Original Article
KRAS Mutation Influences Recurrence Patterns in Patients Undergoing Hepatic Resection of Colorectal Metastases Nancy E. Kemeny, MD1; Joanne F. Chou, MPH2; Marinela Capanu, PhD2; Alexandra N. Gewirtz, BA1; Andrea Cercek, MD1; T. Peter Kingham, MD3; William R. Jarnagin, MD3; Yuman C. Fong, MD3; Ronald P. DeMatteo, MD3; Peter J. Allen, MD3; Jinru Shia, MD4; Celina Ang, MD1; Efsevia Vakiani, MD4; and Michael I. D’Angelica, MD3
BACKGROUND: The validity of the KRAS mutation as a predictor of recurrence-free survival (RFS) or overall survival (OS) is unclear. The current study investigated whether the presence of the KRAS mutation decreased RFS or OS in patients with colorectal cancer who underwent liver resection. METHODS: Patients with resected colorectal liver metastases who received adjuvant hepatic arterial infusion plus systemic therapy and for whom KRAS data was available were evaluated. Correlation between KRAS and clinical factors was done using the Fisher exact test. Kaplan-Meier methods were used to estimate the median RFS and OS. RESULTS: A total of 169 patients were evaluated, 118 of whom had KRAS wild-type (WT) and 51 had KRAS mutated (MUT) tumors. The 3-year RFS rate was 46% for patients with KRAS WT (95% confidence interval [95% CI], 35%-56%) and 30% (95% CI, 16%-44%) for patients with KRAS MUT (P 5.005). The 3-year OS rate was 95% (95% CI, 87%-98%) and 81% (95% CI, 62%-95%), respectively, for patients with KRAS WT and KRAS MUT (P 5.07). On multivariate analysis, KRAS remained a significant predictor of RFS (hazard ratio, 1.9). The 3-year cumulative recurrence rate by site of metastases was as follows: 2% versus 13.4% for bone (P.01), 2% versus 14.5% for brain (P 5.05), 33.2% versus 58% for lung (P.01), and 30% versus 47% for liver (P 5.10) in patients with KRAS WT versus KRAS MUT. CONCLUSIONS: In the current study, among patients with resected colorectal liver metastases who were treated with adjuvant hepatic arterial infusion plus systemic therapy, patients with KRAS MUT were found to have a significantly worse 3-year RFS (30%) compared with KRAS WT (46%) p5.005. The cumulative incidence of bone, brain, and lung metastases was significantly higher for patients with KRAS MUT C 2014 American Cancer Society. compared with those with KRAS WT. Cancer 2014;120:3965-71. V KEYWORDS: colorectal cancer, liver metastases, adjuvant therapy, KRAS mutation, disease recurrence patterns.
INTRODUCTION Many factors predict overall survival (OS) or recurrence-free survival (RFS) for patients with metastatic colorectal cancer such as baseline alkaline phosphatase,1 performance status, white blood cell count, lactate dehydrogenase (LDH),2 and carcinoembryonic antigen (CEA).1,2 There have been conflicting reports regarding whether KRAS mutation influences outcome. In one trial of 394 patients, the OS was 26.7 months for patients with KRAS wild-type (WT) and 18 months for patients with KRAS mutated (MUT) (P 5.002) tumors.3 In this multivariate analysis, KRAS mutation and high LDH were found to be significantly related to worse survival. Other studies have reported no significant difference in OS between patients with KRAS WT and KRAS MUT.4-6 KRAS mutation has also been reported to influence outcomes in patients after liver resection for metastatic disease. Karagkounis et al demonstrated worse RFS (hazard ratio [HR], 1.89) and OS (HR, 2.13) in those patients with a KRAS mutation.7 The current study was performed to determine whether KRAS status affects outcome in patients treated with adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection. MATERIALS AND METHODS The Institutional Review Board allowed a review of patients treated between March 19, 2003 and January 19, 2013 who underwent liver resection followed by adjuvant HAI plus systemic chemotherapy and for whom KRAS data were available. At surgery, all disease was resected or ablated and an HAI pump was placed concurrently. One month after surgery,
Corresponding author: Nancy E. Kemeny, MD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell University, 1275 York Ave, New York, NY 10065; Fax: (646) 888-4541; [email protected] 1 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; 3Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; 4Department of Pathology, Memorial SloanKettering Cancer Center, New York, New York.
