Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.

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Improving detection of Lynch syndrome using a reflex immunohistochemistry algorithm for all patients with newly diagnosed colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.34_suppl.98 ◽

2012 ◽

Vol 30 (34_suppl) ◽

pp. 98-98

Author(s):

Minggui Pan ◽

Elizabeth Hoodfar ◽

JoAnn Bergoffen ◽

Regan Fulton ◽

Laura Hofmeister ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Germline Mutation ◽

Detection Rate ◽

Promoter Hypermethylation ◽

Braf V600e Mutation ◽

Braf V600e ◽

Newly Diagnosed ◽

Mlh1 Promoter ◽

Mmr Proteins

98 Background: Identifying patients with Lynch syndrome has profound impact on the clinical care of patients and their families. Previous guidelines based on family history alone have shown low sensitivity. In our medical center, the detection rate of Lynch syndrome was <1% among colorectal cancer cases. Methods: We have developed a system-based algorithm using centralized testing by immunohistochemistry (IHC) for four mismatched repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) as a screening method for all newly diagnosed colorectal cancer patients, followed by step wise testing of BRAF mutation, MLH1 promoter hypermethylation, +/- microsatellite instability, and germline mutation. Results: From April 1, 2011, to July 11, 2012, we have screened 116 patients. IHC detected absent expression of at least one of the MMR proteins in 18 cases. Three cases showed missing expression of MSH2/MSH6 and the presence of a germline mutation in MSH6 was confirmed in two cases. The newest case is still being investigated for germline mutation. Of the remaining 15 cases, 10 showed the presence of BRAF V600E mutation, two showed hypermethylation of the MLH1 promoter, and one showed germline MLH1 mutation. Two cases showed no BRAF V600E mutation, no MLH1 promoter hypermethylation or germline gene mutation. Overall, of 116 cases, three cases have confirmed Lynch syndrome with the detection of a germline mutation, two cases most likely have Lynch syndrome but without any detectable germline mutation of MLH1 or PMS2 using the current detecting methods. Conclusions: Our system-based screening algorithm using reflex immunohistochemistry of four MMR proteins has resulted in excellent detection rate of approximately 4% to 5% (5 out of 116 cases), consistent with the expected Lynch syndrome prevalence rate in the population. This represents a marked improvement over our previous family history-based approach in Lynch syndrome screening.

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Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9074 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9074-9074

Author(s):

Miguel F. Sanmamed ◽

Sara Fernandez-Landazuri ◽

Eduardo Castanon ◽

Jose Echeveste ◽

Maria D. Lozano ◽

...

Keyword(s):

Metastatic Melanoma ◽

Tumor Markers ◽

Direct Sequencing ◽

Braf Inhibitor ◽

Braf V600e Mutation ◽

Braf V600e ◽

Best Response ◽

Response Table ◽

S 100 ◽

Melanoma Patients

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]

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Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15029 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15029-e15029

Author(s):

Ibrahim Halil Sahin ◽

Wanqi Chen ◽

Mohamad Bassam Sonbol ◽

Satya Das ◽

Zhengjia Chen ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Medical Center ◽

Braf Mutations ◽

Exact Test ◽

Mmr Genes ◽

Cox Proportional Hazard ◽

Predictors Of Response ◽

Best Response ◽

Emory University ◽

The Impact

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]

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BRAF V600E-mutated anaplastic thyroid carcinoma (ATC) and treatment with BRAF-inhibitors: Real-world data from a single-institution, still far from the cure.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18577 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18577-e18577

Author(s):

Francesca Platini ◽

Elisa Ortolan ◽

Stefano Cavalieri ◽

Giacomo Massa ◽

Daria Maria Filippini ◽

...

Keyword(s):

