Prognostic relevance of KRAS genotype in metastatic colorectal cancer patients unfit for FIr-B/FOx intensive regimen
- Authors:
- Published online on: April 4, 2014 https://doi.org/10.3892/ijo.2014.2369
- Pages: 1820-1830
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Copyright: © Bruera et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Abstract
Introduction
Clinical management of metastatic colorectal cancer (MCRC) faces with different options and lines of treatment according to patients’ fitness [age, performance status (PS), comorbidities], extension of metastatic disease [liver-limited (L-L) or other/multiple metastatic (O/MM)], KRAS genotype (1–4). First line triplet chemotherapy, or doublets plus bevacizumab (BEV) or cetuximab, reported overlapping activity and efficacy in phase III trials, ranging between ORR 39–68%, PFS 7.2–10.6 months and OS 19.9–26.1 months (2,5,6). More intensive regimens, consisting of triplet chemotherapy plus targeted agents, can further increase activity, efficacy and effectiveness of liver metastasectomies (7–9).
In clinical practice, a decision-making process including functional, nutritional, and co-morbidity status is required to tailor first line medical treatment (10). Elderly status (age >65 years), PS >2, and/or comorbidities represent major features, to limit toxicities and maintain quality of life (QoL). Elderly MCRC patients are prevalent, and a clinical challenge is to select between intensive or tailored medical treatments, by properly weighing expected safety and efficacy, and according to prognostic factors. Retrospective studies showed that elderly patients benefit from 5-fluorouracil (5-FU) (11–13), irinotecan (CPT-11)-containing therapy (14,15), FOLFOX (16) to the same extent as younger (17–19). In the OPTIMOX1 trial, ORR 59%, PFS 9.0 months and OS 20.7 months were comparable between old-elderly and younger patients treated with FOLFOX (20). Treatment efficacy was also comparable with BEV associated to 5-FU/CPT-11 (21). In elderly patients, addition of BEV to 5-FU based chemotherapy significantly prolonged PFS (9.2-9.3 months) and OS (17.4–19.3 months) (22,23). In BRiTE and BEAT studies, no different PFS was observed in elderly patients; median OS decreased with age (24,25). In the randomized phase III trial comparing FOLFIRI with FOLFOXIRI, age was not significantly related to activity and efficacy, with OS 16.9 and 19.9 months, respectively (26,27). ORR was significantly lower in older patients treated with FOLFOXIRI (27). Patients underwent metastasectomies without increased morbidity or mortality, irrespective of age. Patients with PS 2 presented a significantly lower OS and PFS, irrespectively of FOLFIRI or FOLFOXIRI chemotherapy regimen (27). Age and/or comorbidities did not affect efficacy in patients treated with cetuximab added to FOLFOX or FOLFIRI (28). In elderly and PS 2 patients, PFS was not increased by addition of panitumumab to FOLFOX (29). A meta-analysis showed that PS 1 compared to PS 2 significantly affect prognosis, regardless of treatment, with ORR 43.8 vs 32%, PFS 7.6 vs 4.9 months, OS 17.3 and 8.5 months, respectively (30). The FOCUS2 randomized trial prospectively evaluated first line chemotherapy options consisting of 80% dose 5-FU or capecitabine, with or without oxaliplatin (OXP), in old-elderly and/or frail patients, and showed that addition of OXP significantly improved ORR (35 vs 13%), a trend of PFS (5.8 vs. 4.5 months, hazard ratio 0.84, p=0.07), but not OS (31), without significantly increasing toxicity, with a negative impact on QoL.
KRAS mutations occur in 35–45% of colorectal cancer (CRC), mostly codon 12 (80%), prevalently c.35 G>A (G12D) transversion (32.5%) (32,33), impairing the intrinsic GTPase activity, and leading to constitutive, growth factor receptor-independent activation of downstream signalling (34). In the in vitro model proposed by Guerrero et al (35), codon 12 mutations increase aggressiveness by the differential regulation of KRAS downstream pathways that lead to inhibition of apoptosis, enhanced loss of contact inhibition and increased predisposition to anchorage-independent growth. KRAS genotype, wild-type or mutant, addresses the addition of targeted agents in MCRC medical treatment: anti-EGFR or anti-VEGF to doublet chemotherapy in KRAS wild-type (36–39); BEV to 5-FU, CPT-11 in KRAS mutant, significantly predicting prolonged PFS, while not OS and activity (36,37).
