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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 96-102

The association of clinicopathological features and survival in colorectal cancer patients with kras mutation status


1 Division of Medical Oncology, Tepecik Education and Research Hospital, Izmir, Turkey
2 Division of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
3 Division of Basic Oncology, Dokuz Eylul University, Izmir, Turkey
4 Division of Medical Oncology, Izmir Medical Park University, Izmir, Turkey

Date of Web Publication13-Apr-2016

Correspondence Address:
Tulay Akman
Department of Medical Oncology, Tepecik Education and Research Hospital, Gaziler Caddesi, No: 468, Yenisehir, Izmir
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148684

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 > Abstract 

Background: KRAS mutations have a significant role in the consecutive activation of RAS.RAF.MEK.ERK pathway in colorectal cancer.Approximately 30.35% of sporadic colorectal cancers have KRAS mutation. While the predictive role of KRAS is commonly accepted at the present time, its prognostic role and association with different clinical and histopathological properties are currently unclear and inconsistent. The intent of this study, has been to evaluate the associations between KRAS gene mutations and clinicopathological features and survival times in Turkish colorectal cancer patients.
Materials and Methods: In this study, the file records of 115 metastatic colorectal cancer patients who applied to the Department of Medical Oncology between 2000 and 2011 were monitored; data on clinicopathological features and survival times were collected. DNA.sequencing method with PCR amplification from archival paraffin blocks were used for KRAS mutation status analysis. The associations between KRAS mutation status and clinicopathological features and survival times were compared statistically.
Results: While a significant association hadbeen determined between KRAS mutation status and tumor localization, there was no determined significant association with other clinicopathological properties. Similarly, there was no association between KRAS mutation status and survival parameters.
Conclusions: As a result, the effect of KRAS mutation status on clinicopathological features, survival time and prognosis is unclear.

Keywords: Clinicopathological properties, KRAS, metastatic colorectal cancer, prognosis


How to cite this article:
Akman T, Oztop I, Baskin Y, Unek IT, Demir N, Ellidokuz H, Yilmaz AU. The association of clinicopathological features and survival in colorectal cancer patients with kras mutation status. J Can Res Ther 2016;12:96-102

How to cite this URL:
Akman T, Oztop I, Baskin Y, Unek IT, Demir N, Ellidokuz H, Yilmaz AU. The association of clinicopathological features and survival in colorectal cancer patients with kras mutation status. J Can Res Ther [serial online] 2016 [cited 2019 Oct 15];12:96-102. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/96/148684




 > Introduction Top


Colorectal cancer is the third-most frequent type of cancer in the world and it ranks as the third-most leading cuase of all cancer deaths.[1] Approximately 20-25% of colorectal cancer patients were metastatic at diagnosis and 40-50% of colorectal cancer patients were metastatic during their treatment, as described in the following process. The main treatment for metastatic colorectal cancer (CRC) is systemic chemotherapy. In recent years targeted chemotherapies are commonly being used. Also metastasectomy approaches, local ablative therapies, hepatic artery infusion, and leucoregional therapy approaches, like isolated hepatic perfusion, are being used in patients with metastases. These therapies are most benefical for patients with liver metastases where survival times increase significantly.[2]

The development of colorectal cancer is a multi-stage process. The chromosomal abnormalities, gene mutations and epigenetic modifications in genes that have a role in proliferation, differentiation, apoptosis and angiogenesis, cause colorectal cancers.[3],[4],[5] In this process the epidermal growth factor receptor (EGFR) and angiogenesis pathways are the two important pathways in both tumor proceeding and treatment guidance. In recent years, agents which inhibit EGFR pathway activation are commonly used in metastatic CRC treatment. EGFR is known as HER1 or ErbB. It is a member of ErbB receptor family.[6],[7] EGFR has a significant role in normal cell growth and differentiation. The activation of EGFR signalization occurs commonly in CRC cells and this status results in cell proliferation, migration, metastases, angiogenesis and inhibition of apoptosis.[8]

