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.
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.
Hepatocellular carcinoma (HCC) is a public health problem worldwide and is one of the most common and lethal cancers worldwide, the sixth among the most common cancers and the second mortal cancer worldwide. Viral hepatitis is the main risk factor. Growing evidence suggests that the metabolic syndrome, which includes hyperlipidemia, dyslipidemia, and hypertension, increases the risk of developing HCC. Epidemic of obesity, the proportion of HCC with non-alcoholic fatty liver disease (NAFLD) in the Russian population is 17.4 %. In clinical practice, it is often difficult to identify the leading etiological factor. In a patient with concomitant viral hepatitis, HCC may be associated with alcohol abuse or metabolic disorders. In clinical trials, investigators evaluate the most likely etiology of HCC, and studies analyze subgroup: HBV, HCV, and non-viral etiologies, which include a variety of liver diseases: alcoholic liver disease, NAFLD, autoimmune hepatitis, and others. Differences in the effectiveness of systemic therapy depend on the main etiological factor has been published recently. Pivotal studies of combinations of immuno-oncological drugs have shown mixed results in efficacy. For the combination of atezolizumab with bevacizumab and pembrolizumab with lenvatinib, there was no difference in OS in non-viral subgroups, although the difference was significant for the combination of durvalumab with tremelimumab compared with TKIs from the control group. A multivariate analysis of patient characteristics showed that lenvatinib is an independent prognostic factor for OS, reducing the risk of death by 35 % compared with atezolizumab in combination with bevacizumab in patients with non-viral HCC etiology in the A. Casadei-Gardini study. The same has been proven for the NASH/NAFLD subgroup. Currently, it is difficult to conduct prospective clinical trials to assess the efficacy and safety of treatment depending on the etiology, it is important to focus on data from real-world evidence in order to have guidelines for making decisions regarding the treatment of non-viral HCC.
An obvious trend of the last decade in head and neck squamous cell carcinoma pathogenesis evaluation is awareness of the impact of immune response disorders on disease manifestation. The review presents an analysis of the differences in the type and degree of immunosuppression, as well as treatment response in head and neck squamous cell carcinoma patients in accordance with influencing carcinogenic factor, gender, age of the patient and concomitant diseases. An increase in CD8+ T-lymphocytes and a decrease of memory T-cells has been evaluated in smoking and alcohol abusing patients with head and neck squamous cell carcinoma, and a smaller number of CD8+ T-lymphocytes were detected in the tumor microenvironment compared to non-smoking and non-drinking patients. Studies have shown that the improved prognosis of patients with human papillomavirus (Hpv) – associated head and neck squamous cell carcinoma is largely due to the presence of antibodies against Hpv E6 and E7, E7-specific CD8+T lymphocytes in periphe ral blood and a high level of tumor-infiltrating T lymphocytes. The issue of gender differences in the type of immune response is widely discussed. It has been shown that the use of immune response checkpoint inhibitors is more effective in improving survival rates in men, and the use of these drugs in combination with chemotherapy is more effective in women. In addition, in elderly cancer patients, numerous age-associated T-lymphocyte’s function changes were revealed, including a decrease in the number of naive T-lymphocytes due to age-related involution of the thymus and an in crease in the relative number of memory cells and effector cells. Thus, it is clear that immunosuppression type, as well as treatment response, differ depending on the influencing factor, gender, age of the patient, as well as comorbidities.
Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma.
