Рекомендации Восточно-Европейской группы по изучению сарком. В данном разделе указаны критерии оценки клинической значимости применения дорогостоящей противоопухолевой лекарственной терапии в соответствии со шкалой, разработанной экспертной группой (см. стр. 7). В тексте они обозначены, как магнитуда клинической значимости (МКЗ).

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Background.BRCA1/2 germline testing allows us to optimize treatment strategy for patients with breast and ovarian cancer cases,to provide early diagnosis and also prophylactic measures for mutation carriers. Considering absence of large BRCA studies on Russian population, we do not have any clear understanding of approximate BRCA1/2 germline mutation frequency, a whole number of founder mutations and impact of non-founder BRCA1/2 mutations, which are not included in a standard PCR panel. Objective. Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in breast and ovarian cancer patients in real clinical practice in St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (oncological) named after N.P. Napalkov. Analysis of a database for BRCA1/2-negative patients on a presence of risk factors associated with a probability of carrying a germline mutation in BRCA1/2 genes. Materials and methods. We retrospectively evaluated 335 ovarian and 1196 breast cancer patients, tested for germline BRCA1/2 by PCR in SPb CSPC(o) named after N.P. Napalkov from 01.01.2019 to 31.12.2021. For analysis was used patient’s blood plasma and a standard PCR panel detecting 8 mutation variants. A database for BRCA1/2-negative patients was retrospectively analyzed on a presence of risk factors associated with a high probability of hereditary cancer: an early onset and family history of cancer (BRCA associated). Statistical analysis was carried out using the SPSS software package (IBM® SPPS® Statistics v. 20), a number of graphs were carried out using Microsoft® Excel® 2016 programs. Results. BRCA1/2 germline mutations were detected in 6,4% (n= 98). Mean frequency of detection was 12,6% (n=45) for ovarian cancer patients, 4,3% (n=53) for breast cancer patients. Analysis of a database for BRCA1/2-negative patients demonstrated that 22,5% (n=346) BC and OC cases had an early onset. Family history of cancer was identified for 13,6% (n=195) patients with breast or ovarian cancer, including 3,8% (n=43) with 2 and more family cases of BRCA associated cancers. Conclusions. The frequency of detected BRCA1/2 germline mutations by PCR for breast and ovarian cancer patients in SPb CSPC(o) named after N.P. Napalkov is lower than the one described in international data. A large part of patients BRCA1/2 negative by PCR test has characteristics of hereditary breast cancer syndrome and requires further NGS.

Introduction. Intratumor heterogeneity is one of the key reasons for unfavourable prognosis in malignant tumors. Astrocytic tumors are known to develop therapy resistance inevitably during the course of disease. One of possible reason is tumor heterogeneity. Purpose. The aim of this work was to assess the intratumor morphologic and molecular heterogeneity in diffuse astrocytoma, anaplastic astrocytomas and primary glioblastomas. Material and methods. We conducted morphologic (n=22) and molecular-genetic (n=8) analysis of surgical specimens obtained from primarily operated glioblastoma giv (gb), anaplastic astrocytomas giii (aa) and diffuse astrocytoma gii (da) patients aged 18 years and older in whom total or subtotal tumor resection was performed. Tissue sampling for the analysis was performed from 5 equidistant areas of each tumor. Morphologic diagnosis was established according to who classification of central nervous system tumors (2007/2016). Mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf genes mrnaexpression was assessed by rt-pcr. Idh1 and idh2 mutational status was evaluated by allele-specific pcr. Results. Morphologic heterogeneity was evident in 72,7 % tumors (16/22) overall. Heterogeneity was observed in 68,8 % (11/16) of gb, 80 % (4/5) of aa and in the only case of da. In 50 % of cases at least 3 different morphologic variants were seen in different areas of the tumor. This morphologic heterogeneity presented as the combination of different grades of anaplasia (gii – giv) in one tumor. Molecular profile was assessed in 48 expression analysis of genes: mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf from 8 patients. Intratumoral molecular heterogeneity was revealed in 41,7 % of cases (20/48). Conclusion. The presence of intratumoral heterogeneity should be taken into account during surgery for adequate tumor sampling for histologic and molecular analysis which is critical for proper assessment of prognosis and following treatment planning.

