RAS Status Research Articles

Utility of exome sequencing in routine care for metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) is a heterogenous disease and its prognosis depends on clinical features, such as tumor sidedness, and whether it is metachronous or synchronous. However, little is known about the overall genomic characterization of mCRC in these clinical subtypes. This single-center observational study included 77 patients with mCRC who underwent somatic and germline exome analysis during the first or second line of therapy in 2018. Somatic and germline variants were determined in addition to tumor mutational burden, ploidy, clonality, human leucocyte antigen typing, neoantigens, and mutational and copy number signatures. Variables associated with sidedness, synchronous status and RAS status were determined using Fisher's test; and variables associated with overall survival were determined using univariate Cox survival models. The present study successfully generated whole exome sequencing analysis in 77 mCRC cases. Among them, 50 were left- and rectal-sided, while 27 were right-sided. Furthermore, 27 were metachronous and 46 were RAS-mutated. The median OS was 3.75 years. It was observed that signature single nucleotide variation (SNV) 26, oncogenic alterations in receptor tyrosine kinase and nucleotide excision repair pathways were associated with tumor sidedness. SNV signature 3, Hedgehog signaling and mismatch repair pathways were associated with synchronous status. Phosphatidylinositol signaling system, ERK signaling and chromatin organization pathways were associated with RAS mutant status. In the whole cohort, metachronous metastasis was associated with improved survival. On gene variation, PTEN, PDGFRA, MYCN and SMAD4 were associated with poor prognosis, as was SNV signature 15. In conclusion, this study highlighted that structural and pathway genomic features are associated with sidedness, synchronous status, RAS status and overall survival and could be helpful to improve the stratification of patients with colorectal cancer.

Consensus molecular subtypes in metastatic colorectal cancer treated with sequential versus combined fluoropyrimidine, bevacizumab and irinotecan (XELAVIRI trial)

BackgroundThe XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy. Material and methodsGene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival. ResultsCMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33–0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29–0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41–0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20–0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) ConclusionsIn patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri. Trial registrationTrial registration ID (clinicaltrials.gov) NCT01249638.

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives.

Simple SummaryMetastatic colorectal cancer (mCRC) accounts for relevant cancer-related morbidity and mortality. Novel investigations have reshaped the molecular makeup of mCRC, emphasizing a high degree of heterogeneity that can be leveraged to establish a new concept of biomarker-guided therapy. In contrast to the old-fashioned, “one-size-fits-all” therapeutic approach, within a precision oncology approach, a deeper molecular selection is indeed felt to improve the efficacy of targeted systemic treatments. Here, we review available treatment options in patients with refractory mCRC, who have already received chemotherapy regimens containing fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents, and, when indicated, epidermal growth factor receptor inhibitors. In addition, we examine those molecular pathways now included among the most promising areas of clinical research that will eventually drive innovative and more individualized treatment strategies.Substantial improvements have characterized the systemic treatment of metastatic colorectal cancer (mCRC) over the past 20 years. Besides strong evidence that supports the use of RAS and BRAF status as prognostic and predictive indicators of disease and response, novel technologies have made possible the incorporation of emerging biomarkers for the management of mCRC. On one hand, the discovery of point mutations, amplifications, fusions, and gene expression profiles highlights the genomic and dynamic complexity of CRC. On the other, such discoveries are leading to newer biomarker-driven strategies that add to existing anti-epidermal growth factor receptor (EGFR) and anti-angiogenic approaches. In addition, the availability of a wide molecular profiling has relevant implications for patient prognosis and treatment benefits. Here, we will review the molecular underpinnings and clinical data supporting novel targeted treatments under development for refractory mCRC harboring BRAF mutations, KRAS G12C mutations, HER2 amplification, and less common molecular alterations, such as the re-arrangements of NTRK, ALK, and ROS1. Additionally, we will discuss novel strategies driving the rechallenge of EGFR antibodies and the incorporation of newer anti-angiogenic agents in the therapeutic armamentarium.

