Yiola Marcou

An investigation of breast cancer risk factors in Cyprus: a case control study

BackgroundBreast cancer is the most common form of malignancy affecting women worldwide. It is also the leading cancer in females in Cyprus, with approximately 400 new cases diagnosed annually. It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. The main aim of this study was to assess the strength of associations between recognized risk factors and breast cancer among Cypriot women. This is the first epidemiological investigation on risk factors of breast cancer among the Cypriot female population.MethodsWe carried out a case-control study, involving 1,109 breast cancer patients and a group of 1,177 controls who were recruited while participating in the National screening programme for breast cancer. Information on demographic characteristics and potential risk factors were collected from both groups during a standardized interview. Logistic regression analysis was used to assess the strength of the association between each risk factor and breast cancer risk, before and after adjusting for the possible confounding effect of other factors.ResultsIn multivariable models, family history of breast cancer (OR 1.64, 95% CI 1.23, 2.19) was the strongest predictor of breast cancer risk in the Cypriot population. Late menarche (OR 0.64, 95% CI 0.45, 0.92 among women reaching menarche after the age of 15 vs. before the age of 12) and breastfeeding (OR 0.74, 95% CI 0.59, 0.92) exhibited a strong protective effect. In the case of breastfeeding, the observed effect appeared stronger than the effect of pregnancy alone. Surprisingly, we also observed an inverse association between hormone replacement therapy (HRT) although this may be a product of the retrospective nature of this study.ConclusionOverall the findings of our study corroborate with the results of previous investigations on descriptive epidemiology of risk factors for breast cancer. This investigation provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Cypriot population, including the study of gene-environment interactions. Furthermore, our study provides the first scientific evidence for formulating targeted campaigns for prevention and early diagnosis of breast cancer in Cyprus.

Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus

In Cyprus, the prevalence of breast cancer associated with BRCA1 and BRCA2 mutations in young women is unknown. In this study, we present the results of mutational analysis of the BRCA1 and BRCA2 genes in 26 Cypriot women diagnosed with breast cancer by the age of 40. The entire coding regions, including splice sites, of the BRCA1 and BRCA2 genes were sequenced using cycle sequencing. We identified four pathogenic mutations: two in BRCA1 [c.1840A>T (K614X), c.5310delG (5429delG)] and two in BRCA2 [c.3531‐3534delCAGC (3758del4), c.8755delG (8984delG)] in six of 26 unrelated patients. The BRCA2 mutation c.3531‐3534delCAGC (3758del4) is novel and the BRCA1 mutation c.1840A>T (K614X) is reported for the first time in Cypriot patients. The BRCA2 Cypriot founder mutation c.8755delG (8984delG) was detected in three unrelated patients. Additionally, we identified one novel BRCA1 missense mutation, two novel polymorphisms and three novel intronic variants of which BRCA1 c.4185+3A>G (IVS12+3A>G) may be pathogenic. Of the six BRCA1/2 mutation carriers, only four had a family history. These results show that the prevalence of BRCA1 and BRCA2 mutations in Cypriot women diagnosed with early‐onset breast cancer is high. We conclude that Cypriot women with early‐onset breast cancer should be offered BRCA1/2 testing irrespective of their family history.

Guided Imagery And Progressive Muscle Relaxation as a Cluster of Symptoms Management Intervention in Patients Receiving Chemotherapy: A Randomized Control Trial

