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Imaging, Diagnosis, Prognosis

PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients

Youji He, Laura J. Van't Veer, Izabela Mikolajewska-Hanclich, Marie-Louise F. van Velthuysen, Eliane C.M. Zeestraten, Iris D. Nagtegaal, Cornelis J.H. van de Velde and Corrie A.M. Marijnen
DOI: 10.1158/1078-0432.CCR-09-1165 Published November 2009

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Abstract

Purpose: Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients.

Experimental Design: We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial.

Results: PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage.

Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects. (Clin Cancer Res 2009;15(22):6956–62)

Keywords
  • PIK3CA mutation
  • local recurrence
  • rectal cancer

Translational Relevance

In this article, we have identified the mutation prevalence of PIK3CA, KRAS, and BRAF genes in rectal cancer and showed that PIK3CA mutations are strongly associated with a high risk of local recurrences in nonirradiated stage I to III rectal cancer patients. A study cohort of 240 patients enabled us to perform multivariate analyses, revealing that PIK3CA mutations serve as a prognostic factor independent of tumor-node-metastasis stage. Therefore, our study indicates for the first time that PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of the PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk rectal cancer patients who might otherwise only experience the side effects.

Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide. WHO estimates that 945,000 new cases occur yearly, with 492,000 deaths (1). Approximately 25% of these cases are rectal cancer. In the treatment of rectal cancer patients, local and distant recurrences are a major problem because they are associated with both high morbidity and mortality. The introduction of total mesorectal excision (TME) surgery (2) in combination with preoperative radiotherapy resulted in a reduction of local recurrences (3) and has been recently accepted as standard treatment for rectal cancer in many countries. Although preoperative radiotherapy can prevent local recurrences in certain patients, the majority of patients will not develop a local recurrence without radiotherapy; furthermore, still more than 25% of the patients will develop distant metastases within 5 years of surgery, irrespective of preoperative radiotherapy (3, 4). Moreover, radiotherapy has several substantial negative side effects (5, 6). Therefore, identifying prognostic markers for refinement of personalized treatment is clinically relevant.

Recently, Samuels et al. (7) identified somatic mutations in the PIK3CA gene in various human tumors, including colorectal cancer. PIK3CA mutations have been found in 10% to 30% colorectal cancers (7–12), with most activating mutations clustering in hotspots of exons 9 and 20, affecting the functionally important helical and kinase domains (7, 9, 13). Because there is a close interaction between RAS and phosphoinositide 3-kinases (PI3K; refs. 14–16), activation of the PI3K/AKT signaling pathway through PIK3CA mutations or the RAS–RAF–mitogen-activated protein kinase (MAPK) signaling was considered to be one of the most common mechanisms involved in colorectal carcinogenesis (7, 17). In accordance with this, mutations in the KRAS and BRAF genes are also commonly observed in colorectal cancers with frequencies of 30% to 40% (18–20) and 5% to 22% (21, 22), respectively. KRAS mutations occur mainly in exon 1 at codons 12 and 13 (18, 19, 23). The vast majority of the BRAF mutations are located at codon 600 with a conversion of valine to glutamic acid (V600E; ref. 24). Regrettably, most of the mutation studies make no distinction between rectal and colon cancer. However, any available data that make this distinction largely focus on colon cancer, whereas the prevalence of these gene mutations remains unclear in rectal cancer.

A large cohort study has recently shown that PIK3CA mutation is associated with poor prognosis among patients with resectable stage I to III colon cancer (12). Another large population-based study in colon cancer suggested that the activation of the PI3K/AKT or the RAS-RAF-MAPK pathway by mutation of at least one of the three genes predicted poor patient outcome, but the effect of mutations in PIK3CA only was not discussed (8). Another previous study of a small cohort of colorectal cancer patients reported that PIK3CA mutation is predictive of poor survival (10). To the best of our knowledge, the prognostic value of PIK3CA mutation in rectal cancer patients has thus far been unknown.

In the present study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF in rectal cancer patients to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients.