See editorial on pages 3862-5, this issue. DOI: 10.1002/cncr.28954, Received: January 15, 2014; Revised: March 14, 2014; Accepted: April 2, 2014, Published online August 25, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
December 15, 2014
3965
Original Article
chemotherapy was initiated. Patterns of disease recurrence and survival were evaluated for patients who met the above criteria. Genotyping only became the standard of care at Memorial Sloan-Kettering Cancer Center in 2009. Correlations between KRAS status and clinical factors such as prior chemotherapy, postoperative CEA, clinical risk score (CRS), stage at diagnosis, and whether radiofrequency ablation was performed at the time of pump placement for HAI were evaluated using the Fisher exact test and the Wilcoxon rank sum test. OS and RFS were calculated from time of HAI until the time of any cause of death (for OS) or until the time of first disease recurrence or death, whichever came first (for RFS). In the current study cohort, all deaths, except for one patient who possibly died due to myocardial infarction, were related to disease, and hence OS was equivalent to diseasespecific survival. First disease recurrence was confirmed by computed tomography scan or magnetic resonance imaging. Scans were performed every 3 months for the first 2 years, every 4 months for year 3, every 6 months for year 4, and yearly thereafter. OS and RFS were estimated using the Kaplan-Meier method. The log-rank test was used to determine whether survival functions differed by KRAS mutation status and other clinical and pathologic characteristics. The Cox proportional hazards model was used to examine the association between continuous clinical factors such as baseline CEA and LDH and OS/RFS. Factors found to be significant on the univariate analyses (P .10) were included in the multivariate Cox proportional hazards model examining the effect of KRAS separately on OS and RFS. Left-sided primary tumors were defined as descending colon, rectosigmoid, rectum, and sigmoid colon; all other locations were considered rightsided. A positive surgical margin was defined as one measuring 5 cm, and CEA level >200 ng/mL; it was not found to be significantly different. A CRS >3 was observed in 43% and 57%, respectively, of patients with KRAS WT and KRAS MUT (P 5.10). The median Cancer
December 15, 2014
KRAS Mutation Influences Recurrences/Kemeny et al
TABLE 1. Baseline Characteristics of Patients With KRAS WT Versus KRAS MUT
Median baseline CEA (range), ng/mL Median baseline LDH (range), Units/Lb Median age (range), y Sex Female Male Dukes stage B C Prior chemotherapy No Yes Clinical risk score 0-2 3-5 No. of lesions 1 2 3 Surgical margin status Positive Negative Prior oxaliplatin No Yes Primary tumor (right or left) Right Left
KRAS WT (N5118)
KRAS MUT (N551)
Pa
2.6 (0.8-49.4)
2.4 (0.9-125.9)
.52
156 (99-320)
164 (90-227)
.27
54 (27-83)
56 (36-79)
.45 .86
48 (41%) 70 (59%)
22 (43%) 29 (47%)
56 (47%) 62 (53%)
17 (33%) 34 (67%)
19 (16%) 99 (84%)
8 (16%) 43 (84%)
67 (57%) 51 (43%)
22 (43%) 29 (57%)
.08
.94
.10
.64 32 (27%) 24 (20%) 53 (48%)
11 (22%) 13 (25%) 23 (48%)
7 (6%) 109 (94%)
7 (14%) 44 (86%)
46 (39%) 72 (61%)
14 (27%) 37 (73%)
31 (26%) 87 (74%)
23 (45%) 28 (55%)
.13
.15
.016
Abbreviations: CEA, carcinoembryonic antigen; LDH, lactate dehydrogenase; MUT, mutated; WT, wild-type. a Bold type indicates statistical significance. b Note that 3 patients (2 with KRAS WT and 1 with KRAS MUT) were missing information regarding their baseline LDH.
follow-up was 44.3 months (range, 1.41 months-119 months). Recurrence-Free Survival
At the end of the follow-up, we observed 80 events (disease recurrence or death). The median RFS was 20 months (95% confidence interval [95% CI], 14 months31 months), with a 3-year RFS rate for the entire group of 41% (95% CI, 33%-50%). The 3-year RFS rate for patients with KRAS WT was 46% (95% CI, 35%-56%) and was 30% for patients with KRAS MUT (95% CI, 16%-44%) (P 5.005) (Fig. 1). On univariate analysis, factors found to be significantly associated with a shorter RFS (Table 2) were prior use of oxaliplatin (yes vs no) (median RFS of 15 months vs 62 months; P 5.01), prior use of bevacizumab (yes vs no) (median RFS of 14 months vs 26 months; P 5.03), and number of lesions (3 vs 2) (RFS of 15 months vs 24 months; P .01) (Table 2). There was a borderline association noted between RFS and age (P 5 .08) and bilobar disease (P 5 .07). Positive Cancer
Figure 1. The recurrence-free survival (RFS) rate is shown for patients with KRAS wild-type (WT) versus KRAS-mutated (MUT) tumors, truncated at 60 months. 95% CI indicates 95% confidence interval.
