The role of CDK inhibitors in breast cancer therapy

Cyclin D1 and cyclin-dependent protein kinases CDK4/6 are part of RB-pathway which plays a very important role in the regulation of cell cycle progression and cell death. d-type cyclins associate with cdk4 and 6 to phosphorylate the Rb protein. Hyperphosphorylation of Rb promotes the release of the E2F family of transcription factors that then promotes entry into S phase through activation of key target genes. CDK inhibitors are proteins that suppress CDK-cyclin protein kinase activity in the G1 phase of the cell cycle and promote G1 arrest in response to environmental or intracellular signals. A literature search of these topics was performed through PubMed. Results from preclinical and early-stage clinical trials support the efficiency of CDK inhibitors such palbociclib, abemaciclib and ribociclib for the treatment of human cancers - including breast cancer. The first-in-class CDK4/6 inhibitor, which significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for steroid receptor -positive, HER2-negative advanced breast cancer is Palbociclib. Other inhibitors (abemaciclib, ribociclib) are still in clinical trials and are a very promising group of drugs

Farmakokinetyka i farmakogenetyka w systemowym leczeniu chorych na raka piersi

Pharmacogenetics is an intensively developing branch of science, which investigate the correlation between genetic differentiation and treatment response. The purpose of pharmacogenetics is also a selection of patients, who are the most likely to develope severe side effects. The aim of this study is to recapitulate the pharmacogenetics and pharmacokinetics researches conducted in breast cancer patients received up to now. We concentrated mainly on polymorphisms in transporters proteins and in drug-metabolising enzymes used in cancer chemotherapy in breast cancer patients. Literature review was performed using ScienceDirect and PubMED bases. We discussed the influence of identified gene polymorphisms on development of severe toxic side effects in healthy tissues and tumor response. Onkol. Prak. Klin. 2010; 6, 4: 159–170Farmakogenetyka to intensywnie rozwijająca się dziedzina nauki, która bada zależności pomiędzy zróżnicowaniem genetycznym a odpowiedzią na leczenie. Jej zadaniem jest również próba wyselekcjonowania tych chorych, u których może rozwinąć się silna reakcja toksyczna. Celem tej pracy jest podsumowanie przeglądu badań na temat farmakogenetyki i farmakokinetyki w leczeniu chorych na raka piersi. Skupiono się na badaniach polimorfizmów genowych dotyczących białek transportujących oraz polimorfizmów wpływających na metabolizm leków przeciwnowotworowych stosowanych w terapii chorych na raka piersi. Przeglądu dokonano na podstawie piśmiennictwa dostępnego w bazie PubMed i ScienceDirect. Omówiono wpływ zidentyfikowanych polimorfizmów na rozwój reakcji toksycznych zdrowych tkanek oraz odpowiedzi guza na leczenie Onkol. Prak. Klin. 2010; 6, 4: 159–17

Checkpoint Kinase 2 (CHEK2) Mutation in Renal Cell Carcinoma: A Single-Center Experience

Renal cell carcinoma (RCC) occurs in sporadic and heritable forms. Genetic mutations have been identified as risk factors in 1–2% of RCC. The aim of this study was to evaluate I157T and CHEK2*1100delC mutations of checkpoint kinase 2 (CHEK2) gene in RCC. Medical records of 40 clear cell RCC patients who had genetic tests and consultation at the Genetic Outpatient Clinic, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland, were reviewed retrospectively. Mutation profile was assessed by ASA-PCR and RFLP-PCR techniques. Only three female patients had CHEK2 mutation (I157T). No CHEK2*1100delC was observed in any of the patients. These tumors were N0, and two were Grade 3. One showed capsular infiltration. No blood vessel infiltration or metastases was observed. Overall, RCC from patients with CHEK2 mutation did not display any special characteristics when compared with those without the mutation. While no association between CHEK2 mutation and RCC could be established, all three patients with CHEK2 mutation developed second neoplasms many years after first diagnosis. Further studies, especially regarding CHEK2 mutation as a predictive factor for second neoplasm in RCC patients, are warranted

Tamponada serca w przebiegu raka piersi jako objaw nawrotu choroby

Cardiac tamponade is life-threatening state caused by fluid accumulation in the pericardial sac and consequently by increase of intrapericardial pressure. In neoplastic disease pericardiac involvement which manifests clinical symptoms as cardiac tamponade occurred uncommon and  can be cancer first symptom or develop in it’s terminal period. The most common neoplastic cause of the pericardial effusion are metastatic tumors, especially from lung and breast cancer. In this case report cardiac tamponade was the first symptom of breast cancer recurrence and then occurred again during systemic treatment as the symptom of disease progression.Tamponada serca jest stanem zagrożenia życia wywołanym nagromadzeniem się płynu w worku osierdziowym i w konsekwencji wzrostem ciśnienia śródosierdziowego. W chorobie nowotworowej zajęcie osierdzia manifestujące się objawami klinicznymi w postaci tamponady występuje rzadko i może być pierwszym objawem choroby lub rozwinąć się w jej okresie terminalnym. Najczęstszą przyczyną wysięku nowotworowego są guzy przerzutowe, zwłaszcza z raka płuca i piersi. Prezentowany przypadek dotyczy chorej, u której tamponada serca była pierwszym objawem nawrotu raka piersi a następnie ponownie wystąpiła podczas leczenia systemowego jako objaw progresji.