Braf Mutation ◽

Real Life ◽

Progression Free Survival ◽

Digital Pcr ◽

Anaplastic Thyroid Carcinoma ◽

Braf V600e ◽

Molecular Profile ◽

Rank Test ◽

Real World Data ◽

Best Response

e18577 Background: ATC is a very aggressive disease. In the last years new insights on molecular profile of ATC have led to novel therapeutic options, primarily BRAF-targeted agents. Methods: From May 2018 to December 2019, data on recurrent/metastatic ATC patients treated at our Institution have been reviewed. BRAF V600E was assessed in each patient. BRAF mutation was tested both on tumor sections and on cell-free DNA (cfDNA). Circulating BRAF V600E was assessed by using Droplet Digital PCR (ddPCR) Technology. BRAF wild-type (WT) patients were treated with standard chemotherapy (adriamicin or taxans or platinum-based regimens). BRAF V600E patients were treated with dabrafenib 300 mg per day and trametinib 2 mg per day (combo regimen) until progression or unacceptable toxicities. Response was assessed by RECIST 1.1; progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier method and compared with log-rank test. Safety was evaluated according to CTCAE version 5.0. Results: 16 ATC patients were included. Male/female 5/11, median age was 68 years (range 43-80). Eight patients (50%) carried BRAF mutation. Best response in BRAF V600E was 4 partial response (PR), 3 stable disease (SD) and response in 1 patient has not been assessed yet. Combo was well tolerated, the most common adverse events (G2) were fatigue (14%), pyrexia (14%), nausea and vomiting (9%). Only one patient experienced drugs interruptions. Best response in BRAF WT patients was SD for 1, progressive disease for 4 and 3 patients received supportive care. Concordance between circulating BRAF status with tumor tissue was 80%. Assessment of circulating BRAF performed at baseline and at best response was available for 3 patients achieving a PR: mean reduction was -99.48% from baseline (range -99.37 – -99.66%). Median follow up was 22.8 weeks (95% CI 12.8-22.8). Median PFS was 13 weeks in BRAF V600E and 7.4 weeks in BRAF wt patients (p=0.1); in the same groups median OS was 18.4 and 7.8 weeks, respectively (p=0.051). Conclusions: Real-life data with combo regimen showed an ORR of 50%, with short PFS and OS. Reduction of circulating BRAF observed during treatment might be an indirect marker of tumor shrinkage, even if more data are needed to correlate circulating BRAF and disease response.

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Enrichment of SOX2-Positive Cells in BRAF V600E Mutated and Recurrent Ameloblastoma

Journal of Personalized Medicine ◽

10.3390/jpm12010077 ◽

2022 ◽

Vol 12 (1) ◽

pp. 77

Author(s):

Chih-Huang Tseng ◽

Pei-Hsuan Lu ◽

Yi-Ping Wang ◽

Julia Yu Fong Chang

Keyword(s):

Molecular Mechanisms ◽

Braf V600e Mutation ◽

Braf V600e ◽

Response To Treatment ◽

High Recurrence Rate ◽

Cell Renewal ◽

Loss Of Function ◽

Sox2 Expression ◽

Recommended Treatment ◽

Odontogenic Neoplasm

Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells as both initiators and propagators of the tumors. Elucidation of the cellular and molecular mechanisms underlying the tumor stem cells is of broad interest for understanding tumorigenesis and for developing effective targeted therapies. SRY related HMG box gene 2 (SOX2) is a transcription factor that plays important roles in development, stem cell renewal, and cancer formation. Few studies have revealed increased SOX2 expression in atypical ameloblastoma and ameloblastic carcinoma. For the development of personalized medicine for ameloblastoma, biomarkers that provide prognostic or predictive information regarding a tumor’s nature or its response to treatment are essential. Thus, in this study, we aimed to study if SOX2-positive cells exist in ameloblastomas and their correlation with the clinicopathologic parameters. Our data suggested BRAF(V600E) mutation might contribute to the expansion of SOX2-positive cells. The identification of BRAF(V600E) mutation and the amplification of SOX2-positive cells in ameloblastomas imply the possible benefit of applying BRAF and SOX2 inhibitors in recurrent and un-resectable ameloblastomas.

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Detection of the BRAF V600E mutation in melanocytic lesions using the ligase detection reaction

Yearbook of Pathology and Laboratory Medicine ◽

10.1016/s1077-9108(08)70313-x ◽

2007 ◽

Vol 2007 ◽

pp. 100-101

Author(s):

D.M. Jukic

Keyword(s):

Braf V600e Mutation ◽

Braf V600e ◽

Ligase Detection Reaction ◽

Melanocytic Lesions

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Therapie des BRAF-mutierten NSCLC

Onkologische Welt ◽

10.1055/s-0038-1677603 ◽

2018 ◽

Vol 09 (05) ◽

pp. 239-239

Author(s):

Dr. Susanne Krome

Keyword(s):

Phase Ii ◽

Braf V600e Mutation ◽

Braf V600e ◽

Alk Rearrangement

BRAF-mutierte nicht kleinzellige Bronchialkarzinome (NSCLC) sind besonders aggressiv. Gezielte Antikörpertherapien verbesserten die Behandlungsergebnisse. Bei einem ALK-Rearrangement ging eine lange progressionsfreie Zeit nicht zu Lasten der Post-Progressionsphase. Die Sekundäranalyse einer nicht randomisierten Phase-II-Studie zeigt dies nun auch für Patienten mit einer BRAF-V600E-Mutation.

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