IMMUNOHISTOCHEMICAL EXPRESSION OF BRAFV600E IN MELANOMA CASES

Objective: To evaluate the diagnostic value of Immunohistochemistry (IHC) for finding BRAFV600E mutation in melanoma patients. Study Design: Cross-sectional study. Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, Jan 2018 to Apr 2019. Methodology: Hundred histologically confirmed cases of melanoma aged between 18-80 years were included over a period of one year. To create the tissue microarray and to conduct immunohistochemistry with VE1 antibody melanoma lesion samples were selected. Results: Ninety-four cases out of 100, were melanoma positive for BRAFV600E detected on immunohistochemistry (IHC) using a monoclonal antibody. The skin was the primary site in seventy-nine (79%) patients, unknown (metastatic) in nineteen and uveal was only in two cases. The diagnostic significance of immunohistochemistry (IHC) for detecting the BRAFV600E mutation in melanoma patients was independent of age, site and stage at diagnosis (p-value <0.05). Conclusion: Testing of BRAV600E mutation by immunohistochemistry is a rapid, reliable and cost-effective tool in melanoma patients which may further help clinicians in initiating targeted therapy for these patients.

The Relevance between Iodine Nutritional Status and BRAFV600E Mutation on Papillary Thyroid Cancer

Papillary thyroid carcinoma (PTC) accounts for approximately 85%-90% of all thyroid cancers. BRAFV600E mutation is a highly specific target for papillary thyroid carcinoma (PTC) and may have a reciprocal causative relationship with iodide-metabolizing genes. Here, we performed a review of studies published in the past 10 years to determine the relationship between iodine intake and BRAFV600E mutation in patients with PTC. We searched the MEDLINE, PubMed, and EMBASE databases for studies published from 2009 to 2019; seven partially matched the selection criteria and were suitable for review, and five passed all selection criteria. We divided the patients into three groups by iodine intake: low (urinary iodine concentration [UIC] &amp;lt;100 &mu;g/L), adequate (UIC 100&ndash;200 &mu;g/L), and high iodine intake groups (UIC &ge;200 &mu;g/L). Between-group analysis revealed no significant differences in the odds ratio of the prevalence of BRAFV600E mutation between the high and adequate/low iodine intake groups and between the adequate and low iodine intake groups. To further analyzed the results of studies, they exhibited U-shaped curves in the relation of deficient and excessive dietary iodine intake in BRAFV600E mutation. The results might suggest that iodine intake slightly influences the prevalence of BRAFV600E mutation in patients with PTC despite the heterogeneity of studies. Further research should explore potential mechanisms underlying the associations between iodine intake and BRAF mutation in PTC. The systematic review was registered in PROSPERO (CRD42021279462).

Cutaneous metastasis of cecum cancer with MSI-high and BRAFV600E mutation: a case report

Background Cutaneous metastases of colorectal cancer (CRC) are rare, occurring in 0.7% to 5% of cancer patients. Furthermore, the molecular subtypes of cutaneous metastasis of CRC are unclear. Here, we present a rare case of cutaneous metastasis of high-frequency microsatellite instability (MSI-high)/BRAFV600E-mutant cecum cancer. Case presentation A 77-year-old woman presented at the outpatient clinic with a subcutaneous mass on her left back. An excisional biopsy was performed and metastatic cutaneous adenocarcinoma was diagnosed. A computed tomography scan of the thorax and abdomen showed thickening of the cecum wall, the presence of pericolic lymph nodes, multiple masses in the liver, and a single nodule in the right lung. Right colectomy with D2 lymphadenectomy and functional end-to-end anastomosis was performed because of the almost-complete intestinal obstruction. The expression of KRAS wild type, BRAFV600E mutation, and MSI-high was detected in the cecum cancer using molecular pathological examination. She received chemotherapy with XELOX + BEV regimen (capecitabine + oxaliplatin + bevacizumab). After four administrations, a computed tomography scan showed reduction of distant metastases, which suggested partial response. Conclusions We encountered a rare case of cutaneous metastasis of MSI-high and BRAFV600E-mutant cecum cancer. In the future, it will be necessary to accumulate more cases to identify clinical features and more effective treatments for CRCs with cutaneous metastasis.

Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy.

e21219 Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation.

Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution

Background: Papillary thyroid cancer (PTC) has the highest cancer incidence in Korea. It is known that some thyroid cancers have aggressive clinical behavior and a poor prognosis. Genomic studies have described some somatic mutations that are related to the aggressive features of thyroid cancer, such as the BRAFV600E mutation. Recently, TERT promoter mutations were identified and reported as poor prognostic factors in PTC. Our aim was to identify the frequency and clinical impact of TERT promoter mutation in PTC. Methods: Analysis of both BRAFV600E and TERT promoter mutations in thyroidectomy specimens began in February 2019. As of December 2020, 622 patients had been tested. Data were prospectively collected and retrospectively reviewed to ascertain clinical and pathologic variables. Results: TERT promoter mutations were identified in 13 patients (2.09%); 12 had the C228T mutation, and one had the C216T mutation. In total, ten patients had the BRAFV600E mutation. TERT promoter mutation was significantly associated with advanced age (46.795 ± 12.616 versus 65.692 ± 13.628 years, p < 0.001), large tumor size (1.006 ± 0.829 versus 2.285 ± 1.938 cm, p = 0.035), extrathyroidal extension, surgical margin involvement, angioinvasion, BRAFV600E mutation and advanced TNM stage, a higher MACIS score and a high proportion of radioactive iodine therapy application. Logistic regression showed that lymphatic and angioinvasion and BRAFV600E mutation were predictive of TERT promoter mutation. Conclusions: Our study is the first to report the prospective results of TERT promoter mutations at a single tertiary hospital in Incheon, Korea. PTC with TERT promoter mutation was associated with more aggressive behavior than PTC with wild-type TERT gene status.

MERAIODE: A Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAFV600E Mutation (NCT 03244956)

Background: Two-thirds of patients with metastatic differentiated thyroid cancer (DTC) become refractory to radioactive iodine (RAIR). The inhibition of the MAP-kinase pathway that is activated in case of BRAFV600E mutation might increase RAI incorporation into metastatic foci and reverse the RAI refractoriness. MERAIODE is a prospective multicentric open-label phase II trial, using a one-stage Fleming design, evaluating the efficacy and tolerance of trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor) treatment followed by the administration of RAI in metastatic RAIR DTC patients. Methods: Patients with BRAFV600E mutated RAIR metastatic DTC with RECIST progression within 18 months prior to enrollment and no lesion &gt; 3 cm were included. A baseline rhTSH-stimulated diagnostic whole body scan (dc WBS) was performed prior to treatment initiation. Patients were treated with dabrafenib (150 mg bid) and trametinib (2 mg per day) for 42 days. At day 28, a second rhTSH-stimulated dc WBS was performed. After 35 days, a therapeutic activity of RAI (5.5 GBq) was administered. Primary endpoint was objective response rate (ORR) at 6 months according to RECIST v1.1 (central review). Patients: Among the 24 patients (mean age 67 years, 15 females) with a BRAFV600E mutated RAI refractory papillary DTC included between March 2018 and January 2020 in 8 French centers from the TUTHYREF netwok, 24 patients were treated and 21 patients were evaluable for the principal outcome at 6 months. Results: Abnormal RAI uptake was present in only 1 of the 21 patients (5%; 95%CI 0-24%) on a RAI diagnostic whole body scan (dc-WBS) performed prior to treatment initiation, in 11 patients, 11/17 (65%; 95%CI 38-86) on a dc-WBS performed 4 weeks after dabrafenib-trametinib initiation and in 20/21 (95%; 95%CI 76-100) on the post-therapeutic WBS performed after 5.5 GBq of RAI. The RECIST 6-months tumor response (central review) was partial response (PR) in 38% (95%CI 18-61), stable disease (SD) in 52% (95% CI 30-74) and progressive disease (PD) in 10% (95% CI 1-30). The median change in the sum of target lesions was -22% (range: -79 to +46) at 6 months after baseline. The 6-month fluorodesoxyglucose metabolic PET response was PR in 11/17 (65% 95%CI 38-86), SD in 4/17 (23%) (95% CI 7-50) and PD in 2/17 (12%; 95% CI 1-36). Among the 15 patients without Tg antibodies, 7 (47%) patients had a decrease of serum thyroglobulin level on T4 treatment by more than 50%All patients experienced at least one grade 1-2 adverse event, mainly asthenia, nausea, fever, diarrhea and cutaneous eruption. Nine grade 3 toxicities occurred in 6 treated patients. No grade 4-5 adverse event occurred Conclusion: The association of dabrafenib and trametinib in BRAFV600E mutated patients is effective for restoring RAI uptake and is followed by a tumor control in 90% of patients and by tumor response in 38% with limited adverse events. (PHRC 2015, NCT 03244956)