December 15, 2014
surgical resection margins and baseline CEA and LDH were not found to be significantly associated with RFS (P 5.33, P 5.16, and P 5.86, respectively). On the multivariate analysis (Table 3), the effect of KRAS remained significant after adjusting for prior use of oxaliplatin or bevacizumab, number of lesions, age, bilobar disease, and sex (HR, 1.9 [95% CI, 1.16-3.31]; P 5.01). Overall Survival
The median follow-up was 48 months. The median OS was not reached and the OS rate was 91% (95% CI, 84%-95%) at 3 years. The OS rate at 3 years for patients with KRAS WT and patients with KRAS MUT was 95% (95% CI, 87%-98%) and 81% (95% CI, 62%-95%), respectively (P 5.07) (Fig. 2). On univariate analysis, exposure to oxaliplatin before surgical resection (prior oxaliplatin vs no prior oxaliplatin]: 100% vs 83% at 3 years) (P.01) and positive surgical resection margins were associated with survival (P 5.032). There was a borderline association observed between OS and female sex (95% vs 88% for males at 3 years; P 5.053) and baseline CEA level (P 5.096). Baseline LDH level was not found to be significantly associated with OS (P 5.97). Other patient characteristics did not appear to significantly affect OS. On the multivariate model, the effect of KRAS on OS was not found to be statistically significant after adjusting for prior exposure to oxaliplatin, baseline CEA level, and positive surgical resection margins (HR, 2.0 [95% CI, 0.874.46]; P 5.104). Similar results were found when we further adjusted for age and sex. Cumulative Incidence of Recurrence to Individual Sites
At 3 years, the cumulative incidence of bone metastases was 2% (95% CI, 0%-5.7%) versus 13.4% (95% CI, 3967
Original Article TABLE 2. Univariate Analysis of Recurrence-Free Survivala
TABLE 3. Multivariate RFS Model Characteristic
Characteristics Prior chemotherapy No Yes Prior oxaliplatin No Yes Prior bevacizumab No Yes Sex Female Male Synchronous tumor No Yes Bilobar No Yes Clinical risk score 0-2 3-5 No. of lesions 1 2 3 Largest size of tumor, cm
KRAS Mutation Influences Recurrence Patterns in Patients Undergoing Hepatic Resection of Colorectal Metastases Nancy E. Kemeny, MD1; Joanne F. Chou, MPH2; Marinela Capanu, PhD2; Alexandra N. Gewirtz, BA1; Andrea Cercek, MD1; T. Peter Kingham, MD3; William R. Jarnagin, MD3; Yuman C. Fong, MD3; Ronald P. DeMatteo, MD3; Peter J. Allen, MD3; Jinru Shia, MD4; Celina Ang, MD1; Efsevia Vakiani, MD4; and Michael I. D’Angelica, MD3
BACKGROUND: The validity of the KRAS mutation as a predictor of recurrence-free survival (RFS) or overall survival (OS) is unclear. The current study investigated whether the presence of the KRAS mutation decreased RFS or OS in patients with colorectal cancer who underwent liver resection. METHODS: Patients with resected colorectal liver metastases who received adjuvant hepatic arterial infusion plus systemic therapy and for whom KRAS data was available were evaluated. Correlation between KRAS and clinical factors was done using the Fisher exact test. Kaplan-Meier methods were used to estimate the median RFS and OS. RESULTS: A total of 169 patients were evaluated, 118 of whom had KRAS wild-type (WT) and 51 had KRAS mutated (MUT) tumors. The 3-year RFS rate was 46% for patients with KRAS WT (95% confidence interval [95% CI], 35%-56%) and 30% (95% CI, 16%-44%) for patients with KRAS MUT (P 5.005). The 3-year OS rate was 95% (95% CI, 87%-98%) and 81% (95% CI, 62%-95%), respectively, for patients with KRAS WT and KRAS MUT (P 5.07). On multivariate analysis, KRAS remained a significant predictor of RFS (hazard ratio, 1.9). The 3-year cumulative recurrence rate by site of metastases was as follows: 2% versus 13.4% for bone (P.01), 2% versus 14.5% for brain (P 5.05), 33.2% versus 58% for lung (P.01), and 30% versus 47% for liver (P 5.10) in patients with KRAS WT versus KRAS MUT. CONCLUSIONS: In the current study, among patients with resected colorectal liver metastases who were treated with adjuvant hepatic arterial infusion plus systemic therapy, patients with KRAS MUT were found to have a significantly worse 3-year RFS (30%) compared with KRAS WT (46%) p5.005. The cumulative incidence of bone, brain, and lung metastases was significantly higher for patients with KRAS MUT C 2014 American Cancer Society. compared with those with KRAS WT. Cancer 2014;120:3965-71. V KEYWORDS: colorectal cancer, liver metastases, adjuvant therapy, KRAS mutation, disease recurrence patterns.