KRAS mutation plays an important role in the pathogenesis of CRC. KRAS mutation also has a significant role in the consecutive activation of RAS-RAF-MEK-ERK pathway.[9] It is also known that this mutation is related with unresponsiveness to cetuximab and panitumumab, which are anti-EGFR monoclonal antibodies used in metastatic CRC.[10],[11],[12] KRAS is a proto-oncogene which regulates the responses to many extracellular stimulus.[13] Approximately 30-35% of sporadic CRC have KRAS mutation; 97% of these KRAS mutations are located in codons 12 and 13. Facts about the prognostic value of KRAS in CRC are unclear and inconsistent. Despite the knowledge that the KRAS mutation should be evaluated as a negative predictor in a meta-analysis, it is often pointed out that this property is limited only with codon 12 mutation. In contrast, th e PETACC-3 study, another widerange study, showed that the KRAS mutation has no prognostic value. Thus results reported by different studies evaluating the association between KRAS mutation and the clinicopathological features are inconsistent.[14],[15],[16]

This study aimed to evaluate the association between KRAS mutation status and clinicopathological features with survival times for metastatic colorectal cancer patients, who were followed up and treated in our clinic.


 > Materials and Methods Top


Patient characteristics

In this study, 115 metastatic colorectal cancer patients with determined KRAS status that had applied to Medical Oncology Department, Dokuz Eylul University School of Medicine between 2000 and 2011 were evaluated retrospectively. Patients' demographic characteristics and clinicopathological features, as well as survival data were recorded. The performance status of the patients were evaluated according to ECOG evaluation criterias. Primary tumor location was grouped as proximal colon, distal colon and rectum.

Metastases were classified according to the location, respectively, as follows: Isolated liver, isolated lung, liver and lung, and isolated peritoneum metastases. Also, metastases were grouped according to the number of metastases, that is: One, two and more than two metastases.

Chemotherapy efficiency and survival analysis

Treatment responses were classified according to the The World Health Organization (WHO) response evaluation criterias. Toxicity evaluations were done according to WHO toxicity evaluation criterias. Time of the pathological diagnosis was accepted as the date of diagnosis. The most recent condition of the surviving patients was established from their latest control findings. Overall survival (OS) was calculated as the time from the date of diagnosis to death or the last visit to the clinic. Disease-free survival (DFS) was established as the time from the date of diagnosis to the detection of first recurrence; and finally, progression-free survival (PFS) was calculated as the time from the date that treatment began until the development of first progression of the tumor.

Tissue selection and DNA isolation

One-hundred and fifteen colorectal adenocarcinoma patients, whose archival tumor tissue was sufficient for molecular analysis, were included in this study. KRAS mutation analysis was performed by a pathologist after histological confirmation of the presence of > 70% tumor cells in hematoxylin and eosin-stained slides.

Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue sections (10-μm thick) using a QIAamp DNA FFPE Tissue Kit (Qiagen, Cat no: 56404, Hilden, Germany). Depending on the size of the tumor tissue sample, three to five sections were obtained. Tumor tissues were deparaffinized in xylene, washed with absolute ethanol and air dried. The lysis process was performed with proteinase K treatment at 56°C overnight. The concentration and quality of the extracted DNA were determined by spectrometric measurement.

KRAS mutation analysis

The ARMS/Scorpion-based TheraScreen-KRAS Mutation Kit (Product code: KR-21, DxS Ltd, Manchester, UK) was used for KRAS mutation analysis. The assay is designed to detect the seven most common KRAS gene mutations (Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp) on exon 2. Real-time PCR was performed on a real-time PCR platform (Lightcycler 480, Roche Applied Science, Mannheim, Germany) according to the recommendations of the manufacturer.