Materials and Methods

Patients and tumor samples

Tumor samples were obtained at the time of surgery from rectal cancer patients participating in the Dutch TME trial, a large multicenter trial in which patients (n = 1,861) were randomized for short-term radiotherapy (5 × 5 Gy) followed by TME surgery, or TME surgery only (3). Radiotherapy, surgery, and pathology procedures were standardized and quality controlled. Tumor staging was determined with the tumor-node-metastasis (TNM) classification (25). Patients were selected from the TME-only trial arm (n = 741). All stage I to III patients (n = 665) who complied with the eligibility criteria of the TME trial (3) and of whom fresh-frozen tumor material was available were selected for this study (n = 259). Samples with a tumor cell content of <50% (n = 14) and samples with poor DNA quality (n = 5) were excluded, resulting in a study cohort of 240 patients, which was not different from the TME trial population at major clinicopathologic parameters (Supplementary Table S1). The median follow-up time of surviving patients was 7.2 y. Detailed patient information is listed in Table 1. The study was conducted according to the regulations set by Dutch law for the use of human material for research. Ethics board approval was obtained for gathering all materials and patient data in this study.

View this table:
Table 1.

Clinicopathologic and molecular characteristics and patient outcomes of the 240 included rectal cancer patients and patients with PIK3CA mutation–positive and PIK3CA mutation–negative tumors

DNA extraction and mutation analysis

DNA was extracted according to protocol7 in parallel with total RNA (not used in this study) from 30 sections of 30-μm thickness of macrodissected fresh-frozen tumor samples containing at least 50% tumor epithelium, as determined by H&E-stained cryosections. Exons 9 and 20 of PIK3CA, exon 1 of KRAS, and exon 15 of BRAF were amplified by PCR and the presence of mutations was detected by direct sequencing using the BigDye Terminator Cycle Sequencing kit (Applied Biosystems). For all PCR products with sequence variants, both forward and reverse sequence reactions were repeated for confirmation. Primers used for the amplification and the PCR conditions are listed in Supplementary Table S2.

Statistical analysis

All statistical analyses were done with SPSS statistical software (version 15.0 for Windows, SPSS, Inc.). Data were analyzed with the Mann-Whitney test to compare quantitative and ordered variables and with Student's t test to compare normally distributed data between two groups. χ2 test and Fisher's exact test were used to compare proportions. Recurrences and survival analyses were done using the Kaplan-Meier method with time of surgery as entry date. Log-rank testing was used for comparison of groups. For multivariate analyses, variables associated with PIK3CA mutations or with significant effect on either recurrence or survival in univariate analyses (P < 0.10) were further examined using the Cox proportional hazards regression model with backward stepwise elimination. Variables were eliminated if the P value is >0.10. A two-sided P value of <0.05 was considered statistically significant.

Results

Frequency of PIK3CA, KRAS, and BRAF mutations

PIK3CA mutations in exons 9 and 20 were found in 19 (7.9%) rectal tumors, with 12 cases in exon 9 (5%) and 7 cases in exon 20 (2.9%). The most frequently detected mutation types are E545K in exon 9 and H1047R in exon 20 among a total of seven variants. KRAS mutations in exon 1 were found in 81 (33.8%) rectal tumors; most cases had one KRAS mutation at codon 12 or codon 13 except two cases with double and triple mutations. BRAF V600E mutation was identified in 5 (2.1%) cases. Mutations are summarized in Table 2 and the distribution of the mutations is shown in Fig. 1. In total, 95 cases (39.6%) showed mutation in at least one of the three genes, where 85 cases (35.4%) had mutations in a single gene and 10 cases (4.2%) had mutations in two genes (PIK3CA and KRAS). Mutations in KRAS and BRAF were not observed in the same tumor, which is consistent with previous studies stating they were mutually exclusive (24, 26, 27). Mutations in PIK3CA and BRAF were also not identified in the same tumor (Table 1). Ten of 19 tumors with PIK3CA mutation had an additional KRAS mutation (Table 1).

View this table:
Table 2.

PIK3CA, KRAS, and BRAF mutations identified in 240 rectal cancer patients

Fig. 1.
Fig. 1.

The distribution of mutations is illustrated in a pie chart combined with stacked bar.

