Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

[Ovarian Ablation in Breast Cancer Patients and the Possibility of Influencing Treatment Side Effects]. / Ovariální ablace u pacientek s karcinomem prsu a moznosti ovlivnení vedlejsích úcinku lécby.

Ovarian suppression or ovarian ablation used in treatment of breast carcinoma results in temporary or permanent menopause and associated menopausal symptoms - most frequently vasomotoric symptoms (hot flashes, sweats), vaginal atrophy, sleep disturbances. Patients can also experience frequent decrease in bone density (osteopenia, osteoporosis), mood swings or depression, less frequently cardiac toxicity. Managements of these symptoms is complex. As hormonal replacement therapy (estrogens or combined estrogen/gestagen therapy) is contraindicated in women with breast carcinoma, other available options include non-hormonal pharmacological or non-pharmacological methods or their combinations. Women should be advised about cooling techniques and how to avoid known triggers; these measures should be combined with other non-pharmacological and pharmacological intervention. Non-pharmacological methods include the use of acupuncture or cognitive behavioral therapy. Some tips to help stay cool and decrease hot flashes - avoid hot beverages, spicy food, limit coffee or alcohol intake, dress in layers of clothing that can be removed if necessary. Pharmacological options include most frequently antidepressants - SSRI (selective serotonin reuptake inhibitor), SNRI (serotonin norepinephrin reuptake inhibitor), or alternatively gabapentin or pregabali. A very promising drug is paroxetine with a lot of clinical trials. Only this drug has FDA approval for the indication of hot flashes. Paroxetine can lead to disproportional changes in plasma levels of drug in CYP2D6 metabolism and thus it is not suitable for combination of paroxetine with tamoxifen. Several studies demonstrated the effectiveness of the newer generation of SSRI - citalopram, escitalopram, sertralin and duloxetin in ameliorating hot flashes. Venlafaxine in dose 75 or 150 mg has been associated with a 61% reduction in hot flashes frequency if compared to 27% reduction with placebo. Medroxyprogesterone acetate and megestrol acetate were investigated especially in patients with breast cancer history and both drugs demonstrate an effect in hot flashes treatment. Management of vaginal atrophy is challenging. Vaginal dryness/atrophy can be relieved with use of topical lubricants/gels or possibly in highly symptomatic patients with short term use of topical estrogens. As these symptoms require highly complex management, multidisciplinary approach is recommended.Key words: breast cancer - postmenopause - ovarian suppression - postmenopausal osteoporosis - therapyThis work was supported by grant of the Czech Ministry of Health - RVO (MOÚ, 00209805).The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 20. 7. 2016Accepted: 10. 8. 2016.

[Circulating Levels of Estradiol in Breast Cancer Patients Treated with Aromatase Inhibitors and Their Clinical Implications]. / Sledování cirkulujících hladin estradiolu u pacientek s karcinomem prsu lécených inhibitory aromatázy - prínos v klinické praxi.

Adjuvant treatment with aromatase inhibitors improves outcomes in postmenopausal women with hormone-sensitive early breast cancer; however, they should not be used in premenopausal women. Menopausal status is the most important factor in the choice of the hormonal treatment. There is no direct correlation between amenorrhea and ovarian function, as even the patients with amenorrhea may present with premenopausal plasma estradiol levels. The evaluation of hormonal status becomes more complicated in patients taking tamoxifen, which might lead to further increase of plasma estradiol levels. Therefore, its evaluation before and during the treatment with aromatase inhibitors is clinically important. There is a considerable caution needed when indicating aromatase inhibitors in patients with menopause caused by previous adjuvant chemotherapy, while recovery of ovarian function may appear after a certain period. This could take from 4 to 59 months (12 months on average) and it might not be accompanied by menses. This happens typically in women younger than 40 years, who should, therefore, not be treated by aromatase inhibitors alone. This supports the notion that monitoring of plasma estradiol levels is crucial in women from 40 to 50 years of age, especially before the start of aromatase inhibitors treatment.Key words: breast cancer - premenopause - postmenopause - perimenopause - estradiol - aromatase inhibitorsThis work was supported by MEYS - NPS I - LO1413 for RECAMO.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 18. 2. 2016Accepted: 29. 6. 2016.