Clinical outcome in wild-type and mutant patients assesses the prognostic relevance of KRAS genotype, depending on differential tumor biological aggressiveness (4), including the predictive effectiveness of treatment strategies. Median OS of patients treated with BEV added to CPT-11/5-FU or triplet chemotherapy was different in KRAS wild-type and mutant patients, but not significantly (4,8,36,37); KRAS wild-type L-L patients may achieve a significantly greater benefit from integration with liver metastasectomies, with respect to mutant patients (4). We recently reported that the prevalent KRAS c.35 G>A (G12D) mutant genotype may significantly affect worse OS of MCRC patients treated with FIr-B/FOx, compared to wild-type or different other mutations (40). Here, we report a retrospective exploratory analysis evaluating tailored first line treatments, the prognostic value of KRAS genotype, and of the c.35 G>A mutation, in consecutive MCRC patients not eligible for intensive first line FIr-B/FOx expanded clinical program, due to age and/or comorbidities.
Materials and methods
Patient eligibility
Consecutive MCRC patients not eligible, due to comorbidities and/or age, for expanded clinical program or ongoing phase II trial proposing intensive regimens consisting of triplet chemotherapy plus targeted agent, were treated in clinical practice with first line medical and/or surgical treatments, chosen among those in indication for MCRC treatment and approved by Agenzia Italiana del Farmaco (AIFA) for administration in label in Italian public hospitals, and published in Gazzetta Ufficiale Repubblica Italiana (‘Elenco dei Medicinali erogabili a totale carico del Servizio sanitaria nazionale’, Gazzetta Ufficiale Repubblica Italiana N.1, 2 Gennaio 2009). Thus, it was not a clinical trial and approval by ethics committee and institutional review board was not necessary, because patients were treated with conventional treatments without any additional medical intervention out of the best common clinical practice. Patients had histological confirmed diagnosis of MCRC, age ≥18 years, PS ≤2. Criteria to define patients unfit, or not eligible for intensive regimens were: age ≥75 years; uncontrolled severe diseases; cardiovascular disease (uncontrolled hypertension, uncontrolled arrhythmia, ischemic cardiac diseases in the last year); thromboembolic disease, coagulopathy, preexisting bleeding diatheses; proteinuria >1 g/24 h. Patients were classified according to Cumulative Illness Rating Scale (CIRS) (10). Treatment options were tailored according to age (< or ≥75 years), patient’s fitness (PS, CIRS), KRAS genotype. Patients with PS 3 were not treated. All patients provided written, informed consent to the proposed in label treatment option.
Methods
Medical treatment regimens
Medical treatments included triplet, doublet, or mono-chemotherapy. Triplet FIr/FOx schedule consisted of weekly timed-flat-infusion 5-FU (TFI 5-FU), associated to weekly alternating CPT-11 or L-OXP (41): TFI/5-FU (Fluorouracil Teva; Teva Italia, Milan, Italy), 750–900 mg/m2/die, over 12 h (from 10:00 pm to 10:00 am), days 1–2, 8–9, 15–16, 22–23; CPT-11 (Campto; Pfizer, Latina, Italy), 120–160 mg/m2, days 1 and 15; l-OXP (Eloxatin; Sanofi-Aventis, Milan, Italy), 70–80 mg/m2, days 8 and 22; cycles every 4 weeks. Other triplet, doublet and mono-regimens were administered according to previously reported schedules (7,41,42). Targeted agents were: BEV (Avastin; Roche, Welwyn Garden City, UK), 5 mg/kg, days 1 and 15; cetuximab (Erbitux; Merck, Darmstadt, Germany), 400 mg/m2 initial dose, then 250 mg/m2/week.
Mutational analysis
Genetic analyses were performed on paraffin-embedded tissue blocks from primary tumor and/or metastatic sites, as previously reported (4). Genotype status was assessed for KRAS codon 12 and 13 mutations by direct sequencing. KRAS exon 2 sequence was performed from PCR-amplified tumor DNA using the Big Dye V3.1 Terminator kit, electrophoresis in ABI PRISM 3130xl Genetic Analyzer, and analysis using the GeneMapper Analysis software version 4.0 (Applied Biosystems, Foster City, CA, USA).
