TPS3166 Background: Fibroblast growth factor receptor 1 (FGFR1) plays a key role in the pathogenesis of multiple malignancies; however, no highly selective FGFR1-targeted therapies for solid tumors are currently approved. OM-RCA-01 is a humanized monoclonal antibody that selectively binds extracellular domains II–IIIc of FGFR1 with high affinity (Kd = 1.59 nM) and has demonstrated promising antitumor activity in preclinical models. In the first-in-human, tumor-agnostic (TAGNOT) study, patients with FGFR1-expressing advanced cancers are being treated with OM-RCA-01. Methods: TAGNOT is a phase 1b/2, multicenter, multicohort, prospective study designed according to the FDA-recommended OPTIMUS approach. Key eligibility criteria include FGFR1 expression by immunohistochemistry (IHC 2+ or 3+ in ≥10% of tumor cells) and metastatic disease progressing after ≥2 prior systemic treatment lines. The primary objective of the phase 1b component is to determine the recommended phase 2 dose (RP2D). Two dose levels of OM-RCA-01 (50 mg and 100 mg administered intravenously every 2 weeks) will be compared for safety (CTCAE v5.0), preliminary efficacy (objective response rate [ORR] per RECIST v1.1), pharmacokinetics, neutralizing antibody formation, and circulating tumor DNA dynamics. The primary endpoint of the phase 2 component is ORR in the ITT population. Five tumor-specific cohorts are planned: clear-cell renal cell carcinoma (n = 11), castration-resistant prostate cancer (n = 11), non-small cell lung cancer without EGFR or ALK alterations (n = 11), breast adenocarcinoma with known receptor status (n = 11), and head and neck squamous cell or salivary gland carcinomas (n = 11). Using Simon’s two-stage design, a total of 55 patients will be enrolled. The null hypothesis of a true ORR of 10% will be tested against a one-sided alternative of 25%. The study will be terminated after the first stage if ≤3 responses are observed among 31 patients. Otherwise, 24 additional patients will be enrolled. The null hypothesis will be rejected if ≥10 responses are observed in 55 patients, yielding a one-sided type I error rate of 0.05 and 90% power. Clinical trial information: NCT07292168 .

The low incidence, nonspecific clinical picture and absence of pathognomonic symptoms of vulvar adenocarcinoma make primary diagnosis very difficult. It could take months from the appearance of first symptoms to the final diagnosis and the start of specific treatment.There are limited options of standard treatment for this pathology. Therefore, attempts to use therapy that has proven itself in the other malignant tumors, based on molecular biological characteristics, are promising.Overexpression of HER2, which plays an important role in the carcinogenesis processes, is often observed in cases of extramammary Paget’s disease. We report a case of extramammary Paget’s vulvar cancer treated with a combination of cytostatic and targeted anti-HER2 agents.

Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19–39

In most cases, ovarian cancer is diagnosed at advanced stages, leading to a poor prognosis. Currently, there is no effective screening for ovarian cancer, so detecting it in the early stages is a fairly successful case.

Background. Mutations in the SMARCA4 gene of the SWI/SNF chromatin remodeling complex occur in 10% of nonsmall cell lung cancer (NMRL). SMARCA4-deficient lung tumors are aggressive neoplasm with poor outcome. Morphological, immunohistochemical and clinical description of this tumor type is lacking.The aim of the study was to investigate clinical and morphological characteristics and frequency of SMARCA4 expression loss in patients with lung tumors.Material and methods. Specimens from a total 100 non-small cell lung cancer cases were immunohistochemically examined for expression of SMARCA4 and SMARCA2. EGFR, BRAF mutations and gene rearrangement of ALK or ROS1 were tested by immunohistochemical, PCR-based or FISH techniques among cases with loss of SMARCA4 expression.Results. Loss of SMARCA4 expression was detected in 14 (14%) cases. Most of them are men — 93%. The average age was 63 years. In most cases (64%) SMARCA4-deficient tumors have been diagnosed as adenocarcinoma. The mutation was significantly associated with smoking history (p-value 0.009). Mutations in EGFR, BRAF genes and rearrangement of ALK or ROS1 in the SMARCA4-deficient tumor group have not been detected.Conclusion. SMARCA4-deficient tumors are subgroup of NMRL, prevalent in smoking men and diagnosed as lung adenocarcinoma without activating mutations.

