected from medical records. The MSI analysis was performed using fluorescence-based PCR, and divided into MSI-high (MSI-H) and MSI-low (MSI-L)/microsatellite stable (MSS). Statistical analysis used Kaplan-Meier method, log-rank test and multivariate Cox model.
Results From 1 January 2015 to 1 May 2016, a total of 192 patients with mCRC were included in our study. Among these, 14 (7.29%) exhibited MSI-H and 178 (92.71%) were MSI-L/MSS. The objective response rate (p=0.79), disease control rate (p=0.22) and PFS (p=0.22) of fluoropyrimidine/oxaliplatin first-line chemotherapy were not significantly different between MSI-H and MSI-L/MSS tumours. But MSI-H tumours had a trend to better disease control rate (71.43% vs 54.49%) and PFS (6.50 m vs 5.40 m) than MSI-L/MSS tumours. Multivariate analysis indicated that MSI was not a predictive factor for PFS (p=0.18).
Conclusion The effect of fluoropyrimidine/oxaliplatin first-line chemotherapy was not significantly different between MSI-H and MSI-L/MSS tumours. However, MSI-H tumours tended to have better disease control rate and PFS.
- metastatic colorectal cancer
- microsatellite instability
- predictive marker
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All over the world, colorectal cancer (CRC) is the most common gastrointestinal cancer and one of the leading causes of cancer-related deaths.1 CRC is a heterogeneous disease with significant different clinical presentation, prognosis and individual treatment response, even at the same pathological stage.2 All the above-mentioned factors are very important to make individually tailored treatment decisions. Among these, microsatellite instability (MSI) is a marker of the replication error phenotype, which is caused by defects in the mismatch repair (MMR) processes.2–4
The MMR mechanism identifies and fixes base pair mismatches that occur within the genome, which results in loss of the mechanisms responsible for the precision of the DNA replication and postreplicative DNA repair.2 5 In CRC, MSI is identified in 10%–20% of all cases, including sporadic cancer (12%) and hereditary non-polyposis colorectal cancer (Lynch syndrome; 3%).6 The identification of MSI CRC from microsatellite-stable (MSS) tumours is clinically important. For sporadic stage II CRC, high-frequency MSI (MSI-H) tumours have a better survival compared with MSS tumours and cannot benefit from fluoropyrimidine-based adjuvant chemotherapy.7 8 In metastatic CRC (mCRC), MSI-H tumours have a high response rate to immunotherapy.9 The mainstay treatment of mCRC is chemotherapy, but the relationship between MSI and chemotherapy efficacy of mCRC remains not certain.10 In this study, we retrospectively examined the effect of MSI on the outcomes of fluoropyrimidine/oxaliplatin first-line chemotherapy in mCRC.
Between 1 January 2015 and 1 May 2016, patients with histologically confirmed mCRC and treated with CapeOx or mFOLFOX6 regimens were studied. Patients were selected by screening the database of the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Patients who had a history of preoperative radiotherapy or chemotherapy, inflammatory bowel disease or of familial adenomatous polyposis were excluded. Pathological staging was performed according to the tumour, node, metastases classification system (seventh edition).11 Patients were followed up until 1 May 2018. All procedures performed in this study were conducted in accordance with the ethical standards of the Institutional and National Research Committees and with the 1964 Helsinki Declaration and its later amendments.
The medical records of all 192 patients were reviewed. Demographic data, tumour characteristics, chemotherapy regimens, treatment responses and survival rates were collected. Response evaluation was based on the treating physician’s assessment.
Analysis of microsatellite status
The microsatellite status was determined by fluorescence-based PCR, which uses five Bethesda markers: BAT25, BAT26, D5S346, D2S123 and D17S250.12 The microsatellite status was graded as MSI-H with the presence of two or more unstable markers, as MSI-low (MSI-L) with only one unstable marker and as MSS with no unstable marker. MSI-H or MSI-L tumours were re-examined at least twice to confirm the results. MSI-L was grouped with MSS in this study.
One hundred and forty-six patients received CapeOx regimens, while 46 patients received mFOLFOX6 regimens. Patients received the standard dose of chemotherapy in the first cycle, the subsequent dose was determined by physician’s discretion. Tumour response was assessed at baseline and every two cycles according to Response Evaluation Criteria in Solid Tumors (RECIST). All patients were scheduled to receive chemotherapy until disease progression, intolerable adverse events or the patients’ refusal to continue treatment. CapeOx and mFOLFOX6 were both available first-line regimens for mCRC in our hospital, and the choice of each regimen was entirely based on the physician’s discretion and patient’s request.
The clinicopathological parameters of CRC were assessed using the Fisher’s exact tests for categorical variables and independent t-tests for the continuous variables. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and differences in PFS were evaluated by the log-rank test. Multivariate Cox models were used to assess the effect of individual variables on PFS. All statistical analyses were performed with SPSS Statistics V.20 (SPSS, IBM) and statistical significance was defined as p<0.05.
From 1 January 2015 to 1 May 2016, a total of 192 patients with mCRC were included in this study. Among these, 14 (7.29%) exhibited MSI-H and 178 (92.71%) were MSI-L/MSS. Patient characteristics were displayed in table 1. The median age of patients with MSI-H tumours was 61.00 years (95 CI 59.50 to 63.00) vs 62.00 years (95 CI 58.00 to 62.00) for patients with MSI-L/MSS tumours (p=0.86). There were no significant differences in gender, pathology, differentiation, tumour site, location of metastases, RAS mutation and chemotherapy regimens between the two groups (table 1).