Statistical analysis

The Fisher Chi-square test was used for comparison of homogeneity between groups, overall survival. Disease-free survival curves were obtained by Kaplan-Meier method. A log-rank test was used for the comparison of survival curves. Multivariate analysis was performed; the confidence interval was accepted as 95% and P value for statistical significance was < 0.05. Statistical analysis was performed by using SPSS 15 (Statistical Package for the Social Sciences) (Version 15.0; SPSS, Inc, Chicago, IL, USA) program.

Ethics statement

The study was approved by Dokuz Eylül University Medical Faculty Non-invasive Researches Clinical Research Ethics Committee (606-GOA protocol number, 201217-06 number ethics committee approval).


 > Results Top


Patient characteristics

One-hundred and fifteen metastatic CRC patients with known KRAS mutation status have been evaluated: 68 patients (59.1%) were male and 47 patients (40.9%) were female. The median age was 57.6. At the time of diagnosis, 58 patients (50.5%) were metastatic and 57 patients were early-stage colorectal cancer. Patient tumor location was 44 rectum, 71 colon; in 34 patients, tumor location was left side of the colon while 25 patients had right side tumor location. One patient's tumor was located in the transvers colon and 11 patient's tumors were located in the rectosigmoid region.

Adenocarcinoma was determined in 103 patients (89.6%) and mucinous adenocarcinoma was determined in 12 patients (10.4%). The distribution of patients according to demographic features is presented in [Table 1].
Table 1: Demographic features of patients

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The incidences of distant metastases were as follows 33 patients had isolated liver metastases, 13 patients- isolated lung metastases, 22 patients-liver+lung metastases, 11 patients- isolated peritoneum metastases, 45 patients- multiple organ metastases. Seventy patients' metastases were only in one organ, 40 patients' metastases were in two organs, and five patients' metastases were in more than two organs.

Metastases locations and clinicopathological features according to KRAS mutation status are listed in [Table 2].
Table 2: Clinicopathological features according to KRAS mutation status

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Chemotherapy types

For 57 patients with no metastases at diagnosis, 82.5% (47 patients) received adjuvant therapy while 17.5% (10 patients) did not. Chemoradiotherapy (CRT) was administered to 26.1% (30 patients), all of these patients had their tumor location identified as rectum. Chemoradiotherapy was administered to 76.7% (22 patients) for neoadjuvant purposes due to local advanced rectal cancer and to 23.3% (eightpatients) with metastatic disease for palliative purposes. When the tumor locations were monitored in patients, it was detected that tumor location was at the rectosigmoid in three patients (10%) and located at the rectum in 27 patients (90%).

The most frequently used chemotherapy regimen in the patients with advanced stage was regimens with oxaliplatin (137 patients; 70 of them were in first line, 20 were second line, and 47 were ≥ third line). Following oxaliplatin, irinotecan-based regimens (20 patients; threeof them were first line, ninewere second line and eightwere ≥ third line) and bevacizumab based regimens (142 patients; 36 of them were in first line and 68 were second line and 38 were ≥ third line) were used, respectively. In 43 patients cetuximab was administered; 11 of them were in the second line, 12 were in the third line, and 20 were in the fourth or later line.

Results of KRAS mutation analysis

From the 115 patients studied by the clinic, 71 (61.7%) of the patients had predictably wild-type KRAS gene status; of these, 66 patients (88.7%) showed evidence of the codon 12 mutation and five (11.3%) patients showed codon 13mutation. In the remaining 44 patients theKRAS gene mutation was determined.

No KRAS mutation was determined (wild type) in 71 patients (61.7%) among total 115 patients, and in the rest of them, in 44 patients (38.3%) KRAS mutation was determined. Most of these patients with KRAS mutation (66 patients, 88.7%) were having codon 12 mutation and only in five patients (11.3%) there were codon 13 mutation.

The association between KRAS mutation status and clinicopathological features

There was a significant association between KRAS mutation and tumor localization but there was no significant association between the other clinicopathological properties. When it was evaluated according to tumor localization, the KRAS wild-type gene was detected more frequently in tumors with proximal involvement (P = 0.028).