The comparison between TP53 gene polymorphisms (c.[215G>C]) homozygotes and heterozygotes in Breast Cancer Patients: A clinicopathological analysis

Purpose: TP53 is a tumor suppressor gene which participates in regulation of cell cycle check points, DNA repair, and apoptosis. The aim of this study was to compare TP53 germ line gene polymorphisms (c.[215G>C]) wild – type homozygotes GG with heterozygotes GC according to clinicopathological factors.Methods: We reviewed the medical records of 87 (22% TP53 gene homozygotes and 78% heterozygotes) breast cancer patients who were diagnosed and treated in COI in Gliwice. Polymorphism profile was assessed by RFLP-PCR technique.Results: The presence of lobular invasive carcinoma was observed insignificantly more often in homozygotes, especially in the group of patients at the age below 50 years (29% vs. 4%, p = 0.095). Patients being TP53 gene heterozygotes had larger tumor size (T > 2) than homozygotes (16% vs. 5%, p = 0.450). There was observed a tendency to the presence of lymph node metastases (53% vs. 34%, p = 0.182) and higher Ki67 (> 20%) (69% vs. 46%, p = 0.209) in TP53 gene homozygotes. HER2 overexpression was associated with TP53 heterozygotes, especially in the group of patients at the age above 50 years (33% vs. 8%, p = 0.144). A negative receptor status was reported more frequently in homozygotes (43% vs.21%, p = 0.340) in patients with age below 50 years. Similarly higher histological grade G3 was detected more often in homozygotes in patients at the age below 50 years (80% vs. 33%, p = 0.130).Conclusion: TP53 gene homozygotes and heterozygotes differ from each other in respect of clinicopathological factors such as: histological type, lymph node metastases, higher Ki67 (> 20%), histological grade G3, ER/PR status, tumor size (T > 2), HER2 overexpression, cancer in family history and diabetes. Patient’s age was associated with the pathological characteristics of tumor

Everolimus in every day practice of metastatic renal cell carcinoma therapy – one center experience

Introduction: Everolimus is a selective mTOR inhibitor which received approval for treatment of advanced renal cell carcinoma (mRCC) after progression on or after treatment with VEGF-targeted therapy. The aim of this study was to evaluate the efficiency and toxicity profile of everolimus in second line therapy of mRCC. The authors also assessed the impact of clinicopathological factors on the effectiveness of everolimus. Methods: The retrospective analysis was conducted on the medical records of 33 mRCC patients who were treated with everolimus in second line therapy after progression on interferon or tyrosine kinase inhibitors (sunitinib or pazopanib) during the years 2010–2016. Results: Median time of treatment with everolimus was 4 months (range from 1 to 58 months). Median progression free survival was 4 months and overall survival (OS) was 11 months. The best response (PR + CR + SD) was reported in 57% of patients. Toxicity in grade 3–4 was reported in 9 (27%) of patients. Clinicopathological factors associated with progression during everolimus therapy were: smoking and alcohol abuse (p = 0.029), higher Furman grade (p = 0.166), tumor necrosis (p = 0.383), fat tissue infiltration (p = 0.040), lymph node (p = 0.193) and adrenal metastases (p = 0.067). Factors which increase the risk of everolimus toxicity were worse performance status (p = 0.333) and more advanced disease at the beginning (lymph nodes metastases, p = 0.05) and higher Furman grade (p = 0.04). Conclusions: Cigarettes use and/or alcohol abuse, adrenal metastases, fat tissue had significantly negative influence on survival. Grade 3–4 toxicity were reported more frequently in patients with worse performance status and more advanced disease at the time of diagnosis

The use of imatinib in the treatment of inoperable dermatofibrosarcoma protuberans in the area of the shoulder joint

Introduction. Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin and subcutaneous tissue. The most common clinical problem is its local recurrence. The therapeutic procedure of choice is radical surgery. In the case of inoperable disease, targeted therapy with imatinib, a tyrosine kinase inhibitor, may cause significant reduction of tumor volume and even enable radical surgery. Objective. We present the effectiveness of imatinib for the treatment of unresectable DFSP localized in the area of the shoulder joint of a 62-year-old woman. Case report. The patient met the criteria for inclusion in treatment with imatinib. After 3 cycles of treatment, partial regression of the lesions (above 50%) was observed. Therapy was complicated by hepatological side effects during the sixth cycle. Treatment was continued with a reduced dose when transaminase levels normalized. In a physical examination and imaging studies, further regression was observed. The patient has regained considerable mobility of the shoulder joint. A decision to continue the treatment has been made. Conclusions. The use of imatinib allowed a clinical benefit to be gained in the form of significant regression of lesions. A very good treatment response and significant improvement in quality of life of the patient were achieved. The patient has been treated with imatinib for 30 months