Relationship between microsatellite status and response rate
All patients received first-line fluoropyrimidine/oxaliplatin regimens and were evaluable for response by per-protocol analysis. No significant correlation was found between microsatellite status and objective response rate (CR+PR) (p=0.79). MSI-H patients harboured a trend to better disease control rate (defined as CR+PR+SD) compared with MSI-L/MSS patients (71.43% vs 54.49%). However, this did not reach the predefined significance level (p=0.22, table 2).
Relationship between microsatellite status and PFS
Patients with MSI-H tumours had a median PFS of 6.50 months (95% CI 3.50 to 10.00 months), which is numerically higher than patients with MSI-L/MSS tumours of 5.40 months (95% CI 2.90 to 5.60 months, p=0.17). However, this did not reach the predefined significance level (p=0.22, figure 1).
Multivariate analysis of all patients indicated that pelvic cavity metastases (p=0.016), distant lymph node metastases (p=0.026) and bone metastases (p=0.002) had a significant relationship with PFS (table 3). PFS was not significantly affected by age, gender, pathology, differentiation, tumour site, RAS mutation, chemotherapy regimens and microsatellite status (p>0.05) (table 3).
The currently available data regarding the prognostic and predictive value of microsatellite status in fluoropyrimidine/oxaliplatin first-line chemotherapy in mCRC are limited. We therefore provided one retrospective controlled trial to address these critical clinical questions. In the present study, we could not detect the prognostic or predictive value of microsatellite status in patients with mCRC treated with mFULFOX6 or CapeOx regimens regarding objective response, disease control and PFS. However, MSI-H tumours tended to have a higher disease control rate and PFS although this failed to reach statistical significance.
Although treatment of MSI-H mCRC with immunotherapy has emerged, in clinical practice, decisions remain on standard chemotherapy. Fluoropyrimidine single-agent or fluoropyrimidine-based combination chemotherapy has been the most extensively used first-line treatment for mCRC. However, the role of microsatellite status as a predictive marker of chemotherapy in mCRC remains not certain due to conflicting evidence. Sargent et al 13 and Bertagnolli et al 14 have demonstrated the lack of efficacy of fluoropyrimidine-based regimens in the adjuvant setting in locally advanced MSI-H CRC. Brueckl et al 15 and Liang et al 16 have reported improved outcomes with fluoropyrimidine-based chemotherapy for MSI-H patients compared with non-MSI-H patients. Some other studies reported no significant difference in PFS or overall survival between MSI-H and MSS cases.10 17 18 In our study, MSI-H patients had no significant favourable outcome with fluoropyrimidine/oxaliplatin chemotherapy, which implied that MSI did not predict the effect of chemotherapy.
However, the numerically higher disease control rate and PFS in MSI-H patients are thought provoking. The regimens in our study were mFOLFOX and CapeOx, which used higher doses of 5-FU than some previous studies. The dose of continuous 5-FU (2900 mg/m2, every 2 weeks) in our study was higher than the dose that Alex et al 19 used (500 mg/m2 every week). des Guetz et al 18 have proved that patients with MSI colon cancer are sensitive to FOLFOX6 (5-FU 2800 mg/m2) than mFOLFOX4 (5-FU 2200 mg/m2). In the study of Liang et al, high dose of 5-FU and leucovorin was correlated with a better survival in stage IV sporadic MSI-H CRC.16 High level of thymidylate synthase (TS) has been associated with the 5-FU-resistance of MSI-H tumours.20 It is possible that increasing the doses of 5-FU allows cytotoxic intracellular concentrations to be reached and overcomes the high TS expression. Although our results need confirmation with more cases, they suggest that the use of high doses of 5-FU combined with oxaliplatin (mFOLFOX6 and CapeOx regimen) may benefit for the disease control of MSI-H mCRC.
The main limitation inherent to our study is the retrospective nature and small sample size of patients with mCRC with MSI-H. Retrospective designs are appropriate for exploratory analysis of rare diseases such as MSI-H in mCRC. The advantages of performing the study in a single centre were the homogeneous treatment protocols, imaging tests and RECIST evaluation.
In conclusion, this study showed that MSI-H mCRC had no significant difference in outcomes of fluoropyrimidine/oxaliplatin first-line chemotherapy compared with MSS tumours. However, MSI-H tumours tended to have better disease control rate and PFS. Additional studies are necessary to establish whether microsatellite status could be a significant predictive and prognostic factor for patients with mCRC.
What this paper adds
What is already known on this subject
In sporadic stage II colorectal cancer (CRC), microsatellite instability-high (MSI-H) tumours cannot benefit from fluoropyrimidine-based adjuvant chemotherapy.
In metastatic CRC (mCRC), MSI-H tumours have a high response rate to immunotherapy.
What this study adds
In mCRC, the effect of fluoropyrimidine/oxaliplatin first-line chemotherapy was not significantly different between MSI-H and MSI-low/microsatellite stable tumours.
In mCRC, MSI-H tumours tended to have better disease control rate and progression-free survival.
EAHP Statement 6: Education and Research.
JL and BW contributed equally.
Contributors WF: data calculation, data analysis, article design and writing. JL: manuscript revising. BW: data check and statistical analysis.
Funding This work was supported by the Shire Biological Medicine Fund of Jiangsu Pharmaceutical Society (S201602).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The Ethics Committee of First Affiliated Hospital of Nanjing Medical University (2017 SR-150).
Provenance and peer review Not commissioned; externally peer reviewed.