[Recommended Extension of Indication Criteria for Genetic Testing of BRCA1 and BRCA2 Mutations in Hereditary Breast and Ovarian Cancer Syndrome]. / Doporucení rozsírení indikacních kriterií ke genetickému testování mutací v genech BRCA1 a BRCA2 u hereditárního syndromu nádoru prsu a ovarií.

Genetic testing for hereditary breast and ovarian cancer syndrome is indicated by a genetic counselor on the basis of personal and family history evaluation, with regards to consensual criteria, reflecting the current knowledge. The latest recommendation accepted by Czech Oncology Society and Society of Medical Genetics was published in the supplement 22 to the Journal of Clinical Oncology in 2009. Since the availability of PARP inhibitors for treatment of ovarian cancer in BRCA1/ 2 mutation carriers, an update of these guidelines is urgently needed. Another reason is a higher incidence of other malignancies in high-risk families, such as prostate or pancreatic cancer. The goal is to refine the detection of mutations in selected families, to improve preventive care and collect data necessary for targeted cancer treatment.

[Hereditary Breast and Ovarian Cancer Syndrome]. / Syndrom hereditárního karcinomu prsu a ovarií.

Population with hereditary breast and ovarian cancer syndrome, i.e. BRCA1/2 mutation carriers, are at higher risk of developing breast and ovarian cancer as well as other solid tumours such as pancreatic cancer, prostate cancer and melanoma. With the increasing experience, screening recommendations and preventive strategies including prophylactic surgery are being settled. Surveillance of women with hereditary breast cancer syndrome comprises clinical breast examination every six months, breast ultrasound and MRI in patients aged 25 to 29 and MRI and mammography in women aged 30 to 65. Screening of pancreatic cancer should be considered in BRCA1/2 mutation carriers, who have two cases of pancreatic cancer in their family lineage or one first-degree relative with pancreatic cancer. Prostate cancer screening should be recommended to BRCA2 carriers from the age of 40 onwards and it should be considered in BRCA1 carriers as well. Screening for melanoma should be recommended on an individual basis with regards to a family history.

[Triple Negative Breast Cancer]. / Triple negativní karcinom prsu.

BACKGROUND: In the Czech Republic, around 6,500 women get breast cancer each year; out of this number, nearly 1,000 women are triple negative subtype. Triple negative breast cancer is characterized by lack of expression of α-estrogen, progesterone, and HER2 receptors. Vast majority of these cases are low-differentiated carcinomas, majority belonging to the basal-like subgroup defined originally by DNA chips. Clinically, they are characterized by greater aggressiveness, frequent rate of local recurrence and organ metastases. They are more common in younger women and are associated with the occurrence of hereditary forms of breast cancer caused by pathogenic mutations in the BRCA1 gene and in rare cases also BRCA2. AIM: The objective of this review is to provide comprehensive information about current knowledge of triple negative breast cancer. This paper summarizes information about epidemiology and etiopathogenesis of this disease, describes risk factors for both sporadic and hereditary forms of triple negative breast cancer, addresses histopathologic and molecular classification of triple negative breast cancer, and these characteristics associates with treatment and prediction of disease development. The article also addresses new anticancer drugs tested for triple negative breast cancer. CONCLUSION: Triple negative breast cancer is a heterogeneous group of diseases with limited therapeutic options. The key to further shift in therapy is detailed knowledge of its clinical and molecular diversity and identification of predictive biomarkers. Further improvement of therapy results of triple negative breast cancer cannot be expected before targeted therapy of this disease is found.

[Li-Fraumeni syndrome - a proposal of complex prevention care for carriers of TP53 mutation with total-body MRI]. / Li-Fraumeni syndrom - návrh komplexní preventivní péce o nosice TP53 mutace s pouzitím celotelové magnetické rezonance.

Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.

[Diagnostics of breast cancer in high-risk women - our own experience]. / Diagnostika nádoru prsu ve skupine rizikových zen - vlastní zkusenosti.