Study design
Activity, efficacy, and prognostic relevance of first line treatments, and KRAS genotype on clinical outcomes were evaluated. Patients were classified according to: metastatic extension, L-L and O/MM (3,4); age, non-elderly (<65 years), young-elderly (≥65 <75 years), old-elderly (≥75 years); CIRS stage primary, intermediate, secondary. Clinical evaluation of response was made by CT scan; PET was added based on investigators’ assessment. Follow-up was scheduled every two-three months up to disease progression or death. L-L patients were evaluated at baseline and every two-three cycles of treatment by a multidisciplinary team, to evaluate resectability defined according to reported categories (3). Liver metastasectomies were defined as R0, if radical surgery, R1, if radioablation was added. Surgery was recommended >4 weeks after BEV discontinuation.
Clinical criteria of activity and efficacy were ORR, resection rate of metastases, PFS and OS: ORR, evaluated according to RECIST criteria (43); pathologic complete response, defined as no residual cancer cells in surgical specimens; PFS and OS, evaluated using the Kaplan-Meier method (44). PFS was defined as the length of time from the beginning of treatment and disease progression or death (resulting from any cause) or to the last contact; OS as the length of time between the beginning of treatment and death or to last contact. Log-rank test was used to compare PFS and OS according to medical treatment, KRAS genotype, metastatic extension, age and comorbidity stage (45).
Results
Patient demographics
Forty patients unfit for intensive regimens, among 72 consecutive MCRC (56%), were treated with (Table I): medical treatments, 37 patients (92.5%); surgery, 3 (7.5%). First line medical treatments: triplet, 18 (45%); doublet, 15 (37.5%); mono-therapy, 4 (10%). Among 39 KRAS evaluated patients (97.5%), 23 (59%) were wild-type and 16 (41%) mutant. Clinical features of the 37 patients who underwent first line medical treatments were (Table IIA): male/female ratio, 22/15; median age, 75 years; young- and old-elderly, 28 (76%) and 20 (54%), respectively; PS 0, 15 (41%) and 1–2, 22 (59%); metastatic disease metachronous 24%, synchronous 76%. Liver metastases, 26 patients (70%); L-L 8 (22%), O/MM 29 79%). Distribution of patients according to age and comorbidity stage (Table IIB): non-elderly 9 (24%), young-elderly 8 (22%), old-elderly 20 (54%); CIRS stage primary 4 (11%), intermediate 15 (40%), secondary 18 (42%). KRAS mutations detected in 15 patients were: codon 12, 13 (36.1%), specifically c.35 G>A (G12D), 7 (19.4%), c.35 G>T (G12V), 6 (16.6%); codon 13, 2 (5.5%), c.37 G>T (G13V), 1 (2.7%) and c.38 G>A (G13D), 1 (2.7%).
Medical treatments were tailored according to age and CIRS stage. Triplet regimens were administered in 18 patients (49%): non-elderly 6, young-elderly 4, old-elderly 8; CIRS primary 2, intermediate 10, secondary 6. Doublet regimens were administered in 15 patients (40%): non-elderly 3, young-elderly 3, old-elderly 9; CIRS primary 1, intermediate 4, secondary 10. Mono-regimens were administered in 4 patients (11%): young-elderly 1, old-elderly 3; CIRS primary 1, intermediate 1, secondary 2.
Overall activity and efficacy
Among the 37 patients who underwent medical treatments, 10 were not evaluable for activity: 7 (19%) did not receive at least 2 cycles of treatment; 3 were on-treatment. The intent-to-treat analysis of 27 patients showed ORR 37% (α 0.05, CI ± 19) (Table IIIA). We observed 10 objective responses: 9 partial (33%) and 1 complete (CR 4%); 9 stable diseases (33%); 8 progressive diseases (30%). Disease control rate was 67% (α 0.05, CI ± 18). After median follow-up of 8 months, median PFS was 7 months (1-13+): 28 events occurred. Median OS was 13 months (1+−23+): 22 events occurred (Fig. 1A). R0 liver metastasectomies were performed in 3 patients (8%): 3 out of 8 L-L (37.5%). No surgery-related complications were reported. Overall, 1 clinical plus 1 pathologic CR were reported (7%); 1 patient showed a progressive disease at 8 months; 1 patient was progression-free at 10 months. Pathologic CR was obtained in 1 KRAS wild-type patient (33%), with primary rectal tumor and a single L-L metastasis. Twelve patients (32%) received, at least, a second line treatment.