Background. Endometrial cancer (EC) dominates in the structure of gynecological cancer morbidity. There has been an increase in this nosology in women of reproductive age. The morphological precancerous form of endometrioid adenocarcinoma is endometrial intraepithelial neoplasia (EIN), or atypical endometrial hyperplasia (AEH), that is difficult to diagnose: there is a high percentage of underdiagnosis resulting in a wrong treatment strategy. To improve the accuracy of diagnosis, additional immunohistochemical markers are being studied that are not part of the physician»s routine practice. Extremely promising for the prognosis of endometrial malignancy is the assessment of the functioning of the genes of the DNA mismatched nucleotide repair system (DNA mismatch repair system, MMR).Aim. To assess the diagnostic value of (microsatellite instability, MSI) in patients with AEH to rule out coexisting endometrial cancer.Materials and methods. The study includes 72 histological samples: 36 cases of EIN and 36 cases of EC, 14 of which were combined with EIN. To assess the microsatellite status, immunohistochemical staining of specimens was done with the identification of 4 markers, i. e. MLH1, PMS2, MSH2, MSH6. Results. It was found that out of 36 cases of EIN, only one sample showed loss of the PMS2 and MLH1 genes, which amounted to 3 %; the remaining EIN samples showed microsatellite stability. In 5 (36 %) out of 14 cases of combined EC and EIN pathology, MSI/dMMR was identified. Eight (36 %) out of 22 EC samples were found to have MMR deficiency. Loss of PMS2 increases the likelihood of being classified as EC 9-fold (odds ratio 9.1). With that, the presence of foci of adenocarcinoma in the case of AEH if MSI is confirmed can be asserted with a probability of 93 %. The detection of MSI in a histological sample is more often associated with the presence of EC, while the loss of the PMS2 and/or MLH1 genes increases the likelihood of a cancer diagnosis. If during additional immunohistochemical analysis a loss of these genes is observed, then EC can be diagnosed, even with an ambiguous histological pattern.Conclusion. Detection of MSI/dMMR in AEH indicates the presence of foci of coexisting endometrioid adenocarcinoma with an extremely high degree of probability. Detection of MSI/dMMR in the treatment of EC is advisable at the stage of diagnosis.

Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion is an extremely rare tumor. Its clinical manifestation is unspecific and only molecular genetic method can proof this diagnosis. This paper describes an unusual clinical presentation of primary pulmonary myxoid sarcoma in a 68-year-old patient with involvement of both lungs.

The aim of the study was to compare the spectra of pathogenic BRCA1 and BRCA2 variants in patients with hereditary breast cancer (BC) and ovarian cancer (OC) from two groups of ethnic Armenians: Yerevan and cities of southern Russia.Material and Methods. 106 BC patients from the V.A. Fanardjian National Centre of Oncology (Yerevan, Republic of Armenia) and 117 BC and OC patients of Armenian origin who were referred to the Petrov National Medical Centre of Oncology (St. Petersburg, Russia) from several cancer centers of Russia (Krasnodar, Sochi, Pyatigorsk) were included into the study. The coding sequences of BRCA1 and BRCA2 genes were analyzed by the method of targeted high-throughput sequencing.Results. Pathogenic variants of BCRA1 and BCRA2 genes were detected in 16/106 (BRCA1: n=9, BRCA2: n=7; 15%) BC patients from Yerevan. The only recurrent mutation was the BRCA1 nonsense variant c.5444G>A [W1815X], accounting for 44% of all pathogenic alleles identified. In patients of Armenian origin from Russia, pathogenic BRCA1/2 variants were detected in 16/117 (14%) individuals (BRCA1: n=6, BRCA2: n=10). The proportion of samples with mutations was 13% in the group of BC patients and 19% in the group of OC patients. 75% of pathogenic alleles were represented by five recurrent mutations: BRCA1 c.2649_2650insGGCA, BRCA2 c.2808_2808_2811delACAA, BRCA1 c.4065_4068delTCAA, BRCA2 c.9027delT and BRCA2 c.8437G>T [G2813X]. The independent origin of the pathogenic BRCA2 c.2808_2808_2811delACAA variant in Armenian and non-Armenian patients was shown.Conclusion. A significant difference in the spectrum of BRCA1/2 mutations between Armenian patients from Yerevan and patients from southern regions of Russia was found. This should be taken into account when developing diagnostic programs.

