Dataset Information

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer.

ABSTRACT:

Background

Limited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.

Methods

We conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.

Results

In comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.

Conclusions

Mucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.

SUBMITTER: Wang C

PROVIDER: S-EPMC8895744 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer.

Wang Chongkai C Sandhu Jaideep J Fakih Marwan M

The oncologist 20220301 2

<h4>Background</h4>Limited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.<h4>Methods</h4>We conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.<h4>Results</h4>In comparison to nonmucinous population (n = 98), mucinous histology (n = 20) wa ...[more]

PMID: 35641204

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Project description:BackgroundDoublets plus anti-epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI-bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI-bevacizumab versus doublets plus anti-EGFRs is available in left-sided RAS/BRAF wild-type mCRC.Materials and methodsWe selected patients with left-sided RAS and BRAF wild-type mCRC treated with first-line FOLFOX-panitumumab or FOLFOXIRI-bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score-based analysis was performed to compare FOLFOXIRI-bevacizumab with FOLFOX-panitumumab.ResultsA total of 185 patients received FOLFOX-panitumumab and 132 received FOLFOXIRI-bevacizumab. Median progression-free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI-bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX-panitumumab group (propensity score-adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64-1.04; p = .11; propensity score-adjusted HR for OS, 0.80; 95% CI, 0.59-1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI-bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI-bevacizumab and FOLFOX-panitumumab are valuable treatment options in left-sided RAS/BRAF wild-type mCRC.Implications for practiceA propensity score-based analysis of five trials was performed to compare FOLFOX-panitumumab versus FOLFOXIRI-bevacizumab in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI-bevacizumab achieved numerically superior survival outcomes versus FOLFOX-panitumumab. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group. These observations suggest that although doublet chemotherapy plus anti-EGFRs remains the preferred treatment in patients with left-sided RAS/BRAF wild-type mCRC, FOLFOXIRI-bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients' preference and potential impact on quality of life.

Project description:Colorectal cancer (CRC) patients frequently develop liver metastases. Different treatment strategies are available according to the timing of appearance, the burden of metastatic disease, and the performance status of the patient. Systemic treatment (ST) represents the cornerstone of metastatic disease management. However, in select cases, combined ST and surgical resection can lead to remarkable survival outcomes. In the present multicentric cohort study, we explored the efficacy of a conversion strategy in a selected population of left-sided RAS/BRAF wild-type CRC patients with liver-limited metastatic disease.MethodsThe primary endpoint was to compare survival outcomes of patients undergoing ST not leading to surgery, liver resection after conversion ST, and hepatic resection with perioperative ST. Furthermore, we explored survival outcomes depending on whether the case was discussed within a multidisciplinary team.ResultsBetween 2012 and 2020, data from 690 patients respecting the inclusion criteria were collected. Among these, 272 patients were deemed eligible for the analysis. The conversion rate was 24.1% of cases. Fifty-six (20.6%) patients undergoing surgical resection after induction treatment (i.e., ultimately resectable) had a significant survival advantage compared to those receiving systemic treatment not leading to surgery (176 pts, 64.7%) (5-year OS 60.8% and 11.7%, respectively, Log Rank test p < 0.001; HR = 0.273; 95% CI: 0.16-0.46; p < 0.001; 5-year PFS 22.2% and 6.3%, respectively, Log Rank test p < 0.001; HR = 0.447; 95% CI: 0.32-0.63; p < 0.001). There was no difference in survival between ultimately resectable patients and those who had liver resection with perioperative systemic treatment (potentially resectable-40 pts) (5-year OS 71.1%, Log Rank test p = 0.311. HR = 0.671; 95% CI: 0.31-1.46; p = 0.314; 5-year PFS 25.7%, Log Rank test p = 0.305. HR = 0.782; 95% CI: 0.49-1.25; p = 0.306).ConclusionsIn our selected population of left-sided RAS/BRAF wild-type colorectal cancer patients with liver-limited disease, a conversion strategy was confirmed to provide a survival benefit. Patients not deemed surgical candidates at the time of diagnosis and patients judged resectable with perioperative systemic treatment have similar survival outcomes.

Project description:BackgroundFew data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available.MethodsThis multicenter, retrospective study aimed at evaluating clinicians' attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR).ResultsAt the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9-35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3-17.7, 86 events), 13.0 (95%CI = 11.4-14.5, 56 events), 14.0 (95%CI = 8.1-20.0, 8 events), and 10.1 months (95%CI = 9.0-11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5-47.7, 43 events), 36.1 (95%CI = 31.6-40.7, 36 events), 39.5 (95%CI = 28.2-50.8, 4 events), and 25.1 months (95%CI = 22.6-27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44-0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51-0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38-0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51-0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts.ConclusionAmong the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a "real-life" setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

Project description:BackgroundAnti-epidermal growth factor receptor (EGFR) therapies are important targeted agents in the treatment of metastatic colorectal cancer (CRC). However, clinical benefit is limited to patients with left-sided primary tumors and RAS wild-type (WT) disease. In right-sided chemo-refractory settings, response to anti-EGFR therapy has not been reported to date.Case descriptionWe present a case of a 70-year-old man with metachronous metastatic ascending colon adenocarcinoma who experienced an exceptional response to FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus panitumumab after failing multiple lines of therapy. He was initially diagnosed with stage IIIB (pT4aN1M0) disease and underwent hemicolectomy followed by adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin). Nine months after completion of adjuvant therapy, disease recurred in the liver, peritoneum, and mesenteric lymph nodes. Subsequent treatments included FOLFIRI plus bevacizumab and FOLFOX with eventual progression. Tumor genomic profiling revealed RAS/RAF WT disease, and in the absence of anti-EGFR therapy resistance mutations, the patient was offered treatment with FOLFIRI plus panitumumab. He achieved immediate palliation of his abdominal pain after one cycle, followed by normalization of his tumor markers and significant tumor regression of his hepatic, peritoneal, lung, and distant lymph node metastases within four cycles.ConclusionsTreatment options for right-sided RAS-WT metastatic CRC are limited, particularly after progression on standard chemotherapies. While anti-EGFR antibodies have demonstrated detrimental survival impact in the first-line setting for right-sided CRC, their performance in later lines is less well-characterized. This case challenges the notion of right-sided disease as uniformly resistant to EGFR inhibition and highlights the need for additional biomarker studies to identify the subset of right-sided CRC that may benefit from EGFR targeted strategies. Emerging evidence suggests that more stringent genomic criteria for EGFR resistance, beyond RAS mutation status alone, may refine patient selection for benefit from anti-EGFR therapies.

Project description:BackgroundThe efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis.MethodsRCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3.ResultsThe results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients.ConclusionSo these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.

Project description:PurposeSeveral uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations.Materials and methodsA prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included NTRKs, ERBB3, NF1, MAP2K1/2/4, AKT2 pathogenic mutations; PTEN/NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/BRAF wild-type, PRESSING-negative, and microsatellite stable.ResultsAmong 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% v 13%; P = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes.ConclusionNegative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable mCRC.

Dataset Information

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer.

Background

Methods

Results

Conclusions

Publications

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer.

Similar Datasets

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