<i>PIK3CA</i> Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer

Xu, Jian; Wang, Yan; Wang, Youliang; Liu, Tao; Ni, Ming; Li, Man-Sheng; Li, Lin; Ge, Fei‐Jiao; Gong, Chun; Gu, Jun-Yan; Jia, Ru; Wang, He-Fei; Chen, Yu Ling; Liu, Rongrui; Zhao, Chuanhua; Tan, Zhao-Li; Jin, Yang; Zhu, Yunping; Ogino, Shuji; Qian, Zhi Rong

doi:10.1158/1078-0432.ccr-16-2738

Cited by 71 publications

(63 citation statements)

References 52 publications

(52 reference statements)

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“…In addition to mutations in RAS , mutations in BRAF and PIK3CA can induce constitutive activation of the EGFR and subsequent intracellular signaling, ultimately leading to drug resistance . Several studies have detected these mutations in CTC and ctDNA isolated from patients with CRC . We also detected genomic alterations in KRAS , NRAS , and PIK3CA in CTC and ctDNA using targeted NGS in patients resistant to anti–EGFR therapy, as described in previous reports.…”

Section: Discussionmentioning

confidence: 65%

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Onidani

Shoji²,

Kakizaki³

et al. 2019

Cancer Science

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Liquid biopsy of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) is gaining attention as a method for real‐time monitoring in cancer patients. Conventional methods based upon epithelial cell adhesion molecule (EpCAM) expression have a risk of missing the most aggressive CTC subpopulations due to epithelial‐mesenchymal transition and may, thus, underestimate the total number of actual CTC present in the bloodstream. Techniques utilizing a label‐free inertial microfluidics approach (LFIMA) enable efficient capture of CTC without the need for EpCAM expression. In this study, we optimized a method for analyzing genetic alterations using next‐generation sequencing (NGS) of extracted ctDNA and CTC enriched using an LFIMA as a first‐phase examination of 30 patients with head and neck cancer, esophageal cancer, gastric cancer and colorectal cancer (CRC). Seven patients with advanced CRC were enrolled in the second‐phase examination to monitor the emergence of alterations occurring during treatment with epidermal growth factor receptor (EGFR)‐specific antibodies. Using LFIMA, we effectively captured CTC (median number of CTC, 14.5 cells/mL) from several types of cancer and detected missense mutations via NGS of CTC and ctDNA. We also detected time‐dependent genetic alterations that appeared during anti–EGFR therapy in CTC and ctDNA from CRC patients. The results of NGS analyses indicated that alterations in the genomic profile revealed by the liquid biopsy could be expanded by using a combination of assays with CTC and ctDNA. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (ID: UMIN000014095).

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Section: Discussionmentioning

confidence: 65%

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Onidani

Shoji²,

Kakizaki³

et al. 2019

Cancer Science

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“…Those studies used ddPCR (28), BEAMing (29), or NGS based on previously identified tumor mutations (10,12). Unfortunately, monitoring studies using NGS, especially for mutations not restricted to those previously identified in tumor tissue, are scarce (18,20). Our results demonstrate that using NGS-based ctDNA detection for monitoring mCRC patients' treatment outcome is feasible.…”

Section: Discussionmentioning

confidence: 84%

“…Panels using 54 to 70 genes cover about 80% of cases (15,16), but such an approach may be rather expensive for routine clinical monitoring. Unfortunately, the number of studies utilizing NGS gene panels of different size in colorectal cancer patients is limited (13,(17)(18)(19)(20). Furthermore, the prognostic value of ctDNA in metastatic colorectal cancer (mCRC) is not yet widely established, although several studies indicate its usefulness (10,21).…”

Section: Introductionmentioning

confidence: 99%

Targeted Sequencing of Circulating Tumor DNA to Monitor Genetic Variants and Therapeutic Response in Metastatic Colorectal Cancer

Hsu

Lapke

Wang

et al. 2018

Molecular Cancer Therapeutics

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Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker; however, ctDNA as a marker for mCRC patients is not well established, and there is still no consensus about how to utilize it most cost-effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients. We performed next-generation sequencing (NGS) by using a 12-gene panel to identify genetic variants in 136 tumor tissue and ctDNA samples from 32 mCRC patients. Genetic variants were detected in approximately 70% of samples, and there was a high concordance (85%) between tumor tissue and plasma ctDNA. We observed ctDNA changes in 18 follow-up patients, including the emergence of new variants. Changes in ctDNA levels significantly correlated with tumor shrinkage ( = 0.041), and patients with a ctDNA decrease >80% after treatment had a longer progression-free survival compared with patients with a ctDNA decrease of <80% (HR, 0.22; = 0.015). The objective response rate among patients with a ctDNA decrease of>80% was better than those with a ctDNA decrease <80% (OR, 0.026; = 0.007). In conclusion, this study demonstrates that monitoring of genetic ctDNA variants can serve as a valuable biomarker for therapeutic efficacy in mCRC patients, and that using a moderate-sized 12-gene NGS panel may be suitable for such clinical monitoring..

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“…Although we did not identify any BRAF or PIK3CA mutation in analyzed samples, other mechanisms of acquired resistance to anti-EGFR monoclonal antibodies may occur or co-occur with RAS mutations and have been identified in liquid biopsy samples from patients with disease progression. 5,6,9,11,[34][35][36] However, despite intriguing preliminary proof-ofconcept evidence about the potential role of liquid biopsy in driving therapeutic choices, the translation of these findings from the bench to the bedside will definitely need robust confirmation from biomarker-driven clinical trials. A further step forward on this route will be marked by the currently ongoing CHRONOS (Phase II Trial of Rechallenge With Panitumumab Driven by RAS Clonal-Mediated Dynamic of Resistance) study (NCT03227926), in which patients eligible for anti-EGFR rechallenge are eligible only if a decrease of at least 50% in the fractional abundance of RAS mutations in ctDNA is evident at the time of rechallenge when compared with the time of progression to the first-line anti-EGFRcontaining therapy.…”

Section: Discussionmentioning

confidence: 99%

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

et al. 2019

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IMPORTANCE Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA). OBJECTIVE To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan-and cetuximab-based therapy. DESIGN, SETTING, AND PARTICIPANTS Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan-and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin-and bevacizumab-based treatment.INTERVENTIONS Biweekly cetuximab, 500 mg/m 2 , plus irinotecan, 180 mg/m 2 . MAIN OUTCOMES AND MEASURES Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA. RESULTS Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03).CONCLUSIONS AND RELEVANCE This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan-and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02296203A, Hazard ratio, 0.44 (95% CI, 0.18-0.98; P = .03). B, Hazard ratio, 0.58 (95% CI, 0.22-1.52; P = .24). Research Original InvestigationRechallenge for Patients With RAS and BRAF Wild-Type mCRC With Resistance to Cetuximab and Irinotecan Additional Contributions: We are grateful to all participating patients, their fa...

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PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer

Cited by 71 publications

References 52 publications

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Targeted Sequencing of Circulating Tumor DNA to Monitor Genetic Variants and Therapeutic Response in Metastatic Colorectal Cancer

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

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