New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?

Bronte, Giuseppe; Silvestris, Nicola; Castiglia, Marta; Galvano, Antonio; Passiglia, Francesco; Sortino, Giuseppe; Cicero, Giuseppe; Rolfo, Christian; Peeters, Marc; Bazan, Viviana; Fanale, Daniele; Giordano, Antonio; Russo, Antonio

doi:10.18632/oncotarget.4959

Cited by 82 publications

(58 citation statements)

References 121 publications

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“…In almost all the cases, these mutations were clinically actionable, meaning that they provided information about tumor sensitivity or resistance to approved or investigational targeted therapies. When we took into consideration only the spatial heterogeneity ("liquid" category), we again found a very high frequency of clinically actionable variants (96%), most of them either related to approved targeted therapies -for example KRAS mutations in colorectal cancer are associated with resistance to anti-EGFR antibodies [11] , and MAP2K1 mutations in non-small cell lung cancer are related to sensitivity to MEK inhibitors [15] -or to actively recruiting trials of targeted therapies, such as NCI-MATCH (NCT02465060). This emphasizes that the addition of ctDNA profiling to the analysis of solid biopsies, the current gold standard for tumor molecular characterization, can provide valuable extra information for oncologists, either for the prescription of an approved treatment or for enrolling them in relevant clinical trials.…”

Section: Discussionmentioning

confidence: 88%

“…In fact, the percentage of "shared" mutations markedly decreased when the time space of the collection dates increased. Resistance to anti-EGFR antibodies [11] PIK3CA 1 Resistance to anti-EGFR antibodies [12] Resistance to KIT/PDGFRA-tyrosine kinase inhibitors [13] NSCLC EGFR 1 Resistance to EGFR-tyrosine kinase inhibitors [14] GNAS This temporal heterogeneity provides interesting information about how the subclonal heterogeneity of a tumor evolves over the course of treatment, with some clones persisting or disappearing while new clones appear [18] . Note that this temporal analysis might not always provide useful information about the current treatments that would be of clinical benefit to the patient, as the current molecular status of the tumor is the critical factor in therapy personalization.…”

Section: Discussionmentioning

confidence: 99%

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The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

Finzel¹,

Sadik²,

Ghitti³

et al. 2018

JCMT

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Aim: To investigate if the genetic information provided by sequencing of both solid and liquid biopsies can shed light on tumor heterogeneity, and to understand the clinical usefulness of adding blood profiling to standard tissue analysis in cancer care. Methods:Data from 351 patients with stage IV solid tumors for whom molecular profiling of their solid and liquid biopsies was available were studied, with a focus on the discrepant molecular information found between tissue and blood samples. Results:In 86% of patients, solid and liquid biopsies provided different molecular information. Discrepant gene mutations with a functional impact on the corresponding protein were studied in detail. In 97% of cases, these additional mutations provided clinical value, mainly predicting sensitivity or resistance to targeted therapies. Specifically, 42% of the mutations found only in the liquid biopsy were directly predictive of approved therapies (80% targeted therapies), while 54% were inclusion criteria for molecularly-matched trials. Conclusion:This study suggests that the addition of blood profiling should be considered in routine clinical oncology, especially for patients with metastatic disease where integrated analysis of solid and liquid biopsies provides a more complete characterization of tumor heterogeneity and provides valuable clinical information for patient treatment.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

Finzel¹,

Sadik²,

Ghitti³

et al. 2018

JCMT

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“…CastPCR may be performed to detect certain mutant alleles and is cost-effective (30,(34)(35)(36)(37). Compared with ARMS, the most commonly used method in clinical practice in China, CastPCR has improved sensitivity and specificity owing to its oligonucleotide blocker that suppresses the wild-type allele, which does not exist in ARMS (28). Previous studies have demonstrated this in multiple types of malignant tumor (22,38,39).…”

