Langzeitremission bei einem Patienten mit metastasiertem Adenokarzinom des Pankreas: Aktuelle Therapiemöglichkeiten und neue Therapiealgorithmen mit Hilfe des Molekularen Tumorboards

Zusammenfassung Hintergrund Das Adenokarzinom des Pankreas geht trotz verbesserter diagnostischer Möglichkeiten und neuer teilweise multimodaler Therapien mit einer sehr schlechten Prognose einher. Eine Heilung kann nur in lokalisierten Stadien mittels vollständiger Resektion erreicht werden. Da bei Diagnosestellung jedoch bereits in 45–70% der Fälle eine Fernmetastasierung vorliegt, gelten die meisten Fälle als primär inoperabel. Aufgrund neuer molekularer Erkenntnisse haben sich zielgerichtete Therapiemöglichkeiten eröffnet. Wir berichten von einem Patienten mit metastasiertem Adenokarzinom des Pankreas mit Nachweis verschiedener Mutationen, die Angriffspunkte für gezielte Therapien darstellen und erläutern mögliche Therapieansätze. Fallbericht Bei einem Mitte 50-jährigen Patienten wurde bei abdominellen Schmerzen ein metastasiertes Adenokarzinom des Pankreas diagnostiziert. Unter einer palliativen platinhaltigen Chemotherapie mit FOLFIRINOX konnte bildgebend ein fast komplettes Ansprechen erreicht werden. Nach Nachweis einer BRCA-2-Mutation erfolgte der Einschluss in die POLO-Studie mit einer Erhaltungstherapie mit dem Poly(ADP-ribose)-Polymerase (PARP)- Inhibitor Olaparib, unter dem es nach 8 Monaten zu einem Progress kam. Es folgten Zweit- und Drittlinientherapien mit Gemcitabin in Kombination mit Nab-Paclitaxel und im Verlauf mit Erlotinib. Zudem konnte eine aktivierende Mutation im KRAS-Gen festgestellt werden. Auf eine weitere experimentelle gezielte Therapie bezüglich dieser Mutation wurde von Seiten des Patienten verzichtet. Schlussfolgerung Die Identifizierung prädiktiver Faktoren und spezifischer therapierbarer Mutationen bei Patient*innen mit fortgeschrittenem Adenokarzinom des Pankreas scheint bei aktuell noch sehr schlechter Prognose dieser Erkrankung von großer Bedeutung, um individualisierte Therapien zu ermöglichen.

Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review

Background and aim The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual’s risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations. Methods Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review. Results Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

Investigation of Molecular Modeling And Molecular Dynamics Simulation In BRCA-1 And BRCA-2 Genes of Amygdalin Ligand

Breast cancer is the most common type of cancer and the most fatal type among women. BRCA-1 and BRCA-2 are tumor suppressor genes known to cause breast cancer. Drug studies have become very important to target the production of more accurate drugs by reducing the cost with the previous designs of drugs in this field. Amygdalin is used in the treatment of especially cancer, characterized by the loss of red blood cell production. In this study, which was conducted for the first time, it was aimed to examine the use of amygdalin in breast cancer treatment by coupling to the active regions of BRCA-1 and BRCA-2 genes by molecular docking method. The best attachment scores were selected. Amygdalin was taken from PubChem database in sdf format. According to the molecular insertion results, the free energy of the amygdalin ligand for binding to the BRCA-1 protein was -4.8 kcal/mol and the free energy for binding to the BRCA-2 protein was -7.2 kcal/mol also include Ki values. MD simulation was performed using Desmond. Insertion results show that the amygdalin ligand binds more strongly to the BRCA-2 protein than to the BRCA-1 protein. MD simulation for the highly active inhibitor Amigydalin in complex with protein BRCA-2 revealed that the stabilization of ligand was achieved due to the formation of uninterrupted hydrophobic interactions. Due to the binding power of amygdalin ligand, it reveals a unique structure for breast cancer and it is thought to be a reference for designing new molecules with the same structure against cancer and applying these molecules in vivo and in vitro studies.

