Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy

Vidal, Joana; Bellosillo, Beatríz; Vivas, C. Santos; García‐Alfonso, Pilar; Carrato, Alfredo; Cano, María Teresa; García‐Carbonero, Rocío; Élez, Elena; Losa, Ferrán; Massutí, Bartomeu; Valladares‐Ayerbes, Manuel; Vieitez, José María; Manzano, José Luís; Azuara, Daniel; Gállego, Javier; Pairet, Silvia; Capellà, Gabriel; Salazar, Ramón; Tabernero, Josep; Aranda, Enrique; Montagut, Clara

doi:10.1093/annonc/mdz005

Cited by 20 publications

(22 citation statements)

References 18 publications

(22 reference statements)

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“…32 A recent large multicenter retrospective analysis that compared standard-of-care RAS testing with NGS multigene assessment reported no improvement in the selection of patients for anti-EGFR therapy by lowering the threshold in tissue samples from 5% to 1% MAF. 33 As expected, in this study anti-EGFR treatment was significantly better in mCRC patients with KRAS/NRAS/BRAF/PIK3CA WT tumors. 33 Of note, in the CAPRI-GOIM study we found in 7/10 cases of low KRAS mutational load the presence of additional mutations in PIK3CA, TP53, BRAF, ERBB2, FGFR3, and/or FBXW7 genes, which could equally contribute to anti-EGFR cancer cell resistance.…”

Section: Tumor Heterogeneity For Ras Braf and Pi3kca Mutations And supporting

confidence: 82%

“…33 As expected, in this study anti-EGFR treatment was significantly better in mCRC patients with KRAS/NRAS/BRAF/PIK3CA WT tumors. 33 Of note, in the CAPRI-GOIM study we found in 7/10 cases of low KRAS mutational load the presence of additional mutations in PIK3CA, TP53, BRAF, ERBB2, FGFR3, and/or FBXW7 genes, which could equally contribute to anti-EGFR cancer cell resistance. These findings highlight the existence of a subgroup of mCRC with a mixed genotype, which is characterized by different potentially driver mutations that affect the EGFR pathway.…”

Section: Tumor Heterogeneity For Ras Braf and Pi3kca Mutations And supporting

confidence: 82%

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Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

et al. 2020

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Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

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Section: Tumor Heterogeneity For Ras Braf and Pi3kca Mutations And supporting

confidence: 82%

Section: Tumor Heterogeneity For Ras Braf and Pi3kca Mutations And supporting

confidence: 82%

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

et al. 2020

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“…In particular, digital PCR shows the highest sensitivity, up to a limit of detection of 0.001% for digital droplet PCR [8,9,10] and about 0.1–1% for conventional quantitative PCR [11,12,13]. However, recent reports show how the highest sensitivity of the technique does not reflect a better prediction of the response to anti-EGFR agents, as it may include rare KRAS mutant subclones that do not have clinical significance [14,15,16]. The concordance between tissue and liquid biopsies in mCRC, on the other hand, is strictly related not only to the technology used for tissue and plasma analyses, but also to some clinical parameters of the patients, such as the presence or absence of liver metastases [13,17,18,19].…”

Section: Introductionmentioning

confidence: 99%

Clinical Practice Use of Liquid Biopsy to Identify RAS/BRAF Mutations in Patients with Metastatic Colorectal Cancer (mCRC): A Single Institution Experience

Vitiello

Falco

Giunta

et al. 2019

Cancers

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Tumor heterogeneity represents a possible cause of error in detecting predictive genetic alterations on tumor tissue and can be overcome by testing alterations in circulating tumor DNA (ctDNA) using liquid biopsy. We assessed 72 consecutive patients with a diagnosis of metastatic colorectal cancer (mCRC) using Idylla™ Biocartis, a fully automated platform that evaluates the most frequent mutations of KRAS, NRAS and BRAF genes. We correlated the results of liquid biopsy and standard tissue-based next generation sequencing (NGS) analyses to patient clinical features. The overall agreement was 81.94%. Concordance was 85.71% and 96.15% in treatment-naïve patients and in the patient subgroup with liver metastases, respectively. In liver metastases positive, treatment-naïve patients, sensitivity, specificity and positive predictive value (PPV) were 92.31%, 100% and 100%, respectively. Circulating mutational fraction (CMF) was significantly higher in patients with liver metastases and high carcinoembryonic antigen (CEA) levels. In a subgroup of patients pre-treated with anti-Epidermal Growth Factor Receptor (EGFR) agents, emerging KRAS mutations were evidenced in 33% of cases. Testing RAS/BRAF mutations on plasma using the Idylla™ Biocartis platform is feasible and reliable in mCRC patients in clinical practice.

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“…A major point of discussion is whether the optimal threshold of the RAS mutant allele fraction to identify patients likely to benefit from anti-EGFR drugs should be 1% or 5%. We used a threshold of 5% as it has been reported that reducing the threshold to 1% does not improve outcomes [ 36 , 37 ]. We found one sensitive patient (P28) who harbored the A146V KRAS mutation at 5%.…”

Section: Discussionmentioning

confidence: 99%

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Riera

Rodríguez-Santiago

Lasa

et al. 2020

Cancers

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Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

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Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy

Abstract: Conclusions: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

Cited by 20 publications

References 18 publications

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

Clinical Practice Use of Liquid Biopsy to Identify RAS/BRAF Mutations in Patients with Metastatic Colorectal Cancer (mCRC): A Single Institution Experience

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

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