Background. By 2020, breast cancer (BC) has become the most frequent malignancy in the world. The most common type of BC is HR+/HER2-negative cancer,2540% of which harbors PIK3CA mutations that affect the catalytic subunit of the PI3K protein. PIK3CA alterations are actionable, as such neoplasms can be treated with a combination of fulvestrant and the PI3K inhibitor alpelisib. As PIK3CA mutations have an extremely versatile effect on the characteristics of a tumor cell, numerous associations of PIK3CA mutations and various clinico-pathological characteristics of BC can be traced. Aim. Our aim was to clarify the information on the frequency and spectrum of PIK3CA mutations in Russian patients with HR+/HER2- advanced BC, and to study the association of PIK3CA mutations with clinical and pathological parameters of BC. Materials and methods. Tissue samples from 694 patients with HR+/HER2- advanced BC (mixed population of primary metastatic and relapsed tumors) who received any line of anti-cancer treatment in Dec 2020 to June 2021 in Russian Federation were analyzed by high-resolution melting, allele-specific PCR, digital droplet PCR and Sanger sequencing (exons 7,9, and 20 of the PIK3CA gene). Mutation rates in different BC subgroups were compared using the Fishers exact test. The age at diagnosis in patients with different PIK3CA status was compared using the MannWhitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the CochraneArmitage test for trends. Luminal A and B BC expression subtypes were distinguished with surrogate IHC markers according to St.-Gallen recommendations (2013). Results. Mutations were identified in 220/694 (32%) BC patients. The three most frequent missense substitutions in the PIK3CA gene (p.E542K, p.E545K, and p.H1047R) accounted for 190/220 (86%) mutations. Associations of PIK3CA mutations with luminal A subtype of BC, low proliferation index, small size of the primary tumor, and absence of signs of hereditary cancer were revealed. Associations of mutations in the kinase domain of PIK3CA (p.H1047R) with late recurrence of locally advanced BC and with non-Slavic ethnic origin of patients were found. Conclusion. PIK3CA mutation rate of 32% confirms high prevalence of mutation in Russian population, with some differences reflecting the ethnic origin of patients.

Relevance. PIK3CA belongs to the top three most frequently mutated genes in breast cancer (BC), especially in estrogen receptor (ER) positive, HER2 negative BC subtype. With an approval of selective PI3K-alpha inhibitor, alpelisib, this alteration has become actionable in ER+HER2- tumors. The frequency and spectrum of PIK3CA alterations in various cohorts is affected by a number of factors, including the distribution of BC expression subtypes, histological types, patient age, and even ethnicity. Aim. Aim of the current study was to characterize the frequency and spectrum of PIK3CA alterations in Russian BC patients. Materials and methods. The analysis of PIK3CA exon 7, 9 and 20 mutations was performed in a cohort of Russian ER+HER2- BC patients by a combination of high-resolution melting analysis, allele-specific PCR, and digital droplet PCR. Results. PIK3CA lesions were identified in 62/206 (30%) patients. Noteworthy, 59/62 (95%) of the identified variants were represented by the three most common p.E542K, p.E545K, and p.H1047R substitutions. The analysis of clinical and morphological characteristics revealed the trends towards association of PIK3CA mutations with older age and more frequent metastatic lung involvement. Conclusion. The obtained data on the frequency and spectrum of PIK3CA somatic aberrations can be helpful when organizing molecular genetic testing of breast cancer patients and using PI3K inhibitors in Russian population.

E13035 Background: EMPOWER trial demonstrated the benefit of eribulin administrated post CD4/6i in patients (pts) with HR+ HER2-negative (HR+HER2-) metastatic breast cancer (MBC). There are several important limitations to this trial: > 60% of pts were stage IV at the time of treatment initiation, eribulin used in late lines (2L only in 30% pts) and follow-up data were immature. Current study aimed to provide additional data on the real-world effectiveness and safety of eribulin monotherapy in this setting. Methods: Observation study of eribulin monotherapy in standard regimen enrolled 54 pts (median age 56; range 29-79 years) with HR+ HER2- MBC received at least one dose of eribulin post CDK 4/6i in metastatic settings; 24% pts had de novo metastatic BC, 76% - recurrent BC; 77% received palbociclib, 21% ribociclib, 2% both drugs; 49% pts received CDK4/6i with fulvestrant and 51% with AI. CDK4/6i was used: 49% pts in 1L, 36% in 2L, 16% in 3L. Median DOR of CDK4/6i treatment was 9.07 months (range 2-38). 94% pts received anthracyclines and taxanes, eribulin was used in 2L in 60%, 30% in 3L, 8% in 4L, 2% in 5L. The most common sites of metastases (Mts) were bones (78%), liver (73%), lung (56%) and brain (8%); visceral Mts were seen in 90% pts. Median follow-up – 11,5 months (range 3-36). Results: Median cycles of eribulin therapy was 10,5 (range 1-44); objective response rate was seen in 24%, stabilization - 67%, progression - in 9%. Median PFS was 10.0 months, there were no significant differences in the different subgroups (visceral/no visceral; recurrent/de novo BC; age; CDK4/6i as 1L vs 2L, fulvestrant vs AI), p > 0,05. Median PFS was higher in pts with lung Mts vs non-lung (24 vs 9,1 months, p = 0.056). Most common AEs all grades were neutropenia (26%), anemia (9%), asthenia (9%), polyneuropathy (11.1%). AE did not affect the effectiveness of eribulin (p = 0.648). Dose reduction was in 19% pts and did not affect the effectiveness of eribulin (p = 0.612). At median follow-up of 11.5 months, 92.5% of patients still alive. Conclusions: As post-CDK4/6i therapy, eribulin in HR+HER2- MBC pts was effective and well tolerated, regardless of age, line of CDK4/6, CDK 4/6i combination partner. Patients with metastasis to the lung have better mPFS. Results in this real-world population of pts with HR+HER2- MBC were consistent with the EMPOWER study, and support administration of eribulin in 2-3 lines as an effective option for post-CD4/6i pts.