Preventive oncology clinic of MMCI provides complex preventive care for women with high hereditary risk of breast and ovarian cancer due to germline mutations in BRCA1 and BRCA2 genes. Clinical follow-up is also provided to women with mutations in other genes causing a higher risk of different tumors, and also to women with increased lifetime empirical risk of breast cancer due to positive family history. Our clinic was established in 2000 and takes care for about 700 women. The goal of the clinic is to extend the life expectancy of these women to the level of the regular population. The risk of breast cancer can be reduced by prophylactic surgeries. Prophylactic mastectomy and oophorectomy are offered to women at a high risk. Other modality in breast cancer risk reduction is a chemoprevention by Tamoxifen. Most women accept only secondary prevention with the goal of the detection of breast cancer in clinical stage I, where the tumor is smaller than 1 cm and the risk of recurrence is less than 10%. The algorithm of prevention care was changed over the time and our diagnostic methods were improved by magnetic resonance imaging of breasts. During the 11 years of clinical follow-up 32 breast cancers in 31 women were detected. High risk women are examined every 6 month by physical examination, breast ultrasound and MRI plus mammography yearly.

[Triple-negative breast cancer: analysis of patients diagnosed and/or treated at the Masaryk Memorial Cancer Institute between 2004 and 2009]. / Triple-negativní karcinom prsu: analýza souboru pacientek diagnostikovaných a/nebo lécených v Masarykove onkologickém ústavu v letech 2004 az 2009.

BACKGROUND: Triple-negative breast cancer (TNBC) represents a heterogeneous group of breast cancers that do not express ER-α, PgR and Her-2 receptors. Generally, these tumors are aggressive and more common in younger women, in which an association of TNBC with mutations in the BRCA1 gene was documented. The aim of our study was to create a representative group of patients with TNBC, which could be analyzed and the data gathered to build basic epidemiological, molecular and clinical characteristics of Czech patients with TNBC. PATIENTS AND METHODS: We performed basic clinical-pathologic correlations in a group of 335 patients diagnosed and/or treated for TNBC at the Masaryk Memorial Cancer Institute between 2004 and 2009. We also performed immunohistochemical examination of expression of cytokeratin 5/6, cytokeratin 14 and EGFR to identify the basal-like subset of TNBC. RESULTS: The median age of patients with TNBC was 56 years, range 25-88 years. A total of 9.25% of TNBC cases were diagnosed in patients under the age of 34, and another 15.22% of cases were in the age group of 35 to 44 years. 'Basal-like' carcinomas accounted for 75% of TNBC. We confirmed the aggressive nature of this disease: in the follow-up period we observed a relapse in 25% of patients: 55% of deaths due to disease progression occured within 2 years after diagnosis of the disease. Treatment strategies include chemotherapy, in most cases (88.4%). Chemotherapy was mostly based on regimens with anthracyclines or in combination with taxanes. The most important negative prognostic factors in relation to OS (disease specific OS) were: higher clinical stage (p < 0.0001), pN - positive status (p < 0.0001), high proliferative activity (as measured by Ki-67, cut-off 50%, HR = 0.4740, p = 0.0411) and positive expression of CK5/6 (HR = 0.4274, p = 0.0338). In relation to DFS, the negative prognostic significance was found for these factors: higher clinical stage (p < 0.0001), pN positive status (p < 0.0001), high proliferative activity (Ki-67, cut-off 50%, HR = 0.04993, p = 0.0240). DFS was longer in patients with a higher number of applied cycles of anthracycline-based chemotherapy (> 4 cycles, HR = 1.7273, p = 0.0467). CONCLUSION: TNBC is an aggressive form of breast cancer, which may occur in patients of all ages, but more frequently in younger patients. Only early detection of disease and intensive treatment gives a high chance of cure. Unfortunately, no reliable predictive factors have been identified so far. Better therapeutic results can be expected from targeted therapy.

Genetic testing and prevention of hereditary cancer at the MMCI--over 10 years of experience.

