Susanne Briest

The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study

IntroductionWhile it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations.MethodsA retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status.ResultsThe cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families.ConclusionsContralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion.

Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers. Hypoxia results from an imbalance between the supply and consumption of oxygen (O2). Major pathogenetic mechanisms for the emergence of hypoxia are (i) structural and functional abnormalities in the tumor microvasculature, (ii) an adverse diffusion geometry, and (iii) tumor-related and therapy-induced anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histology and grade. Hypoxia is intensified in anemic patients, especially in tumor (areas) with low perfusion rates. Tumor hypoxia is a therapeutic problem since it makes solid tumors resistant to sparsely ionizing radiation, some forms of chemotherapy, and photodynamic therapy. However, besides more direct mechanisms involved in the development of therapeutic resistance, there are, in addition, indirect machineries that can cause barriers to therapies. These include hypoxia-mediated alterations in gene expression, proteomic and genomic changes, and clonal selection. These in turn can drive subsequent events that are known to further increase resistance to therapy in addition to critically affecting long-term prognosis.

Predictors of emotional distress in patients with head and neck cancer

Patients with head and neck cancer are known to be more commonly emotionally distressed than patients with other tumors. This study investigates reasons for this difference.

Age- and sex-standardised prevalence rates of fatigue in a large hospital-based sample of cancer patients

Background:The aim of this longitudinal study was to determine age- and sex-standardised prevalence rates of cancer-related fatigue in different groups of patients.Methods:This was a prospective study in a cohort of N=1494 cancer patients investigating fatigue at three time points t1–t3 (t1: admission to hospital, t2: discharge, t3: half a year after t1). Fatigue was measured with the Multidimensional Fatigue Inventory. Age- and sex-adjusted norms were derived from a representative community sample of N=2037, using a cutoff at the 75th percentile.Results:At admission to the hospital, 32% of the patients were classified as fatigued. At discharge, the overall prevalence rate was 40%, and at half a year after t1, prevalence was 34%. Fatigue prevalence rates differed according to tumour stage, site, age, and sex of the patients.Conclusion:The prevalence rates provided by this study can be used for the planning of research and clinical routine.

Co-morbid mental health conditions in cancer patients at working age - prevalence, risk profiles, and care uptake

This study examined the prevalence of mental health conditions in cancer patients, the role of socioeconomic position in relation to that, and the use of professional mental health care.

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. In 9,390 families, we determined the predictive performance of the MSS without (MSS‐2004) and with (MSS‐2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS‐2009 (MSS‐recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75–0.79) for MSS‐2004, 0.80 (95%CI 0.78–0.82) for MSS‐2009, and 0.82 (95%CI 0.80–0.83) for MSS‐recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS‐2004 92.2%, MSS‐2009 92.2%, and MSS‐recal 90.3%), but specificity of MSS‐recal (46.0%) was considerably higher than that of MSS‐2004 (25.4%) and MSS‐2009 (32.3%). In the MSS‐recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Is it useful to calculate sum scores of the quality of life questionnaire EORTC QLQ-C30?

The aim of this paper is to test the psychometric properties of sum scores of the quality of life questionnaire EORTC QLQ-C30. A sample of cancer patients (n= 1529) and a sample of the general population (n= 1185) were tested with the EORTC QLQ-C30, the Hospital Anxiety and Depression Scale and the Multidimensional Fatigue Inventory. Three sum scores of the EORTC QLQ-C30 are defined: a score concerning functioning, a score concerning symptoms and a total score. Compared with the two-item quality of life scale of the EORTC QLQ-C30, the psychometric quality of the total score and the functioning score is superior with respect to reliability, convergent validity and discriminant validity. Cronbachs alpha of the total score is 0.94 (cancer patients) and 0.95 (general population). The effect size discriminating between patients and controls is d= 0.83 for the total score, compared to only 0.50 obtained with the two-item quality of life scale. The results prove that the calculation of sum scores provides useful information for clinicians who are interested in one generalising score of quality of life.

Biomarker Modulation following Short-Term Vorinostat in Women with Newly Diagnosed Primary Breast Cancer

Purpose: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. Experimental Design: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. Results: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. Conclusions: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer. Clin Cancer Res; 19(14); 4008–16. ©2013 AACR.

Early retirement in cancer patients with or without comorbid mental health conditions: A prospective cohort study

The authors investigated whether cancer patients who have comorbid mental health disorders (MD) are at greater risk of early retirement compared with those who do not have MD.

Effect of a structured psycho-oncological screening and treatment model on mental health in cancer patients (STEPPED CARE): study protocol for a cluster randomized controlled trial.

BackgroundHigh levels of emotional distress in cancer patients often goes unnoticed in daily clinical routine, resulting in severe undertreatment of mental health problems in this patient group. Screening tools can be used to increase case identification, however, screening alone does not necessarily translate into better mental health for the patient. Doctors play a key role in providing basic emotional support and transferring the patients in need of such specific support to mental health professionals. This study investigates whether a stepped care model, combining screening, doctor consultation and professional psycho-oncological service in a structured way, improves the emotional wellbeing of cancer patients.Methods/DesignThis study is a cluster randomized trial with two parallel groups (intervention vs. care as usual), set in an academic hospital. Participants are cancer patients, a total of 1,000 at baseline. The intervention consists of stepped psychosocial care. Step one: screening for distress, step two: feedback of screening results to the doctor in charge of the patient and consultation with the patient, and step three: based on a shared patient-doctor decision, either transferal to the consultation liaison (CL) service or not. The outcome will be emotional well-being half a year after baseline, ascertained with the Hospital Anxiety and Depression Scale. Randomization will be done by the cluster randomization of wards.DiscussionMental health problems not only cause emotional suffering but also direct and indirect costs. This calls for timely and adequate psychosocial support, especially as we know that such support is effective. However, not every cancer patient can and must be treated by a mental health professional. Allocating limited resources most sensibly and economically is of crucial importance for our healthcare system to ensure the best quality of care to as many patients as possible. It is the hope of the STEPPED CARE trial that this model is both effective and efficient, and that it can be implemented in other hospitals as well, if proven to be effective.Trial registrationClinical Trials Register (Clinicaltrials.gov) identifier: NCT01859429 registration date 17 May 2013.