418P Upfront primary tumour resection (UPTR) and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

Retrospective studies and meta-analysis suggest that UPTR confers a survival benefit in patients with asymptomatic unresectable mCRC undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This study aimed to analyse the survival benefit of UPTR in the context of tumour location and mutational status in patients receiving chemotherapy and targeted therapy.

Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases

Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. To investigate the association of liver metastases with response to PD-1/PD-L1-targeting therapy in MSS metastatic colorectal cancer. This single-center retrospective cohort study evaluated clinical responses to PD-1- or PD-L1-targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1-targeting therapy. Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1-targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1-targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001). Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.

Development of a model to predict pathologic response to chemotherapy in patients with colorectal liver metastases.

Preoperative chemotherapy has widely been used in colorectal cancer liver metastasis (CRLM). Pathological response to chemotherapy is very important in evaluating tumor biology. However, there is still a lack of a non-invasive and accurate method to evaluate pathological response before surgery. We retrospectively analyzed the clinicopathologic data of patients with CRLM who underwent liver resection after preoperative chemotherapy between January 2006 and December 2018. Pathological responses were defined as minor when there are ≥50% remnant viable cells and as major when 0-49% remnant viable cells exist. A total of 482 patients were included and randomly divided into training (n=241) and validation (n=241) cohorts. The proportion of major pathologic response was similar between the two groups (51.5% and 48.5%). Multivariate analysis determined the disease-free interval (DFI), tumor size, tumor number, and RAS status as independent predictors of major pathologic response to preoperative chemotherapy. The nomogram incorporating these variables showed good concordance statistics in the training cohort (0.746, 95% CI: 0.685-0.807) and validation cohort (0.764, 95% CI: 0.704-0.823). In addition, the nomogram showed good applicability in patients with different characteristics. The established nomogram model performed well in predicting pathological response in patients with CRLM.

Prognostic Factors for Survival in Transverse Colon Cancers.

Transverse colon cancer (TCC) is a rare condition that accounts for 10% of all colon cancers. TCC was accepted more likely right-sided colon cancers. We aimed to investigate whether TCC differs from other colon tumors by using clinical, pathological, and molecular prognostic factors known to be important in colon cancer and if it differs in its own anatomical structure. We evaluated local and locally advanced TCC patients between 2007 and 2020years for demographics data, symptoms, treatment status, and histopathological and molecular features. Overall, 107 TCC patients were included in this study. According to the molecular data analysis of 44, 35, and 23 patients for MSI, RAS, and BRAF status, respectively, 7 (15.9%) were MSI-H, 13 (37.1%) were RAS mutant, and 11 (47.8%) had BRAF V600E mutation. The median follow-up time was 31.5months. Median disease-free survival (DFS) was 5.19months, and median OS was 88.3months for the whole study population. The tumor stage was the most significant prognostic factor for DFS and OS. Although BRAF mutation was not a significant marker for DFS, it was an independent prognostic marker for OS (HR 3.90 95% CI 1.42-10.7). There were no statistically significant differences between proximal two-thirds and distal one-third tumor location. TCC has molecular features and prognostic factors more likely RCC and no differences between proximal and distal sub-parts. BRAF V600E mutation status is an independent predictor of survival even in the early stages of TCC.

Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: a systematic review and meta-analysis

BackgroundApproximately 5.0–24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients.MethodsA detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS).ResultsTen studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28–1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14–2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01–1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I–III, 95% CI 1.03–1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20–1.67, P < 0.001), mucinous differentiation (OR = 2.23, 95% CI 1.85–2.70, P < 0.001) and rat sarcoma viral oncogene homolog (RAS) mutation status (OR = 2.13, 95% CI 1.37–3.34, P = 0.001). No connection was found with age, gender, tumor grade, microsatellite instability status and b-viral oncogene homolog B1 mutation status. Besides, publication bias was not observed in any study.ConclusionsThis meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastasis and mucinous differentiation. Our meta-analysis indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies are needed to confirm this conclusion. Since SMAD4 mutations are closely related to RAS mutations, their relationship warrants further investigation.

