Breast cancer therapy for BRCA1 carriers: moving towards platinum standard?

Recently Byrski et al. reported the first-ever breast cancer (BC) study, which specifically selected BRCA1-carriers for the neoadjuvant treatment and used monotherapy by cisplatin instead of conventional schemes. Although the TNM staging of the recruited patients was apparently more favorable than in most of published neoadjuvant trials, the results of Byrski et al. clearly outperform any historical data. Indeed, 9 of 10 BRCA1-associated BC demonstrated complete pathological response to the cisplatin treatment, i.e. these women have good chances to be ultimately cured from the cancer disease. High sensitivity of BRCA1-related tumors to platinating agents has been discussed for years, but it took almost a decade to translate convincing laboratory findings into first clinical observations. With increasing stratification of tumor disease entities for molecular subtypes and rapidly growing armamentarium of cancer drugs, it is getting technically and ethically impossible to subject all promising treatment options to the large randomized prospective clinical trials. Therefore, alternative approaches for initial drugs evaluation are highly required, and one of the choices is to extract maximum benefit from already available collections of biological material and medical charts. For example, many thousands of BC patients around the world have already been subjected to second- or third-line therapy with platinum agents, but the association between BRCA status and response to the treatment has not been systematically evaluated in these women. While potential biases of retrospective studies are widely acknowledged, it is frequently ignored that the use of archival collections may provide preliminary answers for long-standing questions within days instead of years. However, even elegantly-designed, small-sized, hypothesis-generating retrospective studies may require multicenter efforts and somewhat cumbersome logistics, that may explain the surprising lack of historical data on the platinum-based treatment of BC in BRCA1 carriers

GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individual

Молекулярная патология рака легкого: клинические аспекты

Discovery of tyrosine kinase inhibitor sensitizing mutations in lung cancer (LC) appears to be the main event in clinical oncology of the last decade. Activating lesions in epidermal growth factor receptor (EGFR) gene almost guarantee tumor response to gefitinib, erlotinib or afatinib.ALK translocations are strongly associated with efficacy of crizotinib or otherALK inhibitors. Instances of success of targeted therapy have been demonstrated for LC harboring mutations in ROS1, RET, HER2, BRAF and KRAS oncogenes. Whole genome sequencing of LC-derived DNAhas revealed a number of novel potentially druggable molecules. Rapid progress in understanding of lung cancer molecular pathogenesis allows to expect that several new targeted agents for LC treatment will become available already within this decade.Обнаружение мутаций, ассоциированных с беспрецедентной чувствительностью карцином лёгкого к ингибиторам тирозинкиназ, представляется наиболее важным событием клинической онкологии в прошедшем десятилетии. Активирующие повреждения в гене, кодирующем рецептор эпидермального фактора роста (EGFR), практически гарантируют ответ на лечение гефитинибом, эрлотинибом или афатинибом. Перестройки гена ALK ассоциированы с выраженным эффектом на терапию кризотинибом или другими ALK-ингибиторами. Продемонстрирована результативность таргетной терапии по отношению к опухолям, содержащим мутации в генах ROS1, RET, HER2, BRAF и KRAS. Изучение карцином лёгкого посредством полногеномного секвенирования позволило выявить новые перспективные мишени для лечебных воздействий. Тенденции накопления сведений о молекулярном патогенезе РЛ дают основания полагать, что спектр потенциально эффективных таргетных препаратов для лечения РЛ многократно расширится уже в этом десятилети

PALB2 mutations in German and Russian patients with bilateral breast cancer

Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent. Our results indicate that PALB2 germline mutations account for a small, but not negligible, proportion of bilateral breast carcinomas in German and Russian populations

Unexpected “Lazarus response” to single-agent bevacizumab in heavily pretreated patients with HER2-positive breast cancer

Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs. The efficacy of this approach is explained by the ability of bevacizumab to eliminate immature blood vessels thus normalizing intratumoral blood flow and improving the delivery of cytotoxic or targeted agents. This report describes four cases of heavily pretreated patients with metastatic HER2-positive breast cancer, who had no meaningful treatment options left, and who received single-agent bevacizumab as an empirical last-resort therapy. Three of these patients had severe complaints, and they demonstrated striking symptomatic relief within the first day of this treatment. In addition to the observed “Lazarus response”, which was likely attributed to the bevacizumab-driven resolution of edema, some evidence of a direct antitumor effect was observed. These data may call for the reconsideration of bevacizumab monotherapy in patients with HER2-associated breast cancer, and perhaps in some other categories of cancer patients

CHEK2 1100 delC mutation in Russian ovarian cancer patients

BRCA1 and BRCA2 germ-line mutations occur in a significant number of unselected ovarian cancer (OC) patients, thus making a noticeable contribution to OC morbidity. It is of interest whether CHEK2, which is frequently regarded as a third breast cancer specific gene, is also relevant to ovarian cancer pathogenesis. In this report we analyzed the presence of CHEK2 1100 delC founder mutation in 268 randomly recruited OC patients. The mutation was identified in 2 women with OC (0.8%) as compared to 1/448 (0.2%) healthy middle-aged and 0/373 elderly tumour-free women. Taken together this result and the negative findings of two other published reports on an association of CHEK2 with ovarian cancer indicate that there is no justification for intensive ovarian cancer screening in CHEK2 1100 delC carriers

Response to : The GPRC5A frameshift variant c.183del is not associated with increased breast cancer risk in BRCA1 mutation carriers

Non peer reviewe

ГЕНЕТИКА ПРЕДРАСПОЛОЖЕННОСТИ К ИНФЕКЦИОННЫМ ЗАБОЛЕВАНИЯМ

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individualsГенетические особенности организма играют важную роль в развитии инфекционных заболеваний, обусловливая восприимчивость к разнообразным бактериям, вирусам и грибам, а также оказывая влияние на течение болезни. Многочисленные исследования свидетельствуют о существовании аллелей предрасположенности к инфекциям. Кроме того, в настоящее время известно около 300 нозологических форм первичных иммунодефицитов (ПИД), которые представляют собой наследственные дефекты иммунитета. Своевременная диагностика таких состояний представляет значительные трудности, однако она крайне необходима для повышения качества лечения пациентов. Использование современных методов ДНК-анализа во многих случаях позволяет установить генетическую причину уязвимости по отношению к тем или иным инфекционным агентам.

Lack of Response to Imatinib in Melanoma Carrying Rare KIT Mutation р.T632I

Approximately 15% of acral and mucous melanomas carry activating mutations in KIT oncogene. There is a diversity of spectrum of KIT mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with KIT р.T632I mutation, who failed to respond to imatinib