FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

Personeni, Nicola; Rimassa, Lorenza; Verusio, Claudio; Barni, Sandro; Rubino, Luca; Bozzarelli, Silvia; Villa, Eugenio; Carnaghi, Carlo; Tronconi, Maria Chiara; Gerardi, Chiara; Galli, Francesca; Floriani, Irene; Destro, Annarita; Raschioni, Carlotta; Labianca, Roberto; Santoro, Armando

doi:10.1016/j.clcc.2015.02.006

Cited by 11 publications

(10 citation statements)

References 38 publications

(53 reference statements)

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“…Up to 75% of patients were found to have high PTEN‐negative tumors. This percentage is higher compared to that reported in other series . A possible explanation for this could be given by the heterogeneity between the different scoring systems used.…”

Section: Discussioncontrasting

confidence: 70%

“…In patients treated with anti-EGFR antibodies, some authors reported shorter PFS and OS that reached statistical significance when this variable was combined with PIK3CA mutations [31]. On the other hand, other authors did not find any association between PTEN protein expression and clinical outcomes [29,30]. The reason for these different results could be the small sample size of the studies, the heterogeneity of PTEN expression in primary tumor and metastatic sites and the evaluation of protein expression by IHC with different cutoff and threshold levels used for interpretation [33].…”

Section: Discussionmentioning

confidence: 97%

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KRAS mutation in lung metastases from colorectal cancer: prognostic implications

et al. 2015

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KRAS mutant colorectal cancer (CRC) patients develop lung and brain metastases more frequently than KRAS wild‐type (WT) counterpart. We retrospectively investigated the prognostic role of KRAS,BRAF, and PIK3CA (exon 20) mutations and loss of phosphatase and tensin homolog (PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC (mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty‐four percent of patients had KRAS WT lung metastases. PTEN loss‐of‐function was found in 75%. BRAF and PIK3CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival (OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression‐free survival (PFS) and lung disease‐free survival (LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status (OS Hazard ratio (HR) 2.17, 95% IC 1.19–3.96, P = 0.012) and lack of adjuvant chemotherapy (OS HR 0.10, 95% IC 0.01–0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy (LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 97%

KRAS mutation in lung metastases from colorectal cancer: prognostic implications

et al. 2015

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“…These data suggest that MET expression may be predictive of benefit across tumor types. The implications of the results in patients with PTEN‐Low tumors are unclear because recent studies in patients with colorectal cancer receiving cetuximab‐based therapy have yielded conflicting results regarding the influence of PTEN status on PFS or OS . However, a recent meta‐analysis suggested that nonfunctional PTEN predicts resistance to anti‐EGFR therapies such as cetixumab; theoretically, a MET inhibitor may overcome that resistance .…”

Section: Discussionmentioning

confidence: 99%

“…The implications of the results in patients with PTEN-Low tumors are unclear because recent studies in patients with colorectal cancer receiving cetuximab-based therapy have yielded conflicting results regarding the influence of PTEN status on PFS or OS. [45][46][47] However, a recent meta-analysis suggested that nonfunctional PTEN predicts resistance to anti-EGFR therapies such as cetixumab 48 ; theoretically, a MET inhibitor may overcome that resistance. 18,19,49 Indeed, clinical evidence from a phase 2 study in nonsmall cell lung cancer suggests that patients who progressed on erlotinib can achieve an objective response to subsequent treatment with erlotinib plus tivantinib.…”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

Eng

Bessudo

Hart

et al. 2016

Intl Journal of Cancer

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Cetuximab in combination with an irinotecan‐containing regimen is a standard treatment in patients with KRAS wild‐type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti‐EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open‐label 3 + 3, dose‐escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double‐blinded, placebo‐controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression‐free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m2 twice daily) with biweekly cetuximab (500 mg/m2) and irinotecan (180 mg/m2). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55–1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET‐High tumors by immunohistochemistry, PTEN‐Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib‐treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.

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“…We did, however, identify an association between a lack of PTEN protein expression and shorter time to progression in the first-line setting with chemotherapy plus anti-EGFR in RAS wild-type patients. Previous retrospective studies 34–37 showed that this association could well be linked to a prognostic effect of PTEN in this subset of patients 38,39 as opposed to a predictive value 40 .…”

Section: Discussionmentioning

confidence: 83%

Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer

Serna¹,

Ruiz-Pace

Cecchi³

et al. 2019

Sci Rep

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Protein biomarkers are widely used in cancer diagnosis, prognosis, and prediction of treatment response. Here we introduce the use of targeted multiplex proteomics (TMP) as a tool to simultaneously measure a panel of 54 proteins involved in oncogenic, tumour suppression, drug metabolism and resistance, in patients with metastatic colorectal cancer (mCRC). TMP provided valuable diagnostic information by unmasking an occult neuroendocrine differentiation and identifying a misclassified case based on abnormal proteins phenotype. No significant differences in protein levels between unpaired primary and metastatic samples were observed. Four proteins were found differentially expressed in KRAS-mutant as compared to wild-type tumours (overexpressed in mutant: KRAS, EGFR; overexpressed in wild-type: TOPO1, TOP2A). Survival analyses revealed the association between mesothelin expression and poor overall survival, whereas lack of PTEN protein expression associated with lower progression-free survival with anti-EGFR-based therapy in the first-line setting for patients with RAS wild-type tumour. Finally, outlier analysis identified putative targetable proteins in 65% of patients lacking a targetable genomic alteration. Our data show that TMP constitutes a promising, novel molecular prescreening tool in mCRC to identify protein expression alterations that may impact on patient outcomes and more precisely guide patient eligibility to clinical trials with novel targeted experimental therapies.

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FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

Cited by 11 publications

References 38 publications

KRAS mutation in lung metastases from colorectal cancer: prognostic implications

KRAS mutation in lung metastases from colorectal cancer: prognostic implications

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer

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