Immune checkpoint inhibitors show promising results in the treatment of patients with malignant neoplasms. However, the objective response to immunotherapy varies depending on the molecular-genetic characteristics of the tumor tissue. While some patients experience a complete and prolonged response, others do not achieve a significant clinical effect even with the presence of microsatellite instability (MSI) or high expression of PD-L1. Consequently, there is a subset of patients who are insensitive to this category of drugs. The formation of specific antitumor immunity, particularly through complementary T-cell receptors to the antigen, plays a critical role. This work considers the mechanisms behind the formation of antitumor immunity, the resistance to therapy with checkpoint inhibitors, and the development of immune cell receptors that are complementary to tumor antigens. Antigenic drift in tumors can destabilize the specifically formed antitumor immunity, leading to disease progression despite immunotherapy. One of the conditions for establishing stable antitumor immunity is the immune system’s ability to continuously synthesize T-cell receptors for various tumor neoantigens. Determining the number of excision circles of recombination TREC and KREC allows for the assessment of the immune system’s capacity to form specific immunity. In oncological patients, a decrease in TREC and KREC levels in the blood can indicate immunodeficiency and may be a marker of the generalization of malignant neoplasms. In the development of specific antitumor immunity, V(D)J DNA recombination contributes to the formation of a diverse repertoire of antigenic receptors in developing T and B cells. Understanding the pathogenesis and clinical picture of antitumor immunity is crucial for effectively controlling the disease and predicting the effectiveness of using checkpoint inhibitors in the immune response.

Данный обзор посвящен механизмам работы противоопухолевого иммунитета и особенностям его формирования. Ингибиторы контрольных точек иммунного ответа изменили парадигму лечения больных со злокачественными новообразованиями (ЗНО). Иммунотерапия при многих ЗНО показала превосходящую стандартные химиотерапевтические опции эффективность. В данной работе представлен обзор литературных данных о механизмах формирования специфического противоопухолевого иммунитета и резистентности ЗНО к препаратам контроля иммунных точек. Для определения эффективности применения ингибиторов контрольных точек в клинической практике широко распространены маркеры: PD-L1 статус и микросателлитная нестабильность. Результаты исследований показывают, что уровень экспрессии PD-L1 определяет эффективность иммунотерапии. Наличие высокой микросателлитной нестабильности определяет чувствительность к терапии ИКТ независимо от гистологического подтипа. Наличие статусов PD-L1 и MSI является показанием для назначения блокаторов PD1 и PD-L1. Даже при наличии MSI и высокой экспрессии PD-L1 у определенной группы пациентов отсутствует эффект от проводимой терапии, что указывает о резистентности и отсутствии специфического противоопухолевого иммунитета. V(D)J-рекомбинации ДНК обеспечивают продукцию разнообразных антигенных рецепторов в развивающихся Т- и В-лимфоцитах, что представляется ключевым фактором развития специфического противоопухолевого иммунитета. Для определения эффективности иммунотерапии следует рассмотреть количественные показатели TREC и KREC.

Neuroendocrine tumours (NETs) are a heterogeneous group of malignant neoplasms with diverse morphology and nomenclature. Well-differentiated NETs were historically termed carcinoid tumours, which entailed abundant confusion and misclassification. Cross body-localised NETs have been described from the central nervous system, respiratory and gastrointestinal tracts, larynx, thyroid, skin, breast and urogenital system. The evidence on NET prevalence is diverse, with selected sources estimating a 0.5% rate among total malignancies diagnosed. Carcinoid syndrome is a known important associate of NETs. Its presence resulting from the amine and peptide hypersecretion often facilitates the NET diagnosis, and curative surgery becomes a treatment of choice, if technically feasible. Adjuvant therapy is ambiguous. When surgery is impractical due to a usually advanced NET at diagnosis, drug therapy is adopted to relief symptoms and control the disease.