Metastases regions and distribution properties according to KRAS mutation status in patients are listed in [Table 2].

There was no significant association between Body Mass Index and KRAS mutation status. The medium of Body Mass index was detected as 26.1 in KRAS wild-type and 27.0 in KRAS mutant type.

When the patients, who had received chemoradiotherapy were evaluated according to KRAS mutation status, 20 of them were detected as KRAS wild-type and 10 of them were detected as KRAS mutant type. There was no significant association between treatment response (in neoadjuvant chemoradiotherapy patients) and KRAS mutation status.

No statistical significance was found in the response to the first-line chemotherapy used in metastatic disease. On the other hand, when the association between KRAS mutation status and cetuximab-based therapies were evaluated, 38 patients had KRAS wild-type tumors and five patients had KRAS mutations. It was determined that a partial stable response had been obtained in 23 patients of 38 KRAS wild-type patients and a stable response had been obtained in three patients of 5 KRAS mutant-type patients [Table 3].
Table 3: The association between KRAS mutation status and chemotherapy responses in metastatic diseases

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The association between KRAS mutation status and survival

The median length of follow-up was 36.1 months in the total group. The median overall survival time was 49.1 months in all patient groups, OS for 1,3 and 5 years were 96%, 66%, 41%, respectively [Figure 1]a. In the OS analysis which is done according to KRAS mutation status, median survival was 46.9 months in KRAS wild type and 52.1 months in KRAS mutant type. OS for 1,3 and 5 years were 96%, 66%, 37% respectively, in KRAS wild-type group. There was no significant difference between the groups of KRAS wild and mutant type in overall survival analysis [Table 4] and [Figure 1]b.
Figure 1: Overall survival analysis in all group (a) and according to KRAS mutation status (b). Disease-free survival analysis in all group (c) and according to KRAS mutation status (d).

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When the DFS time for early stage patients with no metastasis at the time of diagnosis were evaluated, median DFS time was 17.2 months and DFS for 1,3 and 5 years were, respectively, 70%, 14% and 2% [Figure 1]c. When DFS was evaluated according to the KRAS mutation status, it was 18.3 months in KRAS wild-type group and 16.3 months in KRAS mutant-type group. In KRAS wild-type group, DFS for 1,3 and 5 years were respectively 68%, 10% and 3% and in KRAS mutant-type group, respectively, 72%, 16% and 0% [Figure 1]d. There was no significant difference between KRAS wild and mutant group in terms of DFS [Table 4].{Figure 1}
Table 4: Survival analysis results according to KRAS mutation status

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When the PFS results following the first-line chemotherapy of metastatic disease were evaluated, median PFS time was 13.1 months in all group. When the PFS was analyzed according to the KRAS mutation status, median survival following first-line therapy was 11.7 months in KRAS wild group and 14.2 months in KRAS mutant group, but the differencess between them were not statistically significant. On the other hand median PFS was 4.8 months in patients who had taken cetuximab-based therapies. When the PFS were evaluated according to KRAS mutation status in these patients, no significant differences were detected statistically [Table 4].


 > Discussion Top


In this study, we investigated the association between KRAS mutation status and clinicopathological features and survival parameters. While a significant association had been determined between KRAS mutation status and tumor localization, there was no determined significant association with other clinicopathological features. Similarly, there was no association between KRAS mutation status and overall survival, disease-free survival and progression-free survival times.