Section: Discussionmentioning

confidence: 99%

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

et al. 2017

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Abstract. Epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) expressing sensitive EGFR-mutants. Other drugs target different driver mutants, including the serine/threonine-protein kinase B-raf (BRAF) inhibitor dabrafenib, which has exhibited promising efficacy for treating patients with metastatic BRAF-mutated NSCLC. Therefore, identifying patients carrying mutations that may be treated using targeted therapies is important. However, the methods of molecular detection presently applied in clinical practice, particularly detection of BRAF in NSCLC patients, require further investigation. Therefore, more sensitive and economic methods are required. The present study applied the competitive allele-specific TaqMan polymerase chain reaction (CastPCR) technology to the molecular detection of EGFR (del2235-2249, del2236-2250, T790M, L858R) and BRAF (V600E, G469A, D594G) mutations in 144 treatment-naive patients with lung adenocarcinoma, and analyzed the association between the mutation rates and patients' clinicopathological features. 51.4% (74/144) cases were identified harboring EGFR mutations. A total of 40.3% (58/144) patients carried sensitizing mutations (exon 19 deletion or L858R) and 14.6% (21/144) carried T790M mutations. 6.9% (10/144) mutation-positive patients were double-mutated. Total EGFR mutation rate was significantly increased in female compared with that of males (60.9 vs. 43.8%, P<0.05), in non-smokers compared with that of smokers (62.8 vs. 34.5%, P<0.05). In total, 8.3% (12/144) patients were identified with BRAF mutations. 16.7% were V600E (2/12) and 83.3% (10/12) were non-V600E mutants. Among the 10 non-V600E mutations, D594G accounted for 90.0% (9/10) and G469A accounted for 10.0% (1/10). Statistical analysis demonstrated that the BRAF mutation rate was not associated with any of the following clinicopathological features: Sex, age, smoking history, clinical stages, distant metastasis, differentiation degree, tumor size and regional lymph node metastasis (P≥0.05). CastPCR technology is a robust method with high sensitivity for the molecular detection of EGFR and BRAF mutations in clinical formalin-fixed paraffin-embedded samples.

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“…However, a large number of patients did not respond to this treatment, or even developed resistance [18, 19]. In addition, several problems are associated with antibodies treatment, including high cost, short half-life, and adverse events developed from toxicity [4–6].…”

Section: Discussionmentioning

confidence: 99%

Induction of anti-EGFR immune response with mimotopes identified from a phage display peptide library by panitumumab

Wang

Cui

et al. 2016

Oncotarget

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The epidermal growth factor receptor (EGFR) is overexpressed in several epithelial tumors. Anti-EGFR humanized monoclonal antibodies, cetuximab and panitumumab, in combination with chemotherapy have improved the prognosis for patients with wild-type RAS tumors. To identify mimotopes of EGFR and develop mimotope-based EGFR vaccines, we screened a phage display peptide library with panitumumab. Two EGFR mimotopes P19 and P26, which could be recognized by panitumumab specifically, were isolated. To enhance the immune responses, we generated recombinant proteins of P19 or P26 fused to a heat-shock cognate protein 70 (Hsc70), and evaluated the efficacy of Hsc70-P19 and Hsc70-P26 as vaccines in vivo. Immunization with Hsc70-P19 or Hsc70-P26 fusion protein stimulated the immune system to produce specific antibodies against peptides as well as EGFR. Moreover, antibodies elicited against mimotopes could induce antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and inhibit the proliferation of EGFR-overexpressing A431 cells. Treatment with Hsc70-P19 and Hsc70-P26 significantly reduced tumor growth in BALB/c transplantable lung cancer models. Although there was no sequence homology between the phage-derived peptides and EGFR by alignments, both peptides mimic the conformational structure of EGFR binding to panitumumab. In conclusion, the mimotopes we identified from phage display peptide library could be promising candidate vaccines for active anti-EGFR immunotherapy against cancers.

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New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?

Cited by 82 publications

References 121 publications

The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

Induction of anti-EGFR immune response with mimotopes identified from a phage display peptide library by panitumumab

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