Introduction. Non-metastatic colorectal cancer can recur within five years as distant metastases in about 25% of stage II patients and 50–60% of stage III patients. It is crucial to identify the subgroup of patients with the highest risk of recurrence. Our study aimed to determine the effect of microvascular density (MVD) and pericyte impaired microvessels (PIM) on the risk of metastasis of colorectal adenocarcinomas. Materials and methods. We carried out a retrospective study of the surgical material for colorectal cancer without metastases in regional lymph nodes. The cohorts included cases with synchronous distant metasta-ses (n=53), metachronous metastases (n=45), and without distant metastases (n=53). In the last group, the follow-up period was from 64 up to 92 months. We performed triple immunohistochemical staining: ERG, α-SMA, and Podoplanin. At low magnification, we determined the areas of highest microvessel density, calculated them on an area of 1.0 mm2 with a magnification of x400. The number of microvessels without α-SMA expression was counted, and eventually the microvessel immaturity index Index-V = PIM / MVD was calculated. Results. Normal blood vessels were characterized by the expression of ERG in endothelial cells and α-SMA in pericytes, while at immature tumor microvessels, the latter were absent. The difference in MVD in the groups was statistically insignificant (p=0.414), on average 10/mm2 for non-metastatic tumors and 11/mm2 for metastatic ones. Metastatic tumors showed significantly higher PIM (mean 8/mm2 vs. 2/mm2) and Index-V (mean 0.69 vs. 0.21). Both showed a significant correlation with distant metastases (p <0.001). Conclusion. The data obtained demonstrate that imperfect tumor neovascularization correlates with metasta-sis, which leads to a worse prognosis. The density of microvessels and their structural features are important independent prognostic factors for patients with colorectal cancer. Evaluation of angiogenesis in a tumor in terms of the number and maturity of newly formed vessels enable to elucidate malignant potential of the tumor. Keywords: angiogenesis, pericytes, microvessel density, colorectal cancer, prognosis

Extramammary Paget’s disease (EMPD) is a rather rare variant of adenocarcinoma, most often localized in the anogenital area or perineum. The aim of our study was to determine the prognostic significance of histological variants of primary EMPD in relation to the risk of tumor recurrence. Material and methods . 202 samples of primary EMPD were taken from 158 patients. Sections stained with hematoxylin and eosin were examined. Results and discussion . 23 patients (14.6 %) had recurrent EMPD. The study revealed that «glandular», «pigmented», «signet ring», «acantholytic» morphological variants of EMPD, as well as syringocystadenocarcinoma papilliferum in situ–like changes and the presence in the dermis of structures similar to eccrine syringoma, are associated with the development of disease recurrence. Conclusion . The «signet-ring» and «pigment» morphological variants of EMPD have the highest predictor value in relation to the risk of disease recurrence. The «signet ring-cell» variant of primary EMPD is the only one that influences the time of the first recurrence of the disease.

Gastric cancer is an aggressive malignant neoplasm of the digestive system. These tumors are genetically heterogeneous,and they could be subdivided into four groups. One of such groups, microsatellite instable (MSI) gastric cancer, is of interest considering prognosis and response to therapy. Immune checkpoint inhibitors present a perspective strategy in treating these tumors, however, there is currently insufficient data on their use in microsatellite instable gastric cancer. Aim of this study was to evaluate objective response to neoadjuvant checkpoint inhibitors treatment in patients with MSI gastric cancer. Eleven patients were enrolled. They received Nivolumab or Pembrolizumab (investigator choice) in a neoadjuvant setting. Objective response was registered in 9 (81,8%) patients, two patients had stabilization. Nine patients (81,8%) underwent radical surgery. Pathologic complete response (pCR) was registered in 3 (33,3%). Postoperative complications were tracked and registered in accordance with Clavien-Dindo classification: grade 1 – 2 patients, grade 2 – 2 patients, grade 3 – 1 patient.