In sporadic colorectal cancers KRAS mutation frequency was reported as 30-35%. In our study, KRAS mutation was detected in 38.2% of patients, in appropriate to the literatures.[5]

In our study, when the association between KRAS mutation status and demographic features were evaluated, no association between gender, age and KRAS mutation status could be found. In the literature, it had been reported that there was no association between KRAS mutation status and gender and age.[17],[18],[19] Similarly, there was no association between KRAS mutation status and performance status. Although in one study no association between KRAS mutation status and performance status was determined, in another study better performance status had been reported in KRAS-wild-type group.[17],[20]

There was no significant association between Body Mass Index and KRAS mutation status in our study. An association between increasing body mass index and colon cancer had been reported in the literature. Despite these results there were also studies that showed no significant association between Body Mass Index and KRAS mutation status.[21],[22] Only in one study it had been reported that KRAS mutant female patients had more Body Mass Index.[19]

In our study, no association had been determined between smoking habits and KRAS mutation status. In the literature, KRAS mutation was reported more frequently in lung cancer patients who had smoked, but this is not valid for colon cancer patients.[23] While in some studies an association between smoking habit and CRC patients with wild type KRAS had been reported, in other studies there were no associations.[19],[24]

When the association between KRAS mutation status and clinicopathological features were evaluated, there was a significant association with tumor localization but there was no significant association with other clinicopathological properties. Proximal colon involvement was more in KRAS wild-type group. Although some studies had reported in the literature an association between KRAS mutation status and tumor localization, most had reported no clear association.[20],[25],[26]

There was no association between KRAS mutation status and histological subtype of tumor, tumor degree, lymphovascular and perineural invasion, pT and pN stages, findings about microsatellite instability, peritumoral lymphocytic response, and intratumoral response.[17],[20] In a trial [18] where 404 patients were investigated, no significant association had been determined according to KRAS mutation status and the tumor's histologic type, pT, pN, tumor degree, vascular invasion and peritumoral lymphocytic response. In a study where patients with stage II and III CRC were evaluated, it was shown that patients with detected KRAS mutation had better differentiated tumors, but there was no association between KRAS mutation status and tumor stage.[17],[20],[27] When the association between KRAS mutation status and metastasis locations were evaluated, no clear association was determined between KRAS mutation status and metastasis locations and numbers. It had been reported that more common lung and brain metastasis had been detected in KRAS-mutant tumors.[28] In another study, lung metastases had been observed more in patients with KRAS 13 codon mutation. When the patients that have KRAS codon 13 mutation were compared with patients that have KRAS codon 12 mutation patients, it had been reported that there were more synchronous nodal and organ metastases.[29] Similarly, the frequency of two or more organ metastases were more often found in patients with codon 13 mutation.[17],[20]

KRAS mutation is a specific negative predictor and is associated with poor response to anti-EGFR treatments and should be investigated for every patient who is a candidate for anti-EGFRtreatment. It has been reported that KRAS mutations detected in patients, does predict unresponsiveness to cetuximab or panitumumab treatments.[10],[11],[12],[30] In our study, 43 patients received cetuximab, and only in five patients KRAS mutation had not been identified. The reason why we had given treatment without assessing the mutation status in those patients was that at that time KRAS mutation status was not evaluated by our clinic. We started to perform KRAS mutation tests after the treatments were given to those patients. 39.5% response had been achieved in patients with KRAS wild-type. In five patients cetuximab had been administered as the fourth or fifth-line treatment. In three of these patients stable response and in two patients progression were observed. The anti-EGFR monoclonal antibodies were not used on patients who carry KRAS codon 12 or codon 13 mutations because KRAS mutations are related to non-responsiveness in anti-EFGR treatments. In one trial it was observed that a patient was responsive to cetuximab treatment although he was KRAS mutant. For this reason the anti-EGFR treatment responses according to the subtypes of other mutations are starting to be evaluated in KRAS-mutant patients during the following trials.[10] In a recent retrospective analysis 579 chemotherapy-resistant patients had been evaluated and among patients withKRAS codon 13 mutations, comparison had been made between cetuximab receiving patients and patients who received best supportive treatments, and longer PFS and OS were found in patients who had received cetuximab treatment, but patients with other KRAS mutations did not benefit from this treatment.[31]