PIK3CA mutations and clinicopathologic and molecular parameters

There were no correlations between PIK3CA mutations and clinicopathologic features, including age, gender, tumor location, type of resection, circumferential margin (CRM), differentiation grade, lymph node, and TNM stage (Table 1). In addition, no significant correlation was observed between PIK3CA mutations and the intrinsic apoptosis status defined by immunohistochemistry with the M30 antibody (Table 1; ref. 28). In our previous studies, we found that tumors with below median levels of apoptosis were associated with more local recurrences in nonirradiated patients with a negative CRM (28). Neither KRAS mutation nor BRAF mutation show any significant correlations with any of the features examined (data not shown). A further comparison of patients harboring at least one mutation in any of the three genes to wild-type patients revealed no significant differences in listed features. Comparing patients harboring double gene mutations with wild-type patients did not reveal any significant differences in listed features either, except for the fact that the concomitant PIK3CA and KRAS mutations occurred more frequently in female patients (8% versus 2%. P = 0.023).

Prognostic value of PIK3CA mutations

In total, 24 local recurrences occurred with 5 and 19 events in patients with and without PIK3CA mutations, respectively (Table 1). PIK3CA mutations revealed a strong association with a 3-fold increased local recurrence rate compared with the PIK3CA wild-type tumors (5-year risks, 27.8% versus 9.4%; P = 0.008; Fig. 1A). This was supported by the tendency of shorter interval time from surgery to recurrence (median time, 7.9 versus 19.6 months; P = 0.07). The significance of higher local recurrence risk was retained when 30 patients receiving adjuvant radiotherapy were excluded (5-year risks, 26.7% versus 6.4%; P = 0.004). Further subgroup analysis was not feasible in our case because of the lack of statistical power.

In total, 60 distant metastases occurred with 6 and 54 events in patients with and without PIK3CA mutations, respectively (Table 1). The PIK3CA mutations were not correlated with distant metastases (5-year risks, 37.1% versus 26.4%; P = 0.413; Fig. 2B) and the interval time from surgery to distant metastases was similar in both groups (median time, 26.3 versus 22.8 months; P = 0.99). No correlation was found between PIK3CA mutations with overall recurrences (P = 0.107) or overall survival (P = 0.340).

Fig. 2.
Fig. 2.

Local (A) and distant (B) recurrence rates since TME surgery for patients with (black) and without (gray) PIK3CA mutations. The “N” below the plots indicates the absolute number of patients at risk. Two patients have no available data on local recurrence.

No differences were found between patients with and without KRAS mutations or BRAF mutations in the survival analysis (all P > 0.1). A comparison of wild-type patients to patients harboring at least one mutation in any of the three genes revealed no significant correlation either with local recurrences (5-year risks, 15.7% versus 7.8%; P = 0.088) or with distant metastases (5-year risks, 33.6% versus 23.2%; P = 0.125). Ten patients with concomitant mutations in PIK3CA and KRAS showed a higher local recurrence rate than patients having no or single gene mutation (5-year risks, 33.3% versus 10%; P = 0.012), which is similar to patients with solo PIK3CA mutation, indicating that PIK3CA was the contributor. The concomitant mutations showed no correlation with distant metastases (P = 0.868).

Univariate and multivariate analysis

In univariate Cox regression analysis for local recurrences, the previously established prognostic variables (3, 28) listed in Table 3 and the PIK3CA mutation were examined. Besides TNM stage (P = 0.003) and CRM (P = 0.06), PIK3CA mutation showed a significant association with higher risk of local recurrences [hazard ratio (HR), 3.5; 95% confidence interval (CI), 1.3-9.3; P = 0.013]. The independent prognostic value of the PIK3CA mutation was further tested in multivariate analysis with backward stepwise elimination in the context of the following variables: TNM stage, CRM, and PIK3CA mutation. No significant interactions were observed between the variables. PIK3CA mutation remained as an independent predictor for the development of local recurrences (HR, 3.4; 95% CI 1.2-9.2; P = 0.017), next to TNM stage.

View this table:
Table 3.