OBJECTIVE:To assess the risk of recurrence after surgical treatment is an integral part of the management of patients with colorectal cancer. The AJCC/UICC TNM staging system, in which the risk is identified by grouping the patients on the basis of anatomical elements, is commonly used. Despite the simplicity of implementation, significant heterogeneity remains within each stage group. A better tool for predicting a recurrence is needed in the era of multimodal treatment.SUBJECTS AND METHODS:A total of 1350 archival colorectal cancer cases during 2012 to 2015 were retrospectively analyzed; among which the investigators identified 3 patient groups: 1) 53 patients with non-metastatic colon cancer for at least 5 years; 2) 45 patients with metachronous metastases detected during the same period; and 3) 53 patients with synchronous metastases. Among the estimated 31 parameters, the investigators used a multidimensional analysis to select 6 most significant prognostic factors that were included in the final model based on a logistic regression analysis. The resulting model was applied to assess the risk of metastasis after cytoreductive surgery. It was internally and externally validated in an examination group (n=25).RESULTS:The model has a sensitivity of 97.78% and a specificity of 96.23%, improving the risk stratification for metastatic colon cancer. The factors in the model include extramural venous invasion, the severity of budding, the expression of E-cadherin and β-catenin, the proportion of cytotoxic CD8+ lymphocytes of the total number of T lymphocytes in the microenvironment, and the ratio of newly formed vessels to tumor stromal microvessel density.CONCLUSION:Using morphopathological factors, the resulting model allows better consideration of tumor specificity in a particular patient, thereby providing a more individual prediction of outcome than that provided by the AJCC/UICC TNM staging system. By identifying patients at both high- and low-risk for metastasis, the model can be useful to plan treatment and to choose clinical management tactics for patients with colorectal cancer.

Attempts to determine the biological behavior of tumors have been an integral part of research in oncology for nearly 100 years. During this period, many works have been carried out to assess the value of individual factors, including both clinical information about the patient and the pathomorphological features of the tumor. Various systems have been proposed and modified, combining all possible combinations of neoplasm characteristics and epidemiological parameters. Thus, approaches to predicting the biological behavior of tumors can be conditionally divided into two types: the first, an analytical approach, is based on revealing individual morphological or clinical factors that affect the course of the tumor process, and the second, a systemic approach, which consists in combining several related and interacting constitute signs into a unified predictive model. Existing tumor classification systems are far from perfect. Nevertheless, the general consensus among pathologists, surgeons, and clinical oncologists is that prognosis parameters deserve to be a part of the standard pathology report for most tumors.

Background Inflammatory myofibroblastic tumors (IMTs) are exceptionally rare neoplasms, which are often driven by rearranged tyrosine kinases. Methods This study considered 33 consecutive patients with IMT (median age, 6.6; age range, 0.6-15.8 years). RNA and cDNA were successfully obtained in 29 cases. The molecular analysis included sequential tests for 5 '/3 '-end unbalanced gene expression, variant-specific PCR, and next-generation sequencing (NGS). Results 5 '/3 '-end unbalanced ALK expression was revealed in 15/29 (52%) IMTs. Strikingly, all these tumors demonstrated high amount of ALK protein detected by immunohistochemistry. Variant-specific PCR was capable of identifying the type of ALK rearrangement in 11/15 IMTs with 5 '/3 '-end unbalanced ALK expression. The remaining four tumors were analyzed by NGS; two known and two novel (CLTC-ins6del84-ALK and EEF1G-ALK) ALK rearrangements were detected. Five IMTs demonstrated 5 '/3 '-end unbalanced ROS1 expression, and all these tumors carried TFG-ROS1 fusion. Nine tumors, which were negative for 5 '/3 '-end unbalanced ALK/ROS1 expression, were subjected to further analysis. Variant-specific PCR revealed two additional tumors with gene rearrangements (TFG-ROS1 and ETV6-NTRK3). The remaining seven IMTs were tested by NGS; single instances of TFG-ROS1 and novel SRF-PDGFRb translocations were detected. Conclusions Twenty-four of 29 IMTs (83%) were shown to have druggable rearrangements involving tyrosine kinases, 20 of these 24 gene fusions were detectable by simple and inexpensive PCR assay, which is based on the detection 5 '/3 '-end unbalanced gene expression.

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514–522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5–11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8–2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.