No statistically significant association had been found between KRAS mutations and response rates with various irinotecan, oxaliplatin or bevasizumab-based chemotherapies or neoadjuvant chemotherapies in our study. In QUASAR trial no association could have been found between mutations status and response rates to FU/FA chemotherapy although it had been known that KRAS-BRAF mutation was not responsive to anti-EGFR antibody treatments. No association had been found between responses to irinotecan and oxaliplatin based chemotherapies and mutation status. This indicates that the resistance mechanism of chemotherapeutic agents which show activity by destroying DNA and anti-EGFR antibodies are likely different.[32] No association has been found between KRAS mutation status and bevasizumab-based chemotherapies. This shows that the activity of antiangiogenic treatments targeting VEGF is independent of KRAS mutation.[33],[34]

When the effects of KRAS mutation on survival were evaluated, no association was established between KRAS mutation and disease-free or progression-free and overall survival. Attention was drawn to the study differences in the literature which investigated the association of KRAS mutation with survival results. In a study where 1404 patients with stage II and III colon cancer had been evaluated, it was shown that there was no prognostic value of KRAS mutation on survival without relapse or on overall survival.[35]

In a translational study of patients with stage II and resected stage III colon cancers, PETACC-3, EORTC 40993 and SAKK 60-00 studies were evaluated and it was concluded from these three studies that it is difficult to identify the prognostic value of KRAS mutation andits ability to measure a difference between PFS and OS.[35] Similarly, as most of the retrospective studies indicated KRAS mutation has no prognostic value.[16],[36],[37]

On the other hand in N0147 study where FOLFOX and cetuximab had been evaluated on stage III CRC patients, it was concluded that 3 years DFS was better in the KRAS wild-type patient group. After all the analytical results, it was said that the KRAS mutation is an independent prognostic factor.[38] In another supporting study, when KRAS-mutant tumors were compared with KRAS wild-type tumors, independent of stage or given chemotherapy agents, th e recurrence risk was found to be higher in KRAS-mutant tumors.[25] In a meta- analysis where 22 studies had been evaluated, it has been reported that median PFS and OS were significantly shorter in patients with KRAS mutation and it had been concluded that KRAS mutation could be considered as a negative prognostic and predictive factor on survival and tumor response.[39] In some studies, it was reported that the reason of the shorter PFS and OS in patients with KRAS mutation might be linked with anti-EGFR therapies.[40]

Bazan et al. had shown that there was an association between increased relapse rates and death risk in primary CRC patients with KRAS mutationand who had undergone surgery.[29]

Yokota et al. had performed a study of patients with advanced stage or recurrent colorectal cancers and reported that patients with KRAS 13 mutation had worse general survival time in comparison with patients who had other KRAS mutations or wild-type BRAF patients.[20] According to the authors it was reported that stage III CRC patients with KRAS mutations have more worse DFS than patients with wild-type KRAS. This might be explained by the evidence of apparent negative effects of KRAS 13 mutations on prognosis.[27],[38] Mutations on codons 12 and 13 could influence the prognosis for CRC by different biological, biochemical and functional modifications.[29] Because we did not know the subtype of codon 13 mutation, the survival analysis was made according to only the KRAS mutation status. We think that this may be the reason why no difference was detected between the two groups. Although there have been a lot of studies on the prognostic role of KRAS mutations in CRC, no conclusions could have been drawn on the prognostic value of KRAS.[41] The reason might be the differences in the factors such as the criteria for patients selection, study design, tumor sampling, and laboratory methods such as fresh tissue or archived tissue.

In conclusion, according to our results, the effect of KRAS mutation status on clinicopathologic features, survival time and prognosis is unclear. From the data in the literature, we can say that KRAS mutation can not be used as a prognostic factor. We can not state with clear determination our study draws the same conclusions because our study is retrospective and included a relatively small number of patients. What we can state is, there is a need for more wide-ranged studies on homogenous groups of patients where specific KRAS mutation subtypes and BRAF mutation types are clearly known and studied.

 
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