Objective Patients receiving chemotherapy often experience many different symptoms that can be difficult to alleviate and ultimately negatively influence their quality of life. Such symptoms include pain, fatigue, nausea, vomiting and retching, anxiety and depression. There is a gap in the relevant literature on the effectiveness of cognitive-behavioural and relaxation techniques in symptom clusters. The study reflects this gap in the literature and aimed to test the effectiveness of Guided Imagery (GI) and Progressive Muscle Relaxation (PMR) on a cluster of symptoms experienced by patients undergoing chemotherapy. Methods This was a randomized control trial with 208 patients equally assigned either in the intervention or the control group. Measurements in both groups were collected at baseline and at completion of intervention (4 weeks). Patients were assessed for pain, fatigue, nausea, vomiting and retching, anxiety and depression. The overall management of the cluster was also assessed based on the patients’ self-reported health related quality of life-HRQoL. Chi-square tests (X2), independent T-tests and Linear Mixed Models were calculated. Results Patients in the intervention group experienced lower levels of Fatigue (p<0.0.0225), and Pain (p = 0.0003) compared to those in the control group and experienced better HRQoL (p<0.0001) [PRE-POST: Intervention: Pain 4.2(2.5) - 2.5(1.6), Fatigue 27.6(4.1) - 19.3(4.1), HRQoL 54.9(22.7) - 64.5(23), Control: Pain 3.5(1.7) - 4.8(1.5), Fatigue 28.7(4.1) - 32.5(3.8), HRQoL 51.9(22.3)– 41.2(24.1)]. Nausea, vomiting and retching occurred significantly less often in the intervention group [pre-post: 25.4(5.9)– 20.6(5.6) compared to the control group (17.8(6.5)– 22.7(5.3) (F = 58.50 p<0.0001). More patients in the control group (pre:n = 33-post:n = 47) were found to be moderately depressed compared to those in the intervention group (pre:n = 35-post:n = 15) (X2 = 5.93; p = 0.02). Conclusion This study provided evidence that the combination of GI and PMR can be effective in the management of a cluster of symptoms in cancer patients receiving chemotherapy. These techniques can complement existing management measures to achieve a comprehensive management of this symptom cluster and increase patients HRQoL. Trial Registration ClinicalTrials.gov NCT01275872

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.

Combination Therapy of Lapatinib and Capecitabine forErbB2-Positive Metastatic or Locally Advanced BreastCancer: Results from the Lapatinib Expanded AccessProgram (LEAP) in Central and Eastern Europe

Background: The Lapatinib Expanded Access Program (LEAP) was initiated in 45 countries to provide lapatinib in combination with capecitabine to patients with ErbB2 (HER2)-positive breast cancer already treated with anthracyclines, taxanes and trastuzumab. We report the results from 12 Central and Eastern European countries. Patients and Methods: By 30 September 2008, 293 patients were enrolled. Patients were monitored for serious adverse events (SAEs) and for any decrease in left ventricular ejection fraction (LVEF). Overall survival and progression-free survival were also assessed. Results: Mean treatment duration was 30 weeks; 107 patients (36.5%) discontinued therapy during the study, mainly due to disease progression (n = 86; 29.4%). A total of 78 SAEs were reported from 47 patients; the most frequently reported was diarrhoea (13 reports). Treatment had a relatively small effect on LVEF. Decreases were minor (0 to < 20%) in 61% of patients at the end of the study. During the study, 3 patients had decreased LVEF meeting the definition of an SAE; these events all resolved. Median overall and median progression-free survival were 37.6 and 21.1 weeks, respectively. Conclusions: Heavily pretreated patients with ErbB2-positive locally advanced or metastatic breast cancer may benefit from treatment with lapatinib and capecitabine, with a low risk of cardiac toxicity.

The mutational spectrum of Lynch syndrome in cyprus.

Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1) and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.

