BRCA1 4153delA founder mutation in Russian ovarian cancer patients

The BRCA1 4153delA allele is frequently referred to as the Russian founder mutation, as it was initially detected in several cancer families from Moscow. Our earlier studies have demonstrated 1% occurrence of BRCA1 4153delA heterozygosity in familial and/or early-onset and/or bilateral Russian breast cancer (BC) patients. Since literature data suggest that the 4153delA variant is more associated with ovarian cancer (OC) than with BC, we expected to reveal a highly elevated frequency of this genotype in Russian ovarian cancer series. However, real-time allele-specific PCR genotyping has detected only two BRCA1 4153delA carriers out of 177 unselected OC patients (1.1%). Both these carriers were early-onset and had serous carcinomas of grade 3. Thus, our study supports neither the Russian origin of BRCA1 4153delA mutation, nor its selectivity towards ovarian versus breast cancer predisposition

Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele

КЛИНИЧЕСКАЯ ЭФФЕКТИВНОСТЬ ТАРГЕТНОЙ ТЕРАПИИ В ОТНОШЕНИИ МЕТАСТАТИЧЕСКОГО РАКА ЛЁГКОГО С РАЗЛИЧНЫМИ ТИПАМИ ТРАНСЛОКАЦИЙ ГЕНА ALK

Introduction. Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods. The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results. A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions. There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants.Актуальность. Транслокации рецепторной тирозинкиназы ALK встречаются примерно в 5–9 % аденокарцином лёгкого. Применение ингибиторов данной киназы, как правило, сопровождается выраженным ответом опухоли на лечение. Тем не менее глубина и длительность эффекта таргетной терапии варьируют от пациента к пациенту. Цель исследования – обобщить имеющиеся сведения о причастности различных типов транслокаций ALK к формированию ответа на лечение ингибиторами ALK. Материал и методы. В обзоре представлены результаты опубликованных в базе данных PubMed лабораторных и клинических работ, посвященных указанной проблеме, а также собственных исследований. Результаты. Эксперименты на клеточных культурах продемонстрировали, что структура транслокации ALK влияет на свойства химерного белкового продукта, в частности на его стабильность и чувствительность к воздействию кризотинибом. Немногочисленные выполненные до сих пор клинические исследования, оценивающие эффект ингибиторов ALK в зависимости от типа перестройки, имели разнородные результаты. Если в части работ были обнаружены ассоциации между «короткими» вариантами транслокаций EML4-ALK и худшими показателями выживаемости при использовании кризотиниба в сравнении с вариантом EML4-ALK 1 типа, то другие авторы не наблюдали таких закономерностей. Анализ итогов лечения ингибиторами ALK 64 российских пациентов также не обнаружил влияния типа транслокации на длительность периода до прогрессирования заболевания или частоту объективных ответов. Заключение. В изученных выборках пациентов отмечались различные по своему характеру ассоциации, ни одна из которых не отличалась воспроизводимостью. Таким образом, варианты перестроек ALK нельзя рассматривать в качестве предиктивного фактора ответа на ALK-специфическую терапию

CLINICAL EFFICACY OF TARGETED THERAPY TOWARDS METASTATIC LUNG CANCER CARRYING DISTINCT TYPES OF ALK REARRANGEMENTS

Introduction. Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods. The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results. A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions. There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants

Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study

Background: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. Methods: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. Results: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS. Conclusion: Use of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug

Cost-Efficient Detection of <i>NTRK1/2/3</i> Gene Fusions: Single-Center Analysis of 8075 Tumor Samples

The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5′/3′-end expression imbalances is potentially capable of detecting the entire spectrum of NTRK gene fusions. Archival tumor specimens obtained from 8075 patients were subjected to manual dissection of tumor cells, DNA/RNA isolation, and cDNA synthesis. The 5′/3′-end expression imbalances in NTRK genes were analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific PCR for 44 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). cDNA of sufficient quality was obtained in 7424/8075 (91.9%) tumors. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.9%). Increased frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%), salivary gland carcinomas (5/93, 5.4%), and sarcomas (7/143, 4.9%). None of the 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5′/3′-end expression imbalances. Variant-specific PCR was performed for 744 tumors with a normal 5′/3′-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1–3 analysis