The problem of metastatic breast cancer treatment is linked with clonal selection both in the process of tumor evolution and under the influence of previous treatment. The analysis of metastatic niche microenvironment and the molecular genetic features become essential for treatment individualization. Studies demonstrate hormonal expression and epidermal growth factor receptor (HER2neu) discordance between the primary tumor and the metastatic focus. The advantages of combined hormone therapy (CНT) with CDK4/6 inhibitors were revealed in comparison with hormone therapy (НT) with survival rates benefits in the 1st and 2nd lines of НT, as well as after the 1st line of chemotherapy in clinical trials. However, there are lack of data on patients with multiple lines of chemotherapy. In the present retrospective study, more than half of the patients were treated palliative chemotherapy before administration of CDK4/6 inhibitors. Main metastatic foci represented luminal types after biopsy, however, loss of progesterone receptor expression was noted with the initial luminal A-subtype. At the time of the data cut-off, most patients have a longterm clinical effect, improvement conditions and reduction of pain, including the cases of late line CHT setting after chemotherapeutic regimens. Taking into account the heterogeneity of metastatic breast cancer, clonal selection and phenotype discordance there is the crucial need for molecular and genetic characteristics of the metastatic process. At the same time it is possible to consider the appointment of combined hormone therapy with CDK4/6 inhibitors as additional option for late-line treatment of the disseminated process. Prospective studies on combined hormonal therapy with CDK4/6 inhibitors in metastatic breast cancer in late lines of therapy with proven HR+HER2neu-negative receptor status of the metastatic focus are strongly recommended.
Activation of the estrogen receptor-α (ER-α) signaling pathway is a significant factor in the initiation of carcinogenesis in various types of tumors due to the genomic and non-genomic effects of estradiol in cancer cells. However, data on the expression of ER-α and aromatase on stromal and immune cells in the tumor microenvironment (TME) point to an additional mechanism by which estrogens increase tumor malignancy. There is growing evidence that TME can affect tumor immunity by increasing the immune response or reducing immunoreactivity.The important role of estrogen and the estrogen receptor signaling pathway in the response of the tumor microenvironment in cancer of various localizations, not only classical hormone-dependent cancers, has been proven. However, the clinical effectiveness of blocking the effect of estrogen on tumor growth has been primarily shown in cancer of the female reproductive system. At the same time, data on the significant role of TME in the development of endocrinotherapy resistance in breast cancer treatment are of great interest.Despite the possibilities of standard therapy, a more in-depth study on the role of various TME components in cancer evolution, creation of a micrometastatic niche, as well as in the response to therapy may result in development of new strategies for cancer treatment. It is also necessary to study the possibilities of overcoming the immunosuppressive effect of the estrogen receptor signaling pathway on TME in order to increase the survival rates in patients with hormone-dependent cancers, particularly, breast cancer.
PARP inhibitors. However, in clinical practice, despite the proven antitumor efficacy of drugs, acquired resistance to PARP inhibitors leads to difficulties in selecting further therapy due unknown resistance mechanisms and absence of algorithm of action. Despite the various mechanisms of resistance to PARP inhibitors, the choice of subsequent combination therapy after the detection of resistance to PARP inhibitors should be based on an understanding of these mechanisms and the existence of heterogeneous metastatic process. At the same time, it is very important to study the molecular and genetic characteristics of the disease at each stage of progression, which will help to identify the cause of resistance and select the optimal treatment strategy. It seems that liquid biopsy of circulating tumor DNA, detection of circulating tumor cells, circulating microRNA or exosomes may be more suitable methods of molecular diagnostics than repeated biopsies. Currently, there are data on the identification of two types of resistance to PARP inhibitors: mechanisms independent and dependent on the BRCA1/2 gene and homologous DNA recombination repair (HRR) mechanisms. Strategies for using combinations of different therapeutic regimens in conjunction with PARP inhibitors are very promising options for preventing treatment resistance in view of the increasing number of patients with similar clinical course of the disease.In the presented clinical case, BRCA1-associated triple-negative breast cancer demonstrates an aggressive clinical course in case of adjuvant chemotherapy absence. Using the example of a clinical case, the effectiveness of therapy with the PARP inhibitor olaparib in disseminated BRCA1-mutated breast cancer, including those with brain metastases, was confirmed. At the same time, against the background of good tolerance and сlinical efficacy especially in the case of brain metastases, the use of the PARP inhibitor olaparib is a worthy alternative to chemotherapeutic regimens. The selection of subsequent therapy after a PARP inhibitor requires a balanced approach, taking into account the possible causes of crossresistance with chemotherapy regimens.
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