 | A, Activity, efficacy and effectiveness of first line regimens in unfit patients according to KRAS genotype |
Among 7 evaluable L-L patients, ORR was 71%; 3 performed liver metastasectomies (43%) and 1 cCR (14%); median PFS 11 months (3–13+ months); median OS 12 months (3–13+ months). Among 20 evaluable O/MM patients, ORR was 25%; median PFS 6 months (1–12 months); median OS 13 months (1+−23+ months). Clinical outcome (PFS and OS) in L-L compared to O/MM patients was not significantly different (Fig. 1B).
Activity and efficacy according to first line treatment, elderly and comorbidity status
Among 16 evaluable patients treated with triplet regimens (Table IIIB), ORR was 37.5% (α 0.05, CI ± 24). We observed 6 partial responses (37.5%); 5 stable diseases (31%); 5 progressive diseases (31%). Median PFS was 8 months (3–12): 14 events occurred. Median OS was 12 months (3–23+ months): 12 events occurred. Secondary metastasectomy was performed in 1 patient (6%). Among 15 patients treated with doublet regimens (Table IIIB), ORR was 44% (α 0.05, CI ± 34). We observed 3 partial responses (33%); 1 CR (11%); 3 stable diseases (33%); 2 progressive diseases (22%). Median PFS was 8 months (1–13+): 9 events occurred. Median OS was 15 months (1+−23+ months): 7 events occurred. Among 4 patients treated with mono-regimens, median PFS was 5 months (3–6 months), median OS 6 months (3−13+ months). Among 3 patients who underwent surgery as first line treatment, median PFS was not reached (3+−19+ months); median OS not reached (3+−19+ months). PFS and OS were not significantly different in patients treated with triplet compared to other first line treatments (p=0.947 and 0.557, respectively), and to doublet regimens (p= 0.885 and 0.616, respectively) (Fig. 2).
Moreover, PFS and OS were not significantly different in non-elderly and young-elderly compared to old-elderly patients (p=0.240 and 0.750, respectively), and in primary and intermediate CIRS stage compared to secondary stage patients (p=0.494 and 0.364, respectively).
Prognostic relevance of KRAS genotype and c.35 G>A KRAS mutation
Among 14 KRAS wild-type patients evaluable for activity, ORR was 50% (α 0.05, CI ± 27) (Table IIIA). We observed 7 objective responses: 6 partial (43%) and 1 CR (7%); 4 stable diseases (29%); 3 progressive diseases (21%). Disease control rate was 79% (α 0.05, CI ± 22). Liver metastasectomies were performed in 3 patients (14%), 3 out of 7 L-L (43%). Median PFS was 8 months (1+−13+ months), 15 events occurred (71%). Median OS was 13 months (1+−23+ months), 11 events occurred. Among 12 KRAS mutant patients evaluable for activity, ORR was 25% (α 0.05, CI ± 26). We observed 3 partial responses (25%); 5 stable diseases (42%); 4 progressive diseases (33%). Disease control rate was 67% (α 0.05, CI ± 28). No liver metastasectomies were performed. Median PFS was 6 months (1–11 months), 12 events occurred (80%). Median OS was 8 months (3–18 months), 10 events occurred. KRAS wild-type compared with mutant patients showed significantly different PFS (p=0.043), but not OS (Fig. 1C). KRAS c.35 G>A mutant patients showed significantly worse PFS and OS compared to wild-type (p=0.000, and 0.049, respectively) (Fig. 3A and B), and to other mutant patients (p=0.020 and 0.048, respectively) (Fig. 3C and D). No different clinical outcomes were reported in other than c.35 G>A KRAS mutant compared to wild-type patients (Fig. 3E and F). PFS and OS were also significantly worse in c.35 G>A KRAS mutant patients compared to other mutant plus wild-type patients (p=0.000, and 0.021, respectively) (Fig. 3G and H).