Analysis of local recurrences in 238 rectal patients with TNM stage I to III by univariate and multivariate Cox regression analysis

Discussion

In this study, we determined mutation frequencies of PIK3CA, KRAS, and BRAF in 240 resectable stage I to III rectal cancer patients and evaluated the prognostic value of these mutations. Little is known regarding those mutation frequencies in rectal cancer because most of the mutation studies were done in colon cancer or colorectal cancer as a combined entity. Our large sample of rectal cancers, obtained from a prospective multicenter randomized trial (Dutch TME Trial), enabled us to make a precise estimate of the mutation frequency in rectal cancer. We identified an incidence of 7.9% for PIK3CA mutations, which is lower than most found frequencies of 10% to 30% in colon or colorectal cancer (7–12). The lower incidence is unlikely to be a result of inferior sensitivity of the detection methods, given that the same methodology (PCR/sequencing) has been largely used. In fact, using the same method, we identified KRAS mutations in 33.8% of cases, an incidence that compared well to a compilation of world literature series of KRAS mutation in colorectal cancer (18–20). The issue of whether colon and rectal cancers have the same KRAS mutation incidence has been addressed in a few studies on the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancer, with contradictory results (27, 29, 30). However, those studies all had a relatively small sample size of rectal cancer patients (n = 27, 41, and 55, respectively).

We identified 2.1% BRAF V600E mutations in our study population. It is lower than the average frequency of 10% in colon cancer (21, 22) but similar to the frequency of 3.6% in rectal cancer reported previously (27). Because there is a tight association between BRAF mutations and CpG island methylator phenotype (CIMP)–high in colorectal cancer (21, 31), the low incidence of BRAF mutations we found in rectal cancer is within our expectations, which underlines the fact that CIMP-high is a rare event in rectal cancer (22).

We observed a total of 39.4% cases harboring a mutation in at least one of the three genes, which underlines the same importance of activation of the PI3K/ATK and RAS-RAF-MAPK pathways in rectal carcinogenesis as in colon. A significant concomitant occurrence of PIK3CA and KRAS mutations was reported recently in colon cancer and other human cancer types (8, 11, 12, 32). However, other studies failed to show a significant correlation between them (33). Although 10 tumors showed both PIK3CA and KRAS mutations in our study, this association was not statistically significant (P = 0.07).

Only a few studies have been published on the prognostic value of PIK3CA mutations in colon or colorectal cancer. The first study in colorectal cancer reported that PIK3CA mutations were significantly associated with poor survival (10). They further identified PIK3CA mutations as the only independent and significant prognostic factor for relapse-free survival in stage II to III patients in the multivariate analysis; surprisingly, lymph node metastasis failed to be significant in this model, probably due to the relatively small sample size (n = 96). The second large population-based study in colon cancer suggested that activation of the PI3K/AKT or the RAS-RAF-MAPK pathway by mutation of at least one of the three genes (PIK3CA, KRAS, and BRAF) was associated with a lower 3-year survival, but the effect of mutations in PIK3CA only was not discussed (8). The most recent large cohort study of patients with resectable stage I to III colon cancer showed that PIK3CA mutations were associated with an increased cancer-specific mortality and that the effect of PIK3CA mutations was limited to patients with KRAS wild-type tumors (12). However, data on the types of recurrence were not available in these cohorts. Thus far, the effect of PIK3CA mutations in rectal cancer on patient outcome has not been described. In our study, we determined the prognostic value of PIK3CA mutations in 240 nonirradiated resectable stage I to III rectal cancer patients from the Dutch TME trial. PIK3CA mutations revealed a strong association with a 3-fold increased local recurrence rate, and tumors with PIK3CA mutations showed a tendency to develop local recurrences more rapidly after surgery. Next to TNM stage, PIK3CA mutation revealed itself as an independent predictor for the development of local recurrences. The distinct effect of the PIK3CA mutation on local recurrence was not altered when it was stratified by the KRAS mutation status (data not shown). However, because these are subgroup analyses with a small sample size, the results need to be considered with care.

