Background
Triplet regimens consisting of chemotherapeutic drugs, or doublets plus bevacizumab (BEV) (anti-vascular endothelial growth factor monoclonal antibody) or cetuximab (anti-epithelial growth factor receptor (EGFR) monoclonal antibody) in EGFR-overexpressing and
KRAS wild-type metastatic colorectal cancer (MCRC), reported overlapping activity and efficacy in phase III trials, ranging between objective response rate (ORR) 39% to 68%, progression-free survival (PFS) 7.2 to 10.6 months, overall survival (OS) 19.9 to 26.1 months [
1]. In 'fit' MCRC patients, these first-line options, integrated with secondary resection of liver metastases, significantly increased survival over doublet regimens [
1,
2]. More intensive medical treatment consisting of triplet chemotherapy plus targeted agents can further increase activity, thus raising resection rate of liver metastases and clinical outcome [
1‐
5]. Phase II studies, by Masi
et al. [
3], and by our group [
4], proposed BEV addition to triplet chemotherapy, according to FOLFOXIRI/BEV or FIr-B/FOx schedules, reaching ORR 77% and 82%, median PFS 13.1 and 12 months, median OS 30.9 and 28 months, as first-line treatment of MCRC patients. Liver metastasectomies were performed in 32% and 26% overall and 40% and 54% liver-only patients, respectively. Thus, MCRC patients with liver-limited (L-L) disease, integrating FIr-B/FOx intensive regimen and secondary liver surgery significantly improved clinical outcome compared to MCRC patients with multiple metastatic disease, up to median PFS 17 months and median OS 44 months [
6].
Gain-of-function mutations of
RAS, BRAF, PIK3CA genes, or loss of tumor suppressor function of
PTEN, resulting in continuous activation of the RAS-mitogen-activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K) pathways, characterize most colorectal cancers (CRC) [
7‐
9].
KRAS mutations represent an early event in colorectal tumorigenesis [
10,
11] and occur in 35% to 45% of CRC, mostly represented by codon 12 c.35 G>A (32.5%) [
12,
13], c.35 G>T (22.5%) [
11,
12], and codon 13, prevalently c.38 G>A, transversions [
14]. They impair intrinsic GTPase activity of KRAS, and lead to constitutive, growth factor receptor-independent activation of downstream signaling [
15].
BRAF mutations, prevalently c.1799 T>A (V600E) mutation, characterize 4.7% to 8.7% of CRC [
16‐
20].
Clinical outcome (PFS, OS) according to wild-type and mutant genotype assesses the prognostic relevance of a specific biomarker, potentially including the predictive role of effectiveness of treatment strategies. In randomized studies, the predictive relevance of wild-type or mutant genotype can also be specifically assessed by comparing experimental and control arms. The reported median OS values of
KRAS wild-type and mutant MCRC patients treated with irinotecan, 5-fluorouracil and leucovorin (IFL) plus BEV were 27.7 and 19.9 months, respectively [
18,
21]. The prognostic relevance of
KRAS or
BRAF wild-type compared to
KRAS or
BRAF mutant genotype was not significantly different, even though the hazard ratio (HR) was 0.64 and 0.38, respectively. A significantly better prognosis was reported only when
KRAS/BRAF wild-type patients were compared with patients harboring mutations in the
KRAS or
BRAF genes (HR 0.51) [
18].
KRAS wild-type genotype significantly predicts a favorable clinical outcome of anti-EGFR or anti-vascular endothelial growth factor (VEGF) drugs added to doublet chemotherapy [
18,
21‐
23]. In
the KRAS mutant genotype, BEV addition to IFL significantly prolonged PFS up to 9.3 months, without increasing OS and activity, compared to IFL [
18,
21].
Here, we report a retrospective exploratory analysis evaluating the prognostic value of the
KRAS genotype in MCRC patients enrolled in a previously reported phase II study [
4] and in an expanded clinical program proposing FIr-B/FOx intensive regimen as first-line treatment, also verifying recently reported significantly greater effectiveness in L-L compared to other or multiple metastatic (O/MM) patients [
6].