INTRODUCTION Many factors predict overall survival (OS) or recurrence-free survival (RFS) for patients with metastatic colorectal cancer such as baseline alkaline phosphatase,1 performance status, white blood cell count, lactate dehydrogenase (LDH),2 and carcinoembryonic antigen (CEA).1,2 There have been conflicting reports regarding whether KRAS mutation influences outcome. In one trial of 394 patients, the OS was 26.7 months for patients with KRAS wild-type (WT) and 18 months for patients with KRAS mutated (MUT) (P 5.002) tumors.3 In this multivariate analysis, KRAS mutation and high LDH were found to be significantly related to worse survival. Other studies have reported no significant difference in OS between patients with KRAS WT and KRAS MUT.4-6 KRAS mutation has also been reported to influence outcomes in patients after liver resection for metastatic disease. Karagkounis et al demonstrated worse RFS (hazard ratio [HR], 1.89) and OS (HR, 2.13) in those patients with a KRAS mutation.7 The current study was performed to determine whether KRAS status affects outcome in patients treated with adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection. MATERIALS AND METHODS The Institutional Review Board allowed a review of patients treated between March 19, 2003 and January 19, 2013 who underwent liver resection followed by adjuvant HAI plus systemic chemotherapy and for whom KRAS data were available. At surgery, all disease was resected or ablated and an HAI pump was placed concurrently. One month after surgery,
Corresponding author: Nancy E. Kemeny, MD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell University, 1275 York Ave, New York, NY 10065; Fax: (646) 888-4541; [email protected] 1 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; 3Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; 4Department of Pathology, Memorial SloanKettering Cancer Center, New York, New York.
See editorial on pages 3862-5, this issue. DOI: 10.1002/cncr.28954, Received: January 15, 2014; Revised: March 14, 2014; Accepted: April 2, 2014, Published online August 25, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
December 15, 2014
3965
Original Article
chemotherapy was initiated. Patterns of disease recurrence and survival were evaluated for patients who met the above criteria. Genotyping only became the standard of care at Memorial Sloan-Kettering Cancer Center in 2009. Correlations between KRAS status and clinical factors such as prior chemotherapy, postoperative CEA, clinical risk score (CRS), stage at diagnosis, and whether radiofrequency ablation was performed at the time of pump placement for HAI were evaluated using the Fisher exact test and the Wilcoxon rank sum test. OS and RFS were calculated from time of HAI until the time of any cause of death (for OS) or until the time of first disease recurrence or death, whichever came first (for RFS). In the current study cohort, all deaths, except for one patient who possibly died due to myocardial infarction, were related to disease, and hence OS was equivalent to diseasespecific survival. First disease recurrence was confirmed by computed tomography scan or magnetic resonance imaging. Scans were performed every 3 months for the first 2 years, every 4 months for year 3, every 6 months for year 4, and yearly thereafter. OS and RFS were estimated using the Kaplan-Meier method. The log-rank test was used to determine whether survival functions differed by KRAS mutation status and other clinical and pathologic characteristics. The Cox proportional hazards model was used to examine the association between continuous clinical factors such as baseline CEA and LDH and OS/RFS. Factors found to be significant on the univariate analyses (P .10) were included in the multivariate Cox proportional hazards model examining the effect of KRAS separately on OS and RFS. Left-sided primary tumors were defined as descending colon, rectosigmoid, rectum, and sigmoid colon; all other locations were considered rightsided. A positive surgical margin was defined as one measuring 5 cm, and CEA level >200 ng/mL; it was not found to be significantly different. A CRS >3 was observed in 43% and 57%, respectively, of patients with KRAS WT and KRAS MUT (P 5.10). The median Cancer
December 15, 2014
KRAS Mutation Influences Recurrences/Kemeny et al
TABLE 1. Baseline Characteristics of Patients With KRAS WT Versus KRAS MUT
Median baseline CEA (range), ng/mL Median baseline LDH (range), Units/Lb Median age (range), y Sex Female Male Dukes stage B C Prior chemotherapy No Yes Clinical risk score 0-2 3-5 No. of lesions 1 2 3 Surgical margin status Positive Negative Prior oxaliplatin No Yes Primary tumor (right or left) Right Left
KRAS WT (N5118)
KRAS MUT (N551)
Pa
2.6 (0.8-49.4)
2.4 (0.9-125.9)
.52
156 (99-320)
164 (90-227)
.27
54 (27-83)
56 (36-79)
.45 .86
48 (41%) 70 (59%)
22 (43%) 29 (47%)
56 (47%) 62 (53%)
17 (33%) 34 (67%)
19 (16%) 99 (84%)
8 (16%) 43 (84%)
67 (57%) 51 (43%)
22 (43%) 29 (57%)
.08
.94
.10
.64 32 (27%) 24 (20%) 53 (48%)
11 (22%) 13 (25%) 23 (48%)
7 (6%) 109 (94%)
7 (14%) 44 (86%)
46 (39%) 72 (61%)
14 (27%) 37 (73%)
31 (26%) 87 (74%)
23 (45%) 28 (55%)
.13
.15
.016
Abbreviations: CEA, carcinoembryonic antigen; LDH, lactate dehydrogenase; MUT, mutated; WT, wild-type. a Bold type indicates statistical significance. b Note that 3 patients (2 with KRAS WT and 1 with KRAS MUT) were missing information regarding their baseline LDH.
