138P The impact of variant allele frequency in EGFR mutated NSCLC patients on targeted therapy

3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm->32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.

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JAK2V617F Variant Allele Frequency Identifies Patients with Polycythemia Vera (PV) at High Risk for Venous Thrombosis

Blood ◽

10.1182/blood-2018-99-112287 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1776-1776

Author(s):

Paola Guglielmelli ◽

Giacomo Coltro ◽

Giuseppe Gaetano Loscocco ◽

Benedetta Sordi ◽

Francesco Mannelli ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Venous Thrombosis ◽

Allele Frequency ◽

Variant Allele ◽

Continuous Variables ◽

Variant Allele Frequency ◽

Thrombotic Risk ◽

History Of ◽

The Impact

Abstract Background. Cardiovascular (CV) events are leading cause of morbidity and mortality in PV. Current risk stratification is based on variables predicting thrombotic risk, ie age >60y and history of thrombosis. Recent studies focused on additional thrombotic risk factors in PV, including generic CV factors and leukocytosis. PV patients (pts) are JAK2V617F mutated, and present wide heterogeneity in variant allele frequency (VAF); it was shown that a VAF >75% was associated with higher number of thrombotic events after diagnosis (Vannucchi AM, Leukemia 2007), but the prognostic role of JAK2 VAF is still debated. Aim. The aim of the study was to evaluate the impact of JAK2V617F VAF on rate of thrombosis in WHO-2016 defined PV pts. Patients and Method. In the CRIMM (Florence) database, a total of 577 pts with a JAK2VF VAF determined within 3 years from diagnosis, who met the 2016 WHO criteria for PV, were identified. All pts had information regarding thromboembolic events, including history of thrombosis, occurrence, type and date of thrombosis in the follow-up (FU) and presence of CV risk factors (smoking, hypertension, and diabetes mellitus). Thrombosis‐free survival (TFS) was determined from the time of diagnosis to the time the first thrombotic event occurred. Pts in whom thrombosis did not occur were censored at the time of last FU. Pre-receiver operating characteristic (ROC) plots were used to determine cutoff levels for continuous variables of interest. Differences in the distribution of continuous variables between categories were analyzed by Mann-Whitney or Kruskal-Wallis test. Pts' groups with nominal variables were compared by χ2 test. TFS was estimated by Kaplan Meier analysis; log rank test was used to compare TFS difference between groups. Cox proportional hazards regression was used for multivariable analysis. A two tailed P ≤ 0.05 was considered statistically significant. Results. The median age of pts at diagnosis was 61y, 308 (53.4%) were above 60y; 57.2% were males. All pts were mutated for JAK2V617F with a median VAF 43% (range 1-100%), 62% had at least one CV risk factor; 83 (14.4%) pts suffered from an episode of thrombosis within 3 yr from, or coincident with, diagnosis. The median FU was 7.3y (0.6-35.9y) during which 87 pts (15.1%) developed thrombosis. (50 arterial and 45 venous thrombosis). During the FU, 110 pts (19.1%) died. A JAK2VAF of ≥60% cutoff level, as determined by ROC analysis, correlated with measurements of stimulated erythropoiesis (higher hematocrit, lower mean cell volume and serum ferritin; all P<.01), leukocytosis (P<.0001), lower platelets count (P=.02) and elevated serum lactate dehydrogenase (LDH) (P<.03). Pts with ≥60% JAK2V617F VAF were at higher relative risk (RR) of having splenomegaly (RR 3.1; P<0.001), suffering from pruritus (RR 2.5; P<0.001) or constitutional symptoms (RR 1.9; P=0.01), harboring a BM fibrosis grade-1 (RR 3.1; P<0.001). Additionally, pts with a VAF>60% had greater risk to progress to PPV-MF (RR 8.5, P<.0001) and acute leukemia (RR 4.4, P=0.04) or to die (RR 3.8, P<0.0001). The JAK2VF VAF (continuous or ≥60%) did not correlate with occurrence of thrombosis at diagnosis, while the rate of thrombosis during FU was significantly increased in pts with VAF ≥60% (23.4% vs 11.0%, RR 2.4, 95%CI = 1.4-4.0; P<0.0001), more marked for venous (RR 3.7, 95%CI = 2.0-6.8; P<0.0001) than arterial (RR 1.8, 95%CI = 0.9-3.3; P=0.05) thrombosis. The impact of VAF on thrombosis during FU was then estimated according to the conventional risk category. In low risk pts (LR) (n=236), factors significantly associated with occurrence of FU thrombosis were CV risk factors (dyslipidemia (RR 3.3, P = 0.02) and hypertension (RR 1.8, P=0.048)), a G1 BM fibrosis (RR 5.3, P=0.006), presence of splenomegaly (RR, 3.2, P=0.001) or constitutional symptoms (RR 3.3, P=0.003) and a VAF ≥60% (RR 2.2, P = 0.024). In high risk pts (HR) (n=341), factors significant for FU thrombosis were splenomegaly (RR 2.0, P=0.03), elevated LDH (RR 4.0, P=0.009) and a VAF ≥60% (RR 2.3, P = 0.012). A VAF ≥60% was correlated with shortened venous TFS after diagnosis in HR (P = 0.01, HR = 3.2, 95%CI = 1.2−8.3; fig.) but not in LR pts (P = 0.20, HR = 1.1, 95%CI = 0.5−2.9). Conclusions. This study indicates that conventionally-defined high-risk PV pts with a JAK2V617F VAF ≥60% suffer from increased rate of venous events and might be worthwhile of more intensive antithrombotic prophylaxis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