Combination therapy of bevacizumab with either S-1 and irinotecan or mFOLFOX6/CapeOX as first-line treatment of metastatic colorectal cancer (TRICOLORE): Exploratory analysis of RAS status and primary tumour location in a randomised, open-label, phase III, non-inferiority trial

AimThe TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. MethodsIn total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. ResultsWith a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72–1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71–1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48–0.96, P = 0.028). ConclusionS-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC. Trial registrationUMIN-CTR: 000007834.

Reevaluating the prognostic value of RAS mutation status in patients with resected liver metastases from colorectal cancer: A systematic review and meta-analysis.

Although the value of Rat Sarcoma Oncogene (RAS) mutation status in predicting long-term outcomes in patients with colorectal liver metastases (CRLM) is widely accepted, the magnitude of its impact has recently been challenged by three large cohort studies. The aim of this meta-analysis is to reevaluate the impact of RAS mutations on overall survival (OS) and disease-free survival (DFS) in patients who underwent curative-intent resection of CRLM. A comprehensive literature search was performed for studies reporting outcomes of patients undergoing curative-intent surgery stratified by RAS mutation status. Exclusion criteria were defined a priori. Subgroup analysis was performed to evaluate the effect of publication date, sample size, and KRAS vs any RAS mutation on overall outcomes. Ten studies incorporating 3115 patients with known RAS status were identified. Pooled results revealed significantly worse OS (Hazard Ratio 1.5, 95% CI 1.31-1.71) and DFS (Hazard Ratio 1.36, 95% CI 1.22-1.52) in RAS-mutated patients. Subgroup analyses revealed that studies including more than 300 patients or published after 2015 reported lower HR than their counterparts. The results of this meta-analysis suggest that the prognostic value of RAS mutation status in patients with CRLM has been previously overestimated.

P-173 Customisation of therapeutic strategy in metastatic colorectal cancer by use of liquid biopsies: Final results of an observational study

In metastatic colorectal cancer (mCRC), tumour RAS profiling informs therapeutic decisions regarding the addition of anti-epidermal growth factor receptor (EGFR) antibodies to chemotherapy. However, RAS status may change in the course of the disease and circulating tumour DNA (ctDNA) testing has emerged as a valuable tool for serial testing in oncology.

P-281 Low proliferation indexes in colorectal cancer in Tunisian patients: Association with rectal localization, mucinous histological type and stage

Colorectal cancer is the second most deadly cancer in the world. Since the response rate to chemotherapy is very low, the study of certain specific histological and prognostic parameters has become necessary to adapt the treatment to each patient. Although the anticancer drugs prescribed block cell proliferation, the frequency of proliferative tumors remains poorly studied. The most commonly used proliferation markers in the routine are mitotic index and Ki-67 index. The aims of this study were to assess proliferation indexes in order to estimate the number of patients likely to respond to chemotherapy and to evaluate them according to histological factors and RAS status.

Abstract 541: Liquid biopsy for molecular characterization and monitoring in patients with metastatic colorectal cancer