Advances and challenges in cancer treatment and nutraceutical prevention: the possible role of dietary phenols in BRCA regulation

Over the years, the attention towards the role of phytochemicals in dietary natural products in reducing the risk of developing cancer is rising. Cancer is the second primary cause of mortality worldwide. The current therapeutic options for cancer treatment are surgical excision, immunotherapy, chemotherapy, and radiotherapy. Unfortunately, in case of metastases or chemoresistance, the treatment options become very limited. Despite the advances in medical and pharmaceutical sciences, the impact of available treatments on survival is not satisfactory. Recently, natural products are a great deal of interest as potential anti-cancer agents. Among them, phenolic compounds have gained a great deal of interest, thanks to their anti-cancer activity. The present review focuses on the suppression of cancer by targeting BRCA gene expression using dietary polyphenols, as well as the clinical aspects of polyphenolic agents in cancer therapy. They regulate specific key processes involved in cancer progression and modulate the expression of oncogenic proteins, like p27, p21, and p53, which may lead to apoptosis, cell cycle arrest, inhibition of cell proliferation, and, consequently, cancer suppression. Thus, one of the mechanisms underlying the anti-cancer activity of phenolics involves the regulation of tumor suppressor genes. Among them, the BRCA genes, with the two forms (BRCA-1 and BRCA-2), play a pivotal role in cancer protection and prevention. BRCA germline mutations are associated with an increased risk of developing several types of cancers, including ovarian, breast, and prostate cancers. BRCA genes also play a key role in the sensitivity and response of cancer cells to specific pharmacological treatments. As the importance of BRCA-1 and BRCA-2 in reducing cancer invasiveness, repairing DNA damages, oncosoppression, and cell cycle checkpoint, their regulation by natural molecules has been examined.

Surgical Management of Hereditary Breast Cancer

The identification that breast cancer is hereditary was first described in the nineteenth century. With the identification of the BRCA1 and BRCA 2 breast/ovarian cancer susceptibility genes in the mid-1990s and the introduction of genetic testing, significant advancements have been made in tailoring surveillance, guiding decisions on medical or surgical risk reduction and cancer treatments for genetic variant carriers. This review discusses various medical and surgical management options for hereditary breast cancers.

Germinal mutations landscape, which is responsible for cancer predisposition in multinational Republic of Bashkortostan.

e22504 Background: In oncology hereditary forms of malignant neoplasms occupy a special position due to the frequent cases at a young age and poor prognostic factors. The aim of this work is to determine in cancer patients germinal mutations which are responsible for cancer predisposition. Methods: The study included patients with burdened family history or those with a manifestation of malignant neoplasm at a young age residing on the territory of multinational Republic of Bashkortostan. The patients were diagnosed with one of these diseases: breast cancer, prostate cancer, pancreatic cancer, gastric cancer, colon cancer. The study is based on analyses of the molecular genetic blood testing n cancer patients using real-time polymerase chain reaction (PCR) for detection of 8 widely spread mutations among Russian population: in BRCA 1 gene were detected such mutations as 185delAG, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT, 300T>G, 2080delA; in gene BRCA 2 - 6174delT. Blood samples of the rest amount of patients which proved no mutations by PCR method was tested by the “next-generation” sequencing method (NGS). Results: The results of the study showed territorial features of presence of germinal mutations of Russian multinational region. The results of the study aimed to reveal the spectrum and frequency of gene mutations characteristic for the particular region: BRCA 1 - c.5266dupC, c.3143delG, c.5161C>T, c.5382 insC, c.3819delGTAAA, c.300T>G, c.5136G>A, 185delAG, 4153delA, 2080delA; BRCA 2 - c.6621_6622del, с.39-1_39delGA, c.961_962insAA; CHEK2 - c.470T>C, c.444+1G>A; PALB2 - c.1592delT; RAD50 - c.2157delA; MLH1 - c.1637A>G; MSH6 - c.2554_2556del; STK11 - c.368A>G; MSH2 - c.815C>T. According to the mutation detection the patient consulted a geneticist for making a genealogic tree for future molecular genetics exam. Hereinafter the control group included relatives of patients who remain potential carriers of pathogenic mutations of the proband using Sanger sequencing method. When penetrate mutations are identified in healthy population, a set of measures is taken to prevent and early diagnose malignant tumors. Conclusions: The results of the study showed features of presence of each detected mutation which is characteristic for south-eastern part of the Russian multinational region. This study plays an important role in the process of optimization of screening of germinal mutation carriers among healthy population and as a result it helps to conduct prophylactic measures to early diagnose malignant neoplasms.