Discussion
Patients unfit for first line FIr-B/FOx intensive regimen, due to age (≥75 years) and/or comorbidities, were prevalent (56%), mostly elderly (76%), particularly old-elderly patients (54%), prevalently PS 1–2 (59%), CIRS stage intermediate/secondary (89%), O/MM disease (79%). Most unfit MCRC patients were treated with triplet or doublet regimens (49 and 40%, respectively), and some (19%) did not reach the first evaluation of activity at 2–3 months.
Retrospective evaluations of doublets consisting of CPT-11 or OXP, associated to 5-FU or capecitabine in elderly patients eligible for clinical trials gained ORR 18–59.4%, PFS 4.9–10.0 months and OS 8.5–20.7 months (11–16,20,30,31,46). BEV addition to 5-FU-based chemotherapy in elderly patients significantly increased PFS up to 9.2–9.3 months and OS up to 17.4–19.3 months (22,23). Triplet chemotherapy or doublets plus BEV obtained ORR 34.9–45.9%, PFS 7.9–9.3 months and OS 17.4–20.5 months (23–25). The present tailored approach, based on evaluation of elderly status and/or CIRS, prevalently addressing doublet and triplet regimens, reported ORR 37%, PFS 7 months and OS 13 months. Selected medical treatment, triplet compared to doublet, did not significantly affected PFS and OS, nor advanced age, or CIRS stage. The FOCUS2 randomized trial evaluating first line reduced dose 5-FU or capecitabine and OXP in old-elderly and/or frail patients showed significantly improved ORR 35%, with PFS 5.8 months (31). The meta-analysis evaluating the effect of PS on clinical outcome showed that PS 1 compared to PS 2 significantly affected prognosis, regardless of treatment, with ORR 43.8 vs 32%, PFS 7.6 vs 4.9 months, OS 17.3 and 8.5 months, respectively (30). In the HORG-FOLFOXIRI trial, elderly compared to non-elderly patients treated with FOLFIRI or FOLFOXIRI showed no different clinical outcome; significantly lower PFS and OS were reported in patients with PS 2 (26,27).
Young-elderly patients eligible for FIr-B/FOx intensive regimen, prevalently characterised by PS 0 (89%) and intermediate CIRS stage (93%), reported ORR 79%, PFS 11 months, OS 21 months, equivalent to overall patients (7,47). A complex decision-making process discriminating patients’ fitness, and tailoring a personalized medical treatment, is challenging: patients unfit for FIr-B/FOx can be treated with a two-drug first line combination regimen (31), but showed worse clinical outcome. No increased morbidity, nor mortality was reported in unfit patients who underwent secondary liver metastasectomies, reported as significantly higher in elderly patients (8%) (48).
Overall in MCRC patients treated with BEV added to CPT-11/5-FU, or with more intensive regimens (FIr-B/FOx, FOLFOXIRI/BEV), PFS and OS were not significantly different in KRAS wild-type and mutant (4,6,8,37) as well as in young-elderly patients (47). Recently, KRAS geno-type was reported as significantly affecting PFS and OS in patients treated with XelOx/BEV (49). We recently reported in MCRC patients treated with FIr-B/FOx, that the prevalent KRAS c.35 G>A (G12D) mutant genotype may significantly affect worse OS, compared to wild-type or other mutations (40). Present data reported for the first time that in patients unfit for FIr-B/FOx, KRAS wild-type compared to mutant patients showed a significantly different PFS, and not OS. Furthermore, KRAS c.35 G>A mutant genotype may affect significantly worse PFS and OS, compared to wild-type and/or other mutant, confirming that KRAS genotype, particularly c.35 G>A mutant, confers different biological aggressiveness (35), less effectively overcome by conventional triplet and doublet regimens. The prognostic relevance of KRAS genotype, particularly c.35 G>A mutant (4,40), and the predictive relevance of different medical treatments according to patients’ fitness for intensive regimens, should be prospectively evaluated.
In conclusion, in MCRC patients unfit for first line intensive FIr-B/FOx regimen, tailored doublet and triplet medical treatments showed similar activity and efficacy, also according to age and comorbidities. KRAS genotype may indicate different PFS, and c.35 G>A KRAS mutant a significantly worse PFS and OS, compared to wild-type and other mutations. Present findings warrant prospective trials comparing clinical outcome in unfit patients, according to KRAS genotype.
Acknowledgements
G.B. is a PhD student in Biotechnology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, funded by the University of L’Aquila, Italy.
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