The evolution of drug therapy in solid tumors primarily leads to the increase in cancer specific survival, but inevitably raises financial burden. So far, none of the countries can venture total reimbursement with all necessary contemporary drugs for all patients. Doubling of expenses for cancer drug therapy in Russia in 2019 allowed oncologists using the most expensive treatments in more than 70 % of patients.Purpose: To evaluate efficacy of various treatment types of non‑small cell lung cancer in real clinical setting.Material and methods. We included patients with histologically verified metastatic non‑small cell lung cancer without activating mutations treated with first or second line therapy in 2018 – 2019. In total 287 patients were included: 230 — for the first line efficacy analysis, 100 — for the second. Time to disease progression, overall survival and objective response rate were evaluated.Results. The use of checkpoint inhibitors in accordance with all actual recommendations (first line pembrolizumab monotherapy in PD-L1 > 50 %, chemoimmunotherapy in first line or monotherapy in the second line irrespectively to PD-L1 status) decreased one‑year mortality from 61 % in 2018 to 33 % in 2019, but significantly increased financial cost (p < 0.000). Moreover, checkpoint inhibitors in combination with chemotherapy irrespectively of PD-L1 expression increased response rate (from 10 % and 21 % for monotherapy and platinum doublet, respectively, to 33,2 % for chemoimmunotherapy). PD‑1 inhibitors as monotherapy increased median time to disease progression (4,1 and 6,2 months for monotherapy with chemotherapy and platinum doublet, respectively, to 6,5 months and not achieved for chemoimmunotherapy and monotherapy with checkpoint inhibitors).Conclusion. More than doubling of financial costs spent for non‑small cell lung cancer treatment allowed access to contemporary treatment for all patients. Such unprecedented measures significantly improved efficacy, including double decrease of one‑year mortality. Nevertheless, rational design of regional clinical guidelines interpretation is of great importance in accurate and effective use of the healthcare budget.

e21528 Background: Despite impressive clinical efficacy in response rate, increase in PFS and sometimes in OS EGFR TKI rarely cure cancer patients, as all of them inevitably develop resistance. Small fractions of residual cells appear to be a reservoir of further clones with acquired resistance. For this moment morphological characteristics of “persister” population are not well defined. Methods: We screened hospital data-base containing > 200 pts for EGFRmut NSCLC who underwent cytoreductive surgical treatment during treatment with either TKI and before radiographic disease progression. We obtained 18 pairs of pretreatment biopsy and surgical specimen. 7/18 were male, median age 60.5 yo (45-79). 15/18 had ex19del; 3/18 – L858R. 12/3/2/1 received gefitinib/erlotinib/afatinib/osimertinib before surgery. Median time from treatment initiation to surgery was 8.9 mon (0.7 – 24.3). None of the pts had evidence of increase in any dimension of tumor lesions before surgery. According to RECIST 6/18 pts had SD, 12/18 – PR. 6/18 pts had complete cytoreduction, 4/18 – partial, 8/17 – metastasectomy. All pathologic responses (MPR) were graded according to Hellmann MD et al., 2014. Results: Pathologic response with > 50% of residual tumor – 2/18; 10-50% – 7/18; < 10% – 4/18; pCR – 3/18. Median observation time is 15.4 mon (8.4 – 37.2+). Disease progression after surgery was registered in 6/18 pts. No significant correlations between PFS, MPR, RR, TKI generation, time to surgery were seen. Conclusions: In our serie MPR rate ( < 10% of viable tumor cells according to Hellmann MD et al, 2014) for NSCLC treated with various TKI was 38%, that is higher than in other reports (10.2% in CTONG 1103 for example). Further characterization of the “persister” tumor cells may help to determine mechanisms of intrinsic resistance and direct more efficient antitumor activity.