Several tumor characteristics are known risk factors for local recurrences: positive CRM, TNM stage, and tumor located within 10 cm from anal verge (34–36) are used in deciding on the administration of (neo)adjuvant treatment. However, patients with similar clinocopathologic characteristics still display a large variation in prognosis, suggesting that the prognosis is explained as well by the genetic biology of the tumor. The detection of biological markers that can predict recurrences improves the selection of patients who will benefit from (neo)adjuvant treatment and, on the other hand, spares patients who will only experience side effects. To this purpose, our previous studies on the TME trial have already identified that intrinsic low apoptosis can be used as a risk factor in rectal cancer patients with a negative CRM (28). However, this factor failed to reach statistical relevance in the present study (even when analyzed in the group with a negative CRM; Table 3), most likely due to the smaller sample size compared with the previous study. Many studies have implicated that PIK3CA mutations play a central role in tumorigenesis through the coordinated phosphorylation of proteins or transcription factors that directly regulate cell proliferation, differentiation, and invasion (13, 16). A recent study of Samuels et al. (13) investigated the role of PIK3CA mutation in human colorectal cancer cells using a gene targeting approach and found that PIK3CA mutations resulted in attenuation of apoptosis. Interestingly enough, we found that in the high apoptosis group, three of five patients with PIK3CA mutations developed local recurrences, whereas in the low apoptosis group, only 2 (one with a positive CRM) of 10 patients with PIK3CA mutations had local recurrences, suggesting that the tight association between PIK3CA mutations and local recurrences is relevant only in high-apoptosis rectal cancer patients. Obviously, this observation needs to be confirmed in large studies.

Among the patients with PIK3CA mutations, nine had an E545K mutation. E545K is apparently the most aggressive type of mutation in our observations; 89% of the patients with this type of mutation developed a relapse (six cases had either local or distant recurrence and the other two developed both). Comparing patients bearing an E545K mutation to the remainder, E545K seemed to be associated with inferior prognosis for both local (HR, 11.6; 95% CI, 4.0-33.8; P < 0.001) and distant (HR, 3.7; 95% CI, 1.4-9.4; P = 0.006) recurrences in the multivariate analysis next to TNM stage and CRM. No laboratory evidence is available on the degree of aggressiveness of different mutation types despite the fact that E545K is one of the most frequently found mutation types in colorectal cancer (7). Iknoue et al. (17) examined the three most frequent mutations in their functional analysis, E542K, E545K, and H1047R, demonstrating that all had high enzymatic and transforming activities. Moreover, their results show that almost all colon cancer–associated PIK3CA mutations are functionally active and therefore likely to be involved in carcinogenesis. The recent study in colon cancer assessed the prognostic value of mutations in exons 9 and 20 separately (12). There was, however, no significant difference in cancer-specific mortality between them. Therefore, we analyzed all PIK3CA mutations together, including seven variants, as one prognosticator in this study. Nevertheless, the distinct aggressiveness of E545K observed here implies the existence of potential differences among mutation types and warrants further investigation in similar studies.

In the present study, PIK3CA mutations mainly predict local recurrences in rectal cancer patients. In colon or colorectal cancer, it has been suggested by the above-mentioned literature that PIK3CA mutations predict poor patient outcome (8, 10, 12), mainly referring to distant metastases. As we know, in colon cancer, recurrence-free survival depends on distant metastases rather than on local recurrences. This difference emphasizes the heterogeneity between colon and rectal cancers with respect to clinical as well as to molecular features in tumor biology (30, 37). Our findings further imply that differences in biological behavior between colon and rectal cancers should be considered when prognostic markers are investigated in a larger series (37). However, the real mechanism by which PIK3CA mutations affect tumor biology leading to different invasions needs to be further elucidated.

In conclusion, our study is the first to indicate that PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Comparison with patients within the TME trial who received preoperative radiotherapy is currently under investigation. It should reveal whether these patients indeed benefit from preoperative radiotherapy. A future study of independent validation series is required for confirmation. Nevertheless, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank the Sequencing Core Facility in the Netherlands Cancer Institute for DNA sequencing and J.F.D. Bouricius for editing the text of the manuscript.

Footnotes

  • Grant support: Dutch Cancer Society.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • ↵7The protocol is available on the supplementary Web site of an earlier publication (http://genome-www.stanford.edu/DFSP/materials.shtml).

    • Received May 7, 2009.
    • Revision received July 22, 2009.
    • Accepted August 10, 2009.

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Clinical Cancer Research: 15 (22)
November 2009
Volume 15, Issue 22

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PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients
Youji He, Laura J. Van't Veer, Izabela Mikolajewska-Hanclich, Marie-Louise F. van Velthuysen, Eliane C.M. Zeestraten, Iris D. Nagtegaal, Cornelis J.H. van de Velde and Corrie A.M. Marijnen
Clin Cancer Res November 15 2009 (15) (22) 6956-6962; DOI: 10.1158/1078-0432.CCR-09-1165
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