Discussion
In
KRAS wild-type patients, BEV addition to doublet chemotherapy significantly increased ORR, PFS and OS up to 60% to 61%, 10.5 to 13.5 months and 21.8 to 27.7 months, respectively [
18,
21,
31,
32]. Randomized studies of anti-EGFR added to doublets, in EGFR-overexpressing patients, reported ORR 50% to 61%, PFS 7.7 to 10.6 months, OS 22.4 to 24.9 months [
22,
23,
31‐
33]. First-line cetuximab plus FOLFOX4, significantly improved ORR and PFS in
KRAS/BRAF wild-type population, similarly to
KRAS wild-type patients [
34]. In
KRAS mutant patients, BEV addition to doublet chemotherapy (IFL) significantly increased median PFS up to 9.3 months, while ORR was equivalent to doublet arm (43.2% and 41.2%, respectively), and median OS increased up to 19.9 months, even if not significantly [
21,
35].
In
KRAS wild-type and mutant MCRC patients, BEV addition to triplet chemotherapy, according to FIr-B/FOx schedule, reported high activity and efficacy: ORR 90% and 67%, median PFS 14 and 11 months, median OS 38 and 20 months, respectively. A similar clinical outcome was also obtained in
KRAS/BRAF wild-type patients. Equivalent efficacy was reported with FOLFOXIRI/BEV regimen: ORR 82% and 71%, median PFS 13.6 and 12.6 months, respectively [
3]. In unresectable colorectal liver metastases, ORR 79%, median PFS 14 months, median OS 37 months were reported with chrono-IFLO/cetuximab [
5].
Median PFS and OS values of MCRC patients treated with FIr-B/FOx were different in
KRAS wild-type and mutant patients, even if not significantly, while they were equivalent in the FOLFOXIRI plus BEV study [
3]. BEV addition to doublet IFL chemotherapy gave median PFS 13.5 and 9.3 months, median OS 27.7 and 19.9 months in
KRAS wild-type and mutant patients, respectively [
18,
21]. Significantly better prognosis was reported in
KRAS/BRAF wild-type patients compared with patients harboring mutations in the
KRAS or
BRAF genes (HR 0.51) [
18]. Direct comparison of OS between
KRAS wild-type and mutant MCRC patients treated with BEV-containing chemotherapy failed to significantly differentiate prognosis, as in the present study. Thus, intensive regimens adding BEV to triplet chemotherapy can further increase activity and efficacy in
KRAS wild-type and mutant patients. Randomized studies would be able to properly evaluate this.
The high activity of triplet chemotherapy plus BEV regimens correlated with increased resection rate of liver metastases and pathologic CR, particularly in L-L MCRC patients [
1,
3,
4,
6]. We recently reported that the clinical outcome of L-L compared to multiple metastatic disease was significantly improved up to median PFS 17 months and median OS 44 months [
6] due to the effectiveness of integrated FIr-B/FOx intensive treatment and secondary liver surgery. The present analysis confirms the significantly favorable prognosis of L-L compared to MM patients and show that
KRAS wild-type L-L patients, accounting for 20% of fit MCRC patients, could gain 100% overall activity with an integrated medical and surgical approach, due to performed liver metastasectomies and long-lasting cCRs; median PFS 21 months and OS 47 months. A significantly favorable prognosis was demonstrated in
KRAS wild-type L-L compared to O/MM patients, even if this represents a retrospective, exploratory analysis in a small cohort of MCRC patients. Using neoadjuvant cetuximab with either FOLFOX6 or FOLFIRI for unresectable colorectal liver metastases, metastasectomies were performed in 38% and 30% patients, respectively [
36]. Chrono-IFLO/cetuximab reported a 60% R0 resection rate in unresectable colorectal liver metastases, with ORR 79%, median PFS 14 months and median OS 37 months [
5]. Further prospective studies will properly address whether intensive medical treatments, such as FIr-B/FOx, and secondary liver surgery could represent the standard multidisciplinary strategy for
KRAS wild-type L-L MCRC patients. In
KRAS mutant patients, prevalently harboring c.35 G>A transversion (53.5%), integrated medical and surgical treatment failed to significantly increase PFS and OS in L-L compared to O/MM patients: median PFS was equivalent (11 months), in spite of 54% performed liver metastasectomies in L-L patients; median OS was 39 and 19 months, respectively. These data should be further evaluated in a larger cohort of MCRC patients. A proper multidisciplinary treatment strategy for
KRAS mutant patients, showing different aggressiveness [
37], sensitivity to medical treatment, and worse clinical behavior, is an unmet need.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
Conception and design: GB, ER. Provision of study materials of patients: GB, AD, GC. Collection and/or assembly of data: all authors. Data analysis and interpretation: GB, KC, ER. Manuscript writing: GB, ER. Final approval of manuscript: all authors.