Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15527-e15527
Author(s):  
Ting Xu ◽  
Xicheng Wang ◽  
Qi Changsong ◽  
Zhenghang Wang ◽  
Jian Li ◽  
...  
Keyword(s):  
Disease Progression ◽  
Signaling Pathway ◽  
Clinical Decision Making ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Plasma Samples ◽  
Braf Inhibitors ◽  
Braf Mutations

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.

scholarly journals BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS

2019 ◽  
Vol 5 (8) ◽  
pp. eaav8463 ◽  
Author(s):  
Ruth Röck ◽  
Johanna E. Mayrhofer ◽  
Omar Torres-Quesada ◽  
Florian Enzler ◽  
Andrea Raffeiner ◽  
...  
Keyword(s):  
Resistance Mechanisms ◽  
Tumor Formation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Drug Induced ◽  
Kinase Activation ◽  
Binding Domains ◽  
Intramolecular Communication ◽  
Sequential Formation

Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation–containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.

Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms

2020 ◽  
Vol 20 (12) ◽  
pp. 1415-1430 ◽  
Author(s):  
Qing-Shan Li ◽  
Bang-Nian Shen ◽  
Hua-Jian Xu ◽  
Ban-Feng Ruan
Keyword(s):  
Treatment Strategies ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Therapeutic Effects ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Clinical Benefits ◽  
Melanoma Patients ◽  
Inhibitor Resistance ◽  
Braf Mutant

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

scholarly journals Molecular targeted therapy of BRAF-mutant colorectal cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591985649 ◽  
Author(s):  
Michel Ducreux ◽  
Ali Chamseddine ◽  
Pierre Laurent-Puig ◽  
Cristina Smolenschi ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Line Treatment ◽  
Second Line ◽  
Braf Inhibitors ◽  
First Line ◽  
Braf Mutations

Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.

scholarly journals Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Bilgen Gençler ◽  
Müzeyyen Gönül
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Case Reports ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Cutaneous Side Effects ◽  
Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

scholarly journals Rapid BRAF mutation detection in melanoma patients by immunohistochemistry

2017 ◽  
Vol 4 (1) ◽  
pp. 1-5
Author(s):  
László Fülöp ◽  
Katalin Götzer ◽  
Erzsébet Csernák ◽  
Danyil Szergejevics Kuznyecov ◽  
Erika Tóth
Keyword(s):  
Braf Inhibitor ◽  
Pcr Amplification ◽  
Diagnostic Algorithm ◽  
Braf V600e ◽  
Wild Type ◽  
Braf Gene ◽  
Braf Mutations ◽  
Activating Mutation ◽  
Melanoma Patients ◽  
Braf V600 Mutation

The V600E mutation is the most common (~90%) activating mutation of the BRAF gene. BRAF mutations have been frequently investigated in melanoma, colorectal cancer and papillary thyroid carcinoma. The importance of the detection of BRAF mutations has been rising by the routine use of Braf inhibitor therapy. We evaluated the usefulness of the BRAF V600E mutation-specific monoclonal antibody (VE1) in metastatic melanoma patients. To confirm the results of immunohistochemistry (IHC), we used COBAS 4800 BRAF V600 mutation test and PCR amplification followed by Sanger sequencing.36 of 105 patients have wild-type BRAF gene, 64 have V600E mutation and 5 of 105 have V600K mutation. Predicting the mutation only by IHC using VE1 antibody, all 58 positively scored specimen were V600E mutant. The V600K, the wild-type patients and 7 patients from the V600E mutant group scored as negative. Thus the specificity is 100% and the positive predictive value is 1 of the IHC method. After processing our data we could establish a cheaper diagnostic algorithm for rapid detection ofBRAF mutation.

BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3619-TPS3619
Author(s):  
Scott Kopetz ◽  
Axel Grothey ◽  
Rona Yaeger ◽  
Fortunato Ciardiello ◽  
Jayesh Desai ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Egfr Inhibitor ◽  
Braf Mutations ◽  
Open Label ◽  
Phase 3 ◽  
Previously Treated

TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAFV600E mCRC (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

CA184-240: A single-arm, open-label phase II study of vemurafenib followed by ipilimumab in patients with BRAF V600-mutated advanced melanoma (AM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS9103-TPS9103
Author(s):  
F. Stephen Hodi ◽  
Asim Amin ◽  
Yvonne M. Saenger ◽  
Gregory K. Pennock ◽  
Troy H. Guthrie ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Guidelines ◽  
Cytotoxic T Lymphocyte ◽  
Human Monoclonal Antibody ◽  
Resistance Mechanisms ◽  
Braf V600e ◽  
Phase Iii ◽  
Open Label ◽  
Ecog Ps ◽  
Unacceptable Toxicity