BRCA mutations and their clinical relevance in unselected pancreatic cancer population.

e16240 Background: Germline pathogenetic mutations in BRCA1/2 genes are described in pancreatic cancer patients (PCP) in about 5–9% of cases. The purpose of this study was to determine their relevance in an unselected consecutive cohort of PCP describing family and clinical history. Methods: Patients (pts) were recruited at a single cancer center from September 2019 to October 2020. Participants provided blood for DNA analysis; cancer family history and treatment records were reviewed; DNA was analyzed by Next Generation Sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1/2 Results: 69 pts were included, 61 (88,4%) with locally advanced and metastatic pancreatic cancer received first line chemotherapy and 38 (62%) were full eligible for BRCA analysis; 8 out of 69 pts were BRCA screened even if in adjuvant setting, 10 patients are still under evaluation. Out of the 38 first line screened PCP germline BRCA mutations were found in 9 (19%): 4 pts (8,7%) with pathogenetic BRCA-2 variants (subgroup 1 – S1) and 5 pts (10,8%) with variants of unknown significances (VUSs), i.e. c.5339T>C and c.5096G>A in BRCA1 (subgroup 2 – S2). Samples from 29 pts were established as BRCA wild-type (subgroup 3 – S3). Pathogenetic BRCA-2 variants were observed in 2 male and 2 female (median age, 61.5 years, range 48-69), 3 out 4 without family history of breast, ovarian and pancreatic cancer, one patient (pt) had ovarian cancer family history. All pts had a negative personal history of others cancers. All S1 pts received FOLFIRINOX regimen achieving one complete response, 2 partials responses and 1 disease progression with RECIST criteria. The S2 included 2 male and 3 female (median age, 61 years, range 45-70) 2 with family history of pancreatic cancer, no pt had personal history of others cancers; 2 pts had stable disease and 3 disease progression receiving platinum-based regimen (4 pts) and gemcitabine/nabpaclitaxel (1 pt), respectively. Platinum responders were observed only in the well known pathogenetic BRCA-2 variants group with twice a median progression-free survival (PFS, months -ms-) as compared to the one observed in VUSs group. (>6 C.I. 95% 2- >12 ms; vs 3 ms, 95% C.I. 3-12 ms). S3 included 9 male and 20 female, (median age, 66 years, range 42-78); 5 pts had family history of pancreatic or breast cancer, 5 pts had a personal history of other cancers (breast and thyroid). In this group,16 pts received a platinum based regimen and 12 pts have been treated without platinum based regimen. Conclusions: Our results suggest that: 1) BRCA pathogenetic mutations rate (8,7%) is in line with literature data and seems not to be related with family or personal history, and to be associated with a better outcome; 2) No BRCA mutations were detected in patients over 70 years. 3) VUSs subgroup do not seem to benefit from platinum-regimen.

Cáncer de mama asociado a mutación en genes BRCA-1 y BRCA-2

El cáncer de mama es el tumor maligno más frecuente en mujeres y la primera causa de muerte en países desarrollados. Su incidencia está en aumento pero su diagnóstico precoz ha logrado disminuir la mortalidad. En algunas ocasiones, el cáncer de mama obedece a mutaciones genéticas heredadas. El tejido tumoral de los cánceres de mama relacionado a mutaciones en la línea germinal requiere un detallado estudio histológico y molecular que determinen las principales características del tumor a fin de establecer riesgo, manejo, pronóstico y sobrevida del paciente. Los genes mayormente implicados a mutaciones en la línea germinal son el BRCA1 y BRCA2. Aquellos tumores asociados a estas mutaciones presentan características tumorales más agresivas en relación a quienes no portan una mutación, lo que se relaciona a un peor pronóstico.