Hereditary cancer syndromes are frequently seen in young cancer patients and patients with a positive family history. Genetic testing is important for the identification of high-risk individuals, and for the early introduction of specialized preventive care or prophylactic surgeries. High-risk tumour suppressor genes (BRCA1 and BRCA2) and DNA repair genes (MLH1, MSH2 and MSH6) are responsible for a substantial part of hereditary breast, ovarian and colorectal cancer. Other hereditary cancers are seen less frequently, but genetic testing has increased for many other site-specific cancers and complex syndromes. Genetic centres and molecular genetic laboratories are located mostly within university or regional hospitals. Some genetic centres are private. It is highly recommended (Czech Society for Medical Genetics) that all laboratories are accredited according to ISO 15,189 and that genetic testing of hereditary cancer syndromes is indicated by medical geneticists. The indication criteria and prevention strategies were published in Supplement 22 of Clinical Oncology 2009 (in Czech). Preventive care for high-risk individuals is organized by thirteen Oncology Centres, which provide most of the oncology care in the Czech Republic. Genetic testing and preventive care for high-risk individuals and mutation carriers is covered by health insurance. The molecular genetic laboratory at the MMCI provides molecular genetic testing of BRCA1, BRCA2, CHEK2 for hereditary breast/ovarian cancer, MLH1, MSH2, MSH6 for Lynch syndrome,TP53 for Li-Fraumeni syndrome, CDKN2A for familial malignant melanoma syndrome and CDH1 gene for hereditary diffuse gastric cancer. Other syndromes are tested in specialized laboratories elsewhere.The use of genetic testing is increasing because of more frequent referrals from oncologists and other specialists and the increasing variety of genes tested. However, in some patients the testing is not recommended and other family members are dying because of the late diagnosis of hereditary syndrome. Greater awareness of the importance of genetic testing in oncology is needed.

[Factors predicting failure of adjuvant hormonotherapy of breast carcinoma. A study in tamoxifen treated patients]. / Faktory predikující selhání adjuvantní hormonoterapie u karcinomu prsu, studované na souboru pacientek lécených tamoxifenem.

BACKGROUND: The latest clinical trials indicate better performance of aromatase inhibitors, compared to tamoxifen, in adjuvant hormonotherapy of breast carcinoma. The identification of molecular markers, predicting resistance to tamoxifen, could help to identify patients, which are most likely to benefit from aromatase inhibitors in up-front adjuvant hormonotherapy. MATERIAL AND METHODS: Tissue microarrays were constructed from archival paraffin blocks of primary tumors of 179 patients with estrogen receptor positive operable breast carcinoma in stage I-III, subsequently treated with tamoxifen for five years or until relapse, with at least 7 years follow up available. The amplifications of Her-2 and cyclin D1 genes were evaluated by fluorescence in-situ hybridization. The level of progesterone receptor (PR) and Ki67 were estimated by immunohistochemistry. RESULTS: 54 of above patients recurred during follow up. In univariate analysis of disease free survival, the presence of more than three nodal metastases (RR=4,5 p<0,001), grade 3 (RR=2,3 p=0,035), cyclin D1 (RR=3,06 p<0,001) and Her-2 (RR=3,06 p<0,001) amplifications were identified as significant risk factors, together with the negativity of PR (RR=2,1 p=0,013). In multivariate analysis, only clinical stage III (RR=2,6 p=0,003), cyclin D1 (RR=2,7 p=0,001) and Her-2 (RR=2,1 p=0,014) amplifications proved significant. In 77 patients who received adjuvant chemotherapy no statistically significant risk factor was identified. In multivariate analysis of 102 patients without adjuvant chemotherapy only stage III (RR=6,9 p=0,001) and Her-2 amplification (RR=4,5 p=0,001) were confirmed. CONCLUSION: The advanced clinical stage, cyclin D1 and Her-2 gene amplifications represent factors, predicting the failure of adjuvant tamoxifen treatment, but their predictive value is much lower in patients receiving adjuvant chemotherapy. This fact indicates, they can reflect the common biological aggressiveness of tumor and need not to be tamoxifen specific.

[Primary prevention of malignant tumors]. / Primární prevence zhoubných nádoru.

Primary prevention represents an effective instrument in the battle against tumour diseases. Prevention is aimed to lower the mortality for this disease by means of reduction of the cancer incidence. Our article reviews the main fields of primary prevention, namely the principles of proper nutrition and regimen. Effects of balance in energy and related nutrients, essential components of the diet, types of meals together with problems of food processing and storage are discussed from the view of the cancer prevention. Each chapter brings applicable preventive recommendations. Smoking is considered as a risks factor not only for tumours, but also for other serious diseases. Other carcinogenic factors and possible preventive measures are referred in the last chapter. Though we know that the primary cancer prevention requires active approach of the whole society, we are certain that medical professionals in every day contact with patients can highly improve the public informedness. The article submits substrate for such discussions.