Radiotherapy capacity in Europe

We congratulate Eduardo Rosenblatt and colleagues for an important analysis of radiotherapy capacity and demand in European countries, and we would like to add some additional arguments and evidence in support of their conclusions. In terms of cost, centralisation of services leads to an increase in number of patients treated per radiotherapy centre, which allows for a more effi cient use of linear accelerators— ie, an increased number of fractions per machine, hence a smaller cost per fraction. In other words, increased per-unit activity results in improved cost-eff ectiveness, and centralisation therefore delivers enhanced value for money. Centralisation of radiotherapy services is also necessary to maintain quality of care and optimum outcomes, since radiotherapy is the most complex treatment modality provided in a hospital. This point is especially relevant for the treatment of rare cancers, and for specialist radiotherapy modalities such as stereotactic radiotherapy, paediatric radiotherapy, and brachy therapy. In these cases the need for centralisation of services is even greater, because of the need for highly specialised multidisciplinary teams to treat an adequate number of patients to maintain the necessary clinical skills and expertise. For these reasons, to safeguard specialisation and to provide highquality and cost-eff ective care, the Calman-Hine report set the minimum population to be served by a radiotherapy centre in the UK at 1 million. This model of centralisation has also been followed in the Netherlands, where a national programme to increase radiotherapy capacity was initiated in the late 1990s, and resulted in an annual increase in equipment and personnel by an average of 3·5–4·0% per year, while the same number of radiotherapy centres was maintained. Slotman and Vos argue that the Dutch approach, with the expansion of existing radiotherapy centres instead of the creation of new ones, was a success, since in 2010 no waiting lists and no overcapacity existed in the country, which in turn allowed for the rapid introduction of new technologies (eg, intensitymodulated radiotherapy, imageguided radiotherapy) and suffi cient subspecialisation of staff . On the eff ect of centralisation on outcomes, consistent evidence shows that the more experience doctors or health-care systems have with a procedure, the better the results. Of 128 studies that assessed hospital and physician volume of work or specialisation and outcomes in cancer treatment, 123 showed some evidence of a volume–quality relation. Most of the relevant evidence with respect to oncological outcomes comes from surgical and chemotherapy studies; however, in a phase 3 study of chemoradiation for head and neck cancer by the Radiation Therapy Oncology Group (RTOG) in the USA, patients treated at low-accruing centres had a roughly 90% increase in risk of death compared with patients treated at high-accruing centres, which suggests that a volume–quality relation also exists for complex radiotherapy. In view of the available evidence, we fi rmly believe that, unless a very substantial gain is made in terms of patients’ access to radiotherapy centres (with respect to distance and travel time), radiotherapy commissioning should aim for centralisation and not fragmentation of services.

Epidemiology of breast cancer in Cyprus: Data on newly diagnosed cases and survival rates

This article presents analyzed data on new diagnoses and mortality of breast cancer, between 2005 and 2013, in the Republic of Cyprus. New diagnoses are presented by demographic and clinical/histological variables that include cancer grade, behaviour, stage, and histological type at diagnosis (always as a primary site). Breast cancer-related deaths are presented by gender. Net survival rates based on cohort and period methods are presented by age group, cancer grade, behaviour, and stage at diagnosis, for all cases and for cases of Greek-Cypriot ethnicity. The unprocessed data of the Cyprus Cancer Registry were provided by the Health Monitoring Unit of the Ministry of Health of the Republic of Cyprus.

Evaluation of Patient Response to Neoadjuvant Therapy with the Use of Dynamic Contrast Enhanced Ultrasound (DCEUS): Work in Progress

The aim of this study is to examine whether any significant changes of the dynamic contrast enhanced ultrasound (DCEUS) quantification parameters can be detected during the course of neoadjuvant therapy (NT) undertaken by patients with breast tumors. Six patients were imaged with DCEUS four times during their therapy course. The maximum diameter and volume of the lesion in conventional ultrasound were also recorded during every scanning. The local density random walk (LDRW) model was fitted on time intensity curves to extract various quantification parameters related to perfusion. The Spearman’s correlation coefficient r s was calculated in order to study whether the perfusion changes of the DCEUS quantification parameters during the therapy are associated with volumetric changes. The rise time (RT) and mean transit time (MTT) quantification parameters are weakly associated with the maximum diameter of the lesion (negative correlation, r s = -0.37). Moderate negative correlation is also found between RT and MTT with volumetric measurements (r s = -0.5). This negative correlation enhances the hypothesis that blood flow in the lesion becomes slower during the course of NT. Data from more patients are necessary for further confirmation of our hypothesis.