PD-L1 immunohistochemistry has been approved as a diagnostic assay for immunotherapy. However, an international comparison across multiple cancers is lacking. This study aimed to assess the performance of PD-L1 diagnostic assays in non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC) and urothelial cancer (UC). The excisional specimens of NSCLC, HNSCC and UC were assayed by Ventana SP263 and scored at three sites in each country, including Australia, Brazil, Korea, Mexico, Russia and Taiwan. All slides were rotated to two other sites for interobserver scoring. The same cohort of NSCLC was assessed with Dako 22C3 pharmDx PD-L1 for comparison. The PD-L1 immunopositivity was scored according to the approved PD-L1 scoring algorithms which were the percentage of PD-L1-expressing tumour cell (TC) and tumour proportion score (TPS) by Ventana SP263 and Dako 22C3 staining, respectively. In NSCLC, the comparison demonstrated the comparability of the SP263 and 22C3 assays (cut-off of 1%, κ=0.71; 25%, κ=0.75; 50%, κ=0.81). The interobserver comparisons showed moderate to almost perfect agreement for SP263 in TC staining at 25% cut-off (NSCLC, κ=0.72 to 0.86; HNSCC, κ=0.60 to 0.82; UC, κ=0.68 to 0.91) and at 50% cut-off for NSCLC (κ=0.64 to 0.90). Regarding the immune cell (IC) scoring in UC, there was a lower correlation (concordance correlation coefficient=0.10 to 0.68) and poor to substantial agreements at the 1%, 5%, 10% and 25% cut-offs (κ= -0.04 to 0.76). The interchangeability of SP263 and 22C3 in NSCLC might be acceptable, especially at the 50% cut-off. In HNSCC, the performance of SP263 is comparable across five countries. In UC, there was low concordance of IC staining, which may affect treatment decisions. Overall, the study showed the reliability and reproducibility of SP263 in NSCLC, HNSCC and UC.

Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).

301 Background: FGFR2 status of a patient with metastatic gastric adenocarcinoma could be an important factor in determining optimal treatment strategy with FGFR2 inhibitors and antibodies. The question remains how well different assays agree on the FGFR2 status of the same patient and whether one test can be substituted by another. Methods: Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8] and one FISH test. One hundred and nine formalin-fixed, paraffin embedded samples (including 64 primary tumors and 45 metastases of same patients) were obtained and were stained with FGFR2 IHC assays. Two trained pathologists independently evaluated the percentages of tumor staining and their intensity. FGFR2 FISH was performed as described previously [Su, BJC 2014]. The concordance analysis was performed to assess (1) correlation of FGFR2 expression/amplification between different assays in primary and metastases, (2) the predictive properties of one test of another. Results: After evaluating the expression in the first 19 patients, further study was carried out only using the Abсam assay due to pronounced nuclear staining with other IHC tests. FGFR2 any level expression was detected in 29 (47%) primary tumors and 18 (40%) metastases with concordance of 91%. The prevalence of FGFR2 amplification was 9.4% and intratumoral heterogeneity was observed in 33% of FGFR2 amplified cases. Pearson Correlation Coefficients (PCC) were: 0.89, 0.38 and 0.35 between IHC3+/FISH, IHC≥1% stained cells/FISH and IHC≥10%/FISH, respectively. The table represents how well one assay can predict the same outcome (positivity or negativity) of another assay. Conclusions: Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC. [Table: see text]

This article presents a case of successful treatment of inoperable gastric cancer with impaired mismatched nucleotide repair system (dMMR/MSI-H) in a 72-year-old patient. In view of age, somatic status and the presence of comorbidity, it was decided to prescribe anti-PD-1 therapy in the 1st line of treatment. Currently, after a 2-year course of treatment, the patient is in stable remission.

Данный обзор литературы ставит перед собой целью повысить осведомленность специалистов по обсуждаемой проблеме, а также помочь применять современную молекулярную классификацию рака эндометрия в клинической практике. В нем отражены современные рекомендации, клинические исследования и собственные данные.