Blood Cancer Journal ◽

10.1038/s41408-021-00581-6 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Paola Guglielmelli ◽

Giuseppe G. Loscocco ◽

Carmela Mannarelli ◽

Elena Rossi ◽

Francesco Mannelli ◽

...

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Allele Frequency ◽

Validation Cohort ◽

Multivariable Analysis ◽

Variant Allele ◽

Variant Allele Frequency ◽

Training Cohort ◽

Independent Risk Factors ◽

The Impact

AbstractArterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

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CYP2D6 polymorphisms and the therapeutic outcome with Tamoxifen therapy in breast cancer patients from Kosovo

Macedonian Pharmaceutical Bulletin ◽

10.33320/maced.pharm.bull.2018.64.02.004 ◽

2019 ◽

Vol 64 (02) ◽

pp. 35-42

Author(s):

Selvete Shuleta-Qehaja ◽

Aleksandra Kapedanovska Nestorovska ◽

Zorica Naumovska ◽

Petar Stefanovski ◽

Aleksandar Dimovski ◽

...

Keyword(s):

Breast Cancer ◽

Allele Frequency ◽

Early Stage ◽

Tamoxifen Therapy ◽

Therapeutic Outcome ◽

Variant Allele ◽

Small Scale ◽

Variant Allele Frequency ◽

The Impact ◽

Cyp2d6 Polymorphisms

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the prevention of breast cancer and for the treatment of metastatic and early stage receptor positive breast cancer. It has been shown than tamoxifen is metabolized by the cytochrome P450 2D6 (CYP2D6) enzymes, especially with the CYP26 isoform. The aim of this study was to examine the prevalence of CYP2D6*4, CYP2D6*9 and CYP2D6*10 variants in patients with breast cancer in Kosovo as well as the association between CYP2D6 polymorphisms and the therapeutic outcome in tamoxifen treated patients. The study included 111 patients who were at the age of 25 to 70 years (45.75 ± 9.50). The overall variant allele frequency of CYP2D6*4 was 0.16. The genotypic frequencies of the CYP2D6*4 polymorphism in all patients were 0.02 for *4/*4, 0.28 for *1/*4 and 0.70 for the *1/*1 genotype. The overall CYP2D6*10 variant allele frequency was 0.30 and the frequency of *10/*10, *1/*10 and *1/*1 genotypes was 0.11, 0.37 and 0.52, respectively. In our study, a population of the CYP2D6∗9 variant allele was not detected. In addition, we did not find any correlation between the evaluated genotypes for CYP2D6 polymorphisms and the therapeutic outcome with tamoxifen therapy. Although our study is a rather small- scale compared to large multicentre studies, we believe that it will contribute to determining the impact of CYP2D6 polymorphisms on the success of tamoxifen therapy in patients with a diagnosed breast cancer. Our results are pointing to the direction of the growing number of claims that there is still no strong evidence of any therapeutic connection between the polymorphisms examined and the outcome of the therapy. Keywords: Tamoxifen, breast cancer, CY2D6*4, CYP2D6*9, CYP2D6*10

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Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases

Scientific Reports ◽

10.1038/s41598-021-95521-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Kondo ◽

China Nagano ◽

Shinya Ishiko ◽

Takashi Omori ◽

Yuya Aoto ◽

...

Keyword(s):

Allele Frequency ◽

Carrier Frequency ◽

Japanese Population ◽

Autosomal Recessive ◽

Disease Prevalence ◽

Gitelman Syndrome ◽

Variant Allele ◽

Variant Allele Frequency ◽

Genome Databases ◽

Heterozygous Carriers

AbstractGitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.

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