e15519 Background: Metronomic therapy (MT) is one of the most promising advances in cancer treatment strategy focused on both tumor cells and their microenvironment, specifically anti-angiogenic, immune and metabolic regulation. The treatment modality is a durable cytostatic drugs exposure with less toxicity. We investigated the efficacy of MT in point of prolonged duration of response (more than 6 months) in pts with the advanced resistant tumors. Methods: A total of 678 pts have been enrolled in the study and have been treated MT cyclophosphamide 50 mg (qd, PO) and methotrexate 2.5 mg (BID, PO) twice per week dosing schedule until progression. 508 pts (75%) had disease progression during first 6 months. Long-term efficacy (more than 6 months) was assessed in 170 pts (25%). The study population characteristics were female 122 (72%) vs male 48 (28%). Among the enrolled pts median age was 70 years (range from 37 to 91 years). ECOG status ranged from 0 to 4 (median - 1). The majority of pts received MT as a 2nd and 3rd line (57%) of the therapy (range from 1 to 11): 1-2 – 106 (62%), 3-4 - 52 (31%), 5 and more - 12 (7%). The distribution of pts by diagnosis is presented in the table 1. The majority of MT pts were represented by advanced clinical stage III-IV (97,6%): I - 1 (0,5%), II - 3 (2%), III - 7 (4%), IV - 159 (93,5%). MT commonly used in early-stages cancer in elderly patients with multiple comorbidities contraindicated to standard treatment. Most pts had two or multiple metastatic sites. Results: The ongoing long-term effect for MT indication was from 6 to 46 months. The main group consisted of the breast and colorectal cancer, 27% and 15%, respectively. The median time to progression was 9 months (16 months in CR was achieved (0,4%), 11 months and 9 months with a partial response (3,4%) and stable disease (21,2%), respectively). 12 (1,7%) pts are on ongoing long-term follow up more than 24 months. MT was well-tolerated. Drug related adverse events were described upon the study: hematological (10,2%, Gr 3-4 – 3,5%) vs non-hematological (6,6%, Gr 3-4 1,7%) toxicity. Conclusions: MT schedule demonstrated effectiveness in patients with advanced resistant tumors. The median duration of the effectiveness doesn’t depend on the line of therapy, tumor localization and objective response. The role of possible predictive markers of clinical benefit is question of further trials. [Table: see text]

Морфологическое исследование является единственным способом точной верификации опухолевой патологии и характеристики ее гистологического и молекулярно-генетического профиля, необходимого для персонификации стратегии лечения и прогнозирования течения заболевания.В обзоре обсуждаются организационные и технологические вопросы, касающиеся преаналитического этапа работы с биоматериалом для достижения качественных и достоверных результатов.В частности, уделяется большое внимание

Introduction: There is some evidence suggesting a link between BRCA1/2 germline mutations and increased risk of gastric cancer. Methods: Endoscopic screening for stomach malignancies was performed in 120 BRCA1 mutation carriers in order to evaluate the probability of detecting the tumor disease. Results: No instances of gastric cancer were revealed at the first visit. The analysis of atrophic changes performed by OLGA (Operative Link for Gastritis Assessment) criteria revealed that OLGA stages I–IV alterations were observed in 26 of 41 (63%) subjects aged >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ2 test). One BRCA1 mutation carrier developed gastric cancer 4 years after the first visit for endoscopic examination. We performed next-generation sequencing analysis for this tumor and additional 4 archival gastric cancers obtained from BRCA1/2 mutation carriers. Somatic loss of the remaining BRCA1/2 allele was observed in 3 out of 5 tumors analyzed; all of these carcinomas, but none of the malignancies with the retained BRCA1/2 copy, showed chromosomal instability. Conclusion: Taken together, these data justify further studies on the relationships between the BRCA1/2 and gastric cancer.

Recent study suggested a role of CHEK2 loss-of-function germ-line mutations in the predisposition to testicular cancer (TC) [AlDubayan et al., JAMA Oncol 2019;5:514-522]. We attempted to validate this finding relying on high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 germ-line variants were genotyped by conventional methods in TC patients and healthy controls. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2+1G>A [c.444+1G>A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR = 4.0 (95% CI 1.5–11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was revealed in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. CHEK2 c.470T>C (p.Ile157Thr) polymorphic variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR = 1.5 (95% CI 0.8–2.7), p = 0.3]. Somatic CHEK2 LOH was observed only in 6 out of 21 tumors obtained from CHEK2 c.470T>C (p.Ile157Thr) carriers, with C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients vs. population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.