Abstract The use of liquid biopsy in the clinical management of colorectal cancer (CRC) patients is not yet a routine clinical practice, although it could give important information for tumor baseline characterization and for monitoring during treatment. In this retrospective exploratory study, we examined plasma-circulating tumor DNA (ctDNA) in a series of 27 metastatic CRC patients receiving chemotherapy plus bevacizumab as firstline treatment, both at baseline and at progression. All patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment: 70% of patients were RAS-mutated(16 KRAS, 3 NRAS),15% were BRAF mutated and 15% were RAS/BRAF wild-type. Detection of ctDNA mutations were performed using Oncomine™Colon cfDNA Assay on Ion GeneStudio™ S5 System (Thermofisher). All mutations observed in the tissue were identified also in the baseline ctDNA, excluding one BRAF mutated case that was not detected in the ctDNA. Additional mutations on TP53, APC, PIK3CA, FBXW7 were detected respectively in 11, 12, 3 and 2 cases. TP53 mutations were identified also in 3 RAS/BRAF wild-type cases. Baseline RAS/BRAF variant allele frequency (VAF) lower than 10% was found associated with longer progression free survival (PFS) (log-rank p-value=0.027) (Table 1). At progression, 80% of patients carried the same mutations identified at baseline, and 7 cases carried additional mutations of TP53. Predominantly mutations has a lower VAF at progression with respect to baseline, however RAS/BRAF VAF at progression was found not associated with PFS. In conclusion, we report a concordance-rate &amp;gt;96% between ctDNA and tissue demonstrating the high sensibility of liquid biopsy for detection of mutations in metastatic CRC. Thus, ctDNA could be useful for monitoring of minimal residual disease and tumor heterogeneity during therapeutic treatment. These data, if confirmed in a larger cohort, might support the use of liquid biopsy in the clinical management of CRC patients. Table 1.Relationships between RAS/BRAF mutation VAF and progression free survival during treatmentTimeConditionN. of casesMedian PFS (range), daysχ2p-valueBaselineVAF&amp;lt;10%11504 (244-843)4,8960,0269VAF&amp;gt;10%11373 (41-719)ProgressionVAF&amp;lt;10%14414 (110-763)0,32390,5693VAF&amp;gt;10%8412 (41-843) Citation Format: Milena Urbini, Giorgia Marisi, Alessandro Passardi, Chiara Molinari, Matteo Canale, Laura Matteucci, Gianluca Tedaldi, Giovanni Martinelli, Giovanni L. Frassineti, Ulivi Paola. Liquid biopsy for molecular characterization and monitoring in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 541.

PD-3 Impact of RAS status, prior targeted therapy, age, and gender on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer: Real-world data from the QoLiTrap study

The anti-angiogenic fusion protein aflibercept targets VEGF-A, VEGF-B, and PlGF. It is approved in combination with FOLFIRI for treatment of metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-containing regimen. We evaluated the influence of RAS status (RAS wild-type or RAS mutant), prior targeted therapy (prior anti-EGFR or prior anti-VEGF), age (≤70 years or >70 years) and gender on the effectiveness and safety of aflibercept plus FOLFIRI in daily practice.

The role of R0/R1vasc resection in the treatment of patients affected by marginal resectable colorectal liver metastases: A pairwise propensity score match analysis

Increasingly, patients with multiple colorectal liver metastases (CRLM) are surgically treated. R1par surgery remains one of the negative prognostic factors for overall survival (OS). According to our data on R1 in main intrahepatic vascular contact (MVC), we investigate the oncological outcome of patients with multiple bilobar disease with bilateral MVC (BC), compared to patients with unilateral MVC (UC) and patients with disease and no MVC (NC). This single-institution study included patients who underwent hepatectomy for multiple (≥ 4) bilobar CRLM lesions from 2004-2019. Three-hundred-fifty-five patients meet the inclusion criteria. One-hundred-thirty-two patients with R1par resection were excluded. Three groups were defined: NC, UC, BC. After pairwise propensity score match 145 patients were analyzed. No differences between groups were observed in the preoperative variables. Increased surgical time, hilar clamping, and blood loss were reported in the BC group. Postoperative minor morbidity, liver failure rate, overall and local recurrences were higher in the BC group. BC patients were more likely to be re-resected. Cumulative OS 3-5 years survival in NC, UC, BC were 54%-40%, 49%-35%, 57%-24% (p < 0.91). At multivariate analysis, factors influencing OS, were N status of the primitive lesions, RAS status, and repeated hepatectomy. Patients with BC and lesions ≥ 4 are generally considered unresectable or suitable for staged hepatectomy. This retrospective study shows that these patients can be submitted to the so called enhanced-one-staged hepatectomy with the same oncological results, however surgical complexity, postoperative minor morbidity and postoperative liver failure are increased.

NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?—Case series and review of the literature

Upfront KRAS and NRAS gene testing (‘RAS’) is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent ‘NeoRAS wild-type’ phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.

REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer

BackgroundPrevious clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge.MethodsThis trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360).DiscussionOur trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative.Trial registrationThe REMARRY study: UMIN, UMIN000036424. Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096. Registered date: October 1, 2019.

PCN18 Cetuximab Versus Bevacizumab in Metastatic Colorectal Cancer: A Comparative Effectiveness and Patient-Reported Outcomes Multicohort Study

Uncertainty exists regarding comparative effectiveness of cetuximab versus bevacizumab in metastatic colorectal cancer (mCRC), due to conflicting efficacy evidence of previous randomised clinical trials and the absence of Quality of Life (HRQoL) studies. We conducted a mainly retrospective head-to-head multi-cohort study comparing clinical outcomes from both antibodies, in which was nested a smaller prospective cohort study for measuring patient-reported outcomes (PROs). Retrospective cohorts were defined by treatment line, and subgroups by (K)RAS status and tumour sidedness. Among other effectiveness outcomes, we compared response rates, progression-free (PFS) and overall survival (OS). PROs were measured prospectively through EORTC disease-specific instruments. Methods and reporting followed STROBE guidelines and SISAQOL / SPIRIT-PRO recommendations. Between 2010 and 2018, 311 patients were included in overall analysis. 44 were further allocated to PROs nested cohorts. Except for (K)RAS mutation status, baseline characteristics were balanced across groups. In full analyses, PFS (first-line: HR=0.85; P=0.26; second-line: HR=1.16; P=0.51) and OS (first-line: HR=0.83; P=0.26; second-line: HR=0.88; P=0.58) were similar between treatment arms. In subgroup analyses (first-line), we found a survival difference favouring bevacizumab in right-sided tumours (PFS: HR=0.52; P=0.025; OS: HR=0.60; P=0.11), but not in left-sided or (K)RAS wild-type tumours. Response rates were higher for bevacizumab in patients bearing right-sided primaries and similar across other comparisons. During initial 12 weeks of treatment, a higher proportion of patients in cetuximab arm experienced clinically meaningful (≥10%) deterioration of HRQoL: 53.8% vs 18.2% at 6 weeks and 66.7% vs 12.5% at 12 weeks. We also observed increased scoring on symptom scales in cetuximab cohort. This study provides evidence suggesting bevacizumab and cetuximab-containing regimens result in similar clinical effectiveness outcomes in mCRC, except for right-sided tumours, where bevacizumab performed better. Cetuximab led to a progressive negative impact on HRQoL, when compared to baseline and bevacizumab. These findings should be further explored through randomised studies.

Examination of Micro Vascular Density on Metastatic Colorectal Cancer of RAS Mutant-Type as Anti Vegf Therapy Predictor

According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Colon Cancer Version 2.2019, mCRC patients with mutant type RAS were treated with anti-VEGF. However, the use of the targeting therapy still had inconsistent results. Neoangiogenesis studies had been used as a basis to assess the prognosis of mCRC. Microvascular density (MVD) had become the morphological gold standard to assess neovascularization in human tumors. This study proved the existence of low microvascular density (MVD) in mCRC patients with mutant type RAS status as a predictor of failure of anti-VEGF therapy. There were 29 patients at Dr. Soetomo Academic Hospital from 2015-2018 who had their RAS status checked and tested for microvascular density (MVD). The results of this study were analyzed using SPSS 23.0. In the Mutant-type of RAS group, this study examined microvascular density (MVD). 11 (73%) research subjects with high MVD scores and 4 (27%) research subjects had low MVD scores. Besides, 27% microvascular density (MVD) was low, in the mutant-type of RAS mCRC patient which could be a predictor factor for the failure of anti-VEGF therapy.

Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p &lt; 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.