TPS9103 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 expressed on T cells, and vemurafenib (Vem), a small molecule inhibitor of BRAF V600-mutated kinase, are both approved treatments for AM. Ipi has shown improved overall survival (OS) in two randomized phase III trials of patients with previously treated (3 mg/kg monotherapy) and previously untreated (10 mg/kg plus dacarbazine) AM. Vem has shown improved OS in a randomized phase III trial of patients that harbor the BRAF V600E mutation. The most common drug-related adverse events (AEs) with Ipi monotherapy were immune-related GI tract and skin toxicities, which were generally manageable using treatment guidelines. The most common AEs with Vem were arthralgia, rash, and fatigue. Vem can induce rapid and substantial responses, and resistance mechanisms are a focus of current investigation. This study will evaluate the safety of Vem lead-in followed by Ipi (prior to resistance) in patients with BRAF V600-mutated AM. Methods: An estimated 45 patients will be enrolled. Eligible patients include those ≥18 years old with previously untreated AM, a BRAF V600 mutation, and an ECOG PS of 0 or 1. Major exclusion criteria are primary ocular melanoma, active brain metastases, and autoimmune disease. Patients will initially receive Vem for 6 weeks (960 mg twice daily). After a washout period of 3-10 days (per protocol), patients will be initiated on Ipi at 10 mg/kg (every 3 wk for 4 doses, then once every 12 wk beginning at week 24, until disease progression or unacceptable toxicity). Vem will be restarted at the time of disease progression on Ipi (no minimum time to restart) or unacceptable toxicity on Ipi (restart minimum of 1 mo after the last dose of Ipi). Vem will be restarted at the last dose level tolerated at the end of the lead-in phase. Patients will be followed every 12 weeks for toxicity and/or disease progression, and subsequently will be followed every 12 weeks for survival. The objectives of this study are to estimate the incidence of grade 3-4 drug-related AEs. Exploratory objectives include the evaluation of efficacy (OS). Clinical trial information: NCT01673854.

Outcome and prognostic factors in BRAF mutation positive metastatic melanoma treated with a BRAF inhibitor: A population-based study in British Columbia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20045-e20045
Author(s):  
Joanna Vergidis ◽  
Richard John Klasa ◽  
Youwen Zhou ◽  
Elena Moon ◽  
Debbie Jepson ◽  
...  
Keyword(s):  
British Columbia ◽  
Braf Mutation ◽  
Mutation Screening ◽  
Braf Inhibitor ◽  
Population Based ◽  
Braf V600e ◽  
Phase Iii ◽  
Braf Mutations ◽  
Assistance Program ◽  
Line Therapy

e20045 Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients > 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) > 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.

Frequency of BRAF V600E variant in circulating free DNA compared with the single melanoma biopsy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9092-9092
Author(s):  
Lorenza Di Guardo ◽  
Viviana Vallacchi ◽  
Simona Frigerio ◽  
Agata Cova ◽  
Paola Squarcina ◽  
...  
Keyword(s):  
Mutation Detection ◽  
Braf V600e ◽  
Plasma Samples ◽  
Braf Inhibitors ◽  
Wild Type ◽  
Sensitivity Testing ◽  
Circulating Free Dna ◽  
Free Dna ◽  
Mutational Status ◽  
Detection Assay

9092 Background: To select melanoma patients for treatment with BRAF inhibitors, the BRAF mutational status is determined in the most recent tumor biopsy. However, tumor specimens are not always available for the analysis, and relying on a single biopsy specimen can potentially exclude from treatment patients with heterogeneity among metastatic tumors due to polyclonality of BRAF mutation, which appears as a rather common condition. As an alternative approach we explored a blood-based mutation detection assay. Methods: We developed a method including enrichment for the BRAV600E variant by selective elimination of the wild type allele by TspRI digestion and BRAFV600E detection by TaqMan Mutation Detection Assay (BRAF_476_mu, Life Technologies). Sensitivity testing showed that BRAFV600E variant was detected starting from 6.25X10-5 ng of DNA, and specificity testing showed that the variant can be detected when diluted in 8X105 copies of wild-type alleles. Results: Mutational analysis performed by Sanger sequencing of exon15 in 114 melanoma biopsies showed that 4 (3%) harbored the c.1798_1799GT>AA (V600K) mutation, 1 (1%) the c.1799_1800TG>AA mutation (V600E), and 56 (49%) the most common c.1799T>A mutation (V600E), while by the novel method the latter mutation was detected in 9 additional specimens (8% increment) and confirmed by sequencing the PCR product after TspRI digestion. Pre-surgery plasma was available for 50/114 patients at advanced stages, 26/50 (52%) showing a mutated specimen, including 4 with a double nucleotide substitution (V600K and V600E). The matched plasma samples resulted mutated in 25/26 cases with mutated biopsy and in further 14/25 samples with biopsy resulting wild type; in contrast, plasma of 50 healthy controls tested negative. Taken together, these results indicate that V600E circulating variant was detectable in 39/50 (78%) plasma samples and in 22/50 (44%) tumor specimens. Conclusions: Detection of BRAF V600E variant in circulating free DNA may represent a more sensitive approach for patient selection and decision making process during the treatment with BRAF inhibitors.

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