Deficient DNA mismatch repair (dMMR) is a rare molecular disorder found in 20-30 % of endometrial tumors. Laboratory identification of dMMR/microsatellite instability (MSI) has a high diagnostic value, since these impairments are considered as biomarkers of endometrial adenocarcinoma. They help to identify patients at high risk of Lynch syndrome, evaluate the disease prognosis, and estimate the efficacy of immune checkpoint inhibitors and their combinations. This review details current concepts of MSI diagnostics and discusses its predictive value in patients with endometrial cancer. It also describes a new diagnostic algorithm for the detection of dMMR and MSI.

Microsatellite instability, which is caused by a deficiency in the DNA unpaired nucleotide repair system, is an important pathogenetic event for some tumors. In addition, the detection of this molecular feature becomes an independent prognostic factor in the course of the disease and a predictor for the appointment of therapy with immune checkpoint inhibitors. Immunohistochemistry is a reliable and available method for detecting a deficiency in the DNA mismatch repair system, and it has recommended as a screening for hereditary syndromes associated with microsatellite instability. This article discusses the advantages and disadvantages of this research method from the point of view of the practitioner.

BACKGROUND:Assessment of FGFR2 status in gastric cancer is an important task, without clarification of which it is impossible to identify a cohort of patients in whom the best response to treatment with anti-FGFR2 drugs could be obtained.OBJECTIVE:To conduct a comparative analysis of the expression and amplification of the FGFR2 gene in gastric cancer in primary tumors and metastases in the lymph nodes.MATERIAL AND METHODS:FGFR2 status was studied in 61 patients with stage III gastric adenocarcinoma using an immunohistochemical method (Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8, Abcam clone 1G3) and FISH.RESULTS:The antibody Abcam clone EPR24075-418 was found satisfactory for the immunohistochemical study of FGFR2. FGFR2 expression was detected in 26 (43%) cases, amplification in 5 (8%) cases. Amplification of FGFR2 in 4 cases out of 5 was accompanied by the expression of 3+, in 1 case - 2+. Discordance between FGFR2 expression in primary tumor and lymph node metastases was revealed in 13 (21%) cases.CONCLUSION:Clone EPR24075-418 showed the best result in assessing the expression of FGFR2: the correlation with FISH results in reaction 3+ was 100%. Due to the high heterogeneity of FGFR2 expression, it is recommended to either examine the material of the primary tumor and metastasis, or evaluate a large volume of the primary tumor.

PURPOSE:To develop a method for testing the MSI based on targeted NGS. METHODS:Based on the results of previous studies, 81 microsatellite loci with high variability in MSI-H tumors were selected, and a method for calculating the MSI score was developed. Using the MSI score, we defined the MSI status in endometral (162), colon (153), and stomach (190) cancers. Accuracy of the MSI scores was evaluated by comparison with MMR immunohistochemistry for 137 endometrium (63 dMMR and 74 pMMR), 76 colon (29 dMMR and 47 pMMR), and 81 stomach (8 dMMR and 73 pMMR) cancers. RESULTS:Classification of MSS and MSI-H tumors was performed with AUC (0.99), sensitivity (92%), and specificity (98%) for all tumors without division into types. The accuracy of MSI testing in endometrial cancer was lower than for stomach and colon cancer (0.98, 87%, and 100%, respectively). The use of 27 loci only, the most informative for endometrial cancer, increased the overall accuracy (1.00, 99%, and 99%). Comparison of MSI score values in 505 tumors showed that MSI score is significantly higher in colon (p < 10-5) and stomach (p = 0.008) cancer compared with endometrial cancer. CONCLUSION:The MSI score accurately determines MSI status for endometrial, colon, and stomach cancers and can be used to quantify the degree of MSI.

OPINION Oncol Rev., 14 December 2023 https://doi.org/10.3389/or.2023.11790

В обзоре представлена сравнительная характеристика эндометриоза и злокачественных опухолей с учетом актуализации классификаций опухолей яичников, рассмотрены факторы риска, морфологическая картина, специфические признаки атипичного эндометриоза, особенности этиопатогенеза. Показана ассоциация большинства хронических заболеваний, встречающихся в популяции, и эндометриоза. Приведены клинические случаи редких форм эндометриоз-ассоциированного рака различной локализации. Описаны потенциальные факторы злокачественной трансформации эндометриоза. На основании представлений о некотором сродстве эндометриоза и рака рассмотрена потенциальная возможность использования лекарственных препаратов в лечении онкологических заболеваний.