follow-up was 44.3 months (range, 1.41 months-119 months). Recurrence-Free Survival
At the end of the follow-up, we observed 80 events (disease recurrence or death). The median RFS was 20 months (95% confidence interval [95% CI], 14 months31 months), with a 3-year RFS rate for the entire group of 41% (95% CI, 33%-50%). The 3-year RFS rate for patients with KRAS WT was 46% (95% CI, 35%-56%) and was 30% for patients with KRAS MUT (95% CI, 16%-44%) (P 5.005) (Fig. 1). On univariate analysis, factors found to be significantly associated with a shorter RFS (Table 2) were prior use of oxaliplatin (yes vs no) (median RFS of 15 months vs 62 months; P 5.01), prior use of bevacizumab (yes vs no) (median RFS of 14 months vs 26 months; P 5.03), and number of lesions (3 vs 2) (RFS of 15 months vs 24 months; P .01) (Table 2). There was a borderline association noted between RFS and age (P 5 .08) and bilobar disease (P 5 .07). Positive Cancer
Figure 1. The recurrence-free survival (RFS) rate is shown for patients with KRAS wild-type (WT) versus KRAS-mutated (MUT) tumors, truncated at 60 months. 95% CI indicates 95% confidence interval.
December 15, 2014
surgical resection margins and baseline CEA and LDH were not found to be significantly associated with RFS (P 5.33, P 5.16, and P 5.86, respectively). On the multivariate analysis (Table 3), the effect of KRAS remained significant after adjusting for prior use of oxaliplatin or bevacizumab, number of lesions, age, bilobar disease, and sex (HR, 1.9 [95% CI, 1.16-3.31]; P 5.01). Overall Survival
The median follow-up was 48 months. The median OS was not reached and the OS rate was 91% (95% CI, 84%-95%) at 3 years. The OS rate at 3 years for patients with KRAS WT and patients with KRAS MUT was 95% (95% CI, 87%-98%) and 81% (95% CI, 62%-95%), respectively (P 5.07) (Fig. 2). On univariate analysis, exposure to oxaliplatin before surgical resection (prior oxaliplatin vs no prior oxaliplatin]: 100% vs 83% at 3 years) (P.01) and positive surgical resection margins were associated with survival (P 5.032). There was a borderline association observed between OS and female sex (95% vs 88% for males at 3 years; P 5.053) and baseline CEA level (P 5.096). Baseline LDH level was not found to be significantly associated with OS (P 5.97). Other patient characteristics did not appear to significantly affect OS. On the multivariate model, the effect of KRAS on OS was not found to be statistically significant after adjusting for prior exposure to oxaliplatin, baseline CEA level, and positive surgical resection margins (HR, 2.0 [95% CI, 0.874.46]; P 5.104). Similar results were found when we further adjusted for age and sex. Cumulative Incidence of Recurrence to Individual Sites
At 3 years, the cumulative incidence of bone metastases was 2% (95% CI, 0%-5.7%) versus 13.4% (95% CI, 3967
Original Article TABLE 2. Univariate Analysis of Recurrence-Free Survivala
TABLE 3. Multivariate RFS Model Characteristic
Characteristics Prior chemotherapy No Yes Prior oxaliplatin No Yes Prior bevacizumab No Yes Sex Female Male Synchronous tumor No Yes Bilobar No Yes Clinical risk score 0-2 3-5 No. of lesions 1 2 3 Largest size of tumor, cm
