Uwe Güth

Role of KCNMA1 in breast cancer

KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca2+-activated (BK) potassium channel and has been reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH) in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fraction of breast, ovarian and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3–7%). We performed an extensive analysis on breast cancer tissue microarrays (TMA) of 1,200 tumors linked to prognosis. KCNMA1 amplification was significantly associated with high tumor stage, high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 protein expression in 8 out of 9 human breast cancers and in the breast cancer cell line MFM223. KCNMA1-function in breast cancer cell lines was confirmed by whole-cell patch clamp recordings and proliferation assays, using siRNA-knockdown, BK channel activators such as 17ß-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expression of KCNMA1 correlates with and contributes to high proliferation rate and malignancy of breast cancer.

Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers

BackgroundClinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes.MethodsA tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival.ResultsCD4+ lymphocytes were more prevalent than FOXP3+ TILs whereas IL-17+ TILs were rare. Increased numbers of total CD4+ and FOXP3+ TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4+ and FOXP3+ lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3+ TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4+ infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3+/CD4+ ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033).ConclusionsDuctal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4+ and FOXP3+ TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3+/CD4+ TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.

Metastatic patterns at autopsy in patients with ovarian carcinoma.

Previously published studies concerning autopsy findings in ovarian cancer failed to consider the broad differences in factors that influence the course of disease. Furthermore, those studies were conducted when the currently accepted standards in diagnostics and therapy had not been fully established. The objective of the current study was to determine the frequency and sites of metastases in patients with ovarian cancer with particular attention to the clinical course and therapy.

Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer

Inhibitor of growth 4 (ING4) is a candidate tumor suppressor gene that was shown to be deleted in 10% to 20% of breast cancers by array comparative genome hybridization analysis. We developed fluorescent in situ hybridization to detect the ING4 gene directly in the tissue samples on tumor tissue microarrays. We evaluated the ING4 gene status in 1033 breast cancer tissue samples and observed that ING4 was deleted in 16.5% (170/1033) of all breast cancers. ING4 deletion was significantly associated with Her2 overexpression: of the tumors with ING4 deletion, 23.8% (39/164) were human epidermal growth factor 2 (HER2) positive, as compared with 14.1% (115/814) of the tumors without ING4 deletion (P = .002). In addition, the tumors with ING4 deletion were more likely to belong to the HER2 molecular subtype (estrogen receptor negative/progesterone receptor negative/human epidermal growth factor positive) of breast cancer, compared with the other subtypes (28.4% HER2 versus 15.7% all, P = .002). ING4 deletion did not affect survival outcome of all patients with breast cancer (P = .797) or of the patients with HER2-positive tumors (P = .792). We conclude that ING4 deletion in breast cancer is relatively common, as 1 in 6 breast cancer harbors ING4 deletion. Furthermore, ING4 deletion is more prevalent in HER2-positive tumors, suggesting a functional antagonistic relationship between the ING4 tumor suppressor and the HER2 oncogene. These results sustain the view that ING4 is a tumor suppressor in breast cancer and suggest that ING4 deletion may contribute to the pathogenesis of HER2-positive breast cancer.

Cannabinoid hyperemesis syndrome: an underreported entity causing nausea and vomiting of pregnancy

IntroductionIn the western world, cannabis is the most widely used drug of abuse. Cannabinoid hyperemesis syndrome, which seems to be a rare paradoxical reaction in individuals with a particular predisposition, is characterized by cyclic severe nausea and vomiting in long-term cannabis users. While the symptoms are unresponsive to antiemetic drugs, compulsive hot baths result in a considerable symptom relief.MethodsWe report the first case of cannabinoid hyperemesis syndrome in pregnancy. A 26-year-old patient was admitted to our clinic in the 10th week of gestation.ConclusionBefore undertaking time-consuming and expensive medical examinations to rule out other medical reasons for therapy-resistant hyperemesis in pregnancy, obstetricians should determine whether compulsive bathing or showering provides symptomatic relief and ask specific questions regarding possible/suspected cannabis consumption.

Distant Metastatic Breast Cancer as an Incurable Disease: A Tenet With a Need for Revision

Purpose:Published reports provide level-III evidence in support of the hypothesis that distant metastatic breast cancer (MBC) might be curable in up to 3% of cases through a multidisciplinary approach including combination chemotherapy regimens in selected patients, usually young, and with limited metastases. Our study evaluates the rate and characteristics of long-term survivors based on a nonselective study cohort. Patients and Methods:We analyzed the data from 149 patients in whom distant MBC was diagnosed from 1990 to 1999. Results:Five patients (3.4%) were long-term survivors (9-14 years after initial diagnosis of MBC) without any clinical evidence of disease. They had a 2-peaked distribution of age: 3 were 41-57 years old at the diagnosis of MBC and 2 were much older (76, 79 years). Median survival time after diagnosis of MBC was 152 (range, 109-172) months. Three patients had isolated metastatic lesions, although 1 patient had multiple organ metastases and another extensive bone metastases. In 4 of 5 cases, long-term survival was achieved without the administration of chemotherapy. Discussion:Long-term survivors in MBC comprise a relatively heterogeneous group, and the factors which lead to the quite rare situation of long-term survival can hardly be evaluated systematically. Aggressive chemotherapy regimens appear not to be a key factor for survival. Furthermore, in a nonselective study cohort, some patients clearly are not only alive but also disease-free more than 12 years after initial relapse. This fraction may be small, but the chance for survival, and even for cure, truly exists.

Breast cancer with non-inflammatory skin involvement : current data on an underreported entity and its problematic classification

We evaluated 166 breast cancer cases with non-inflammatory skin involvement (NISI), which were classified in the TNM classification as T4b. The distribution of tumour sizes and stages was: < or =3 cm:24.1%, 3.1-5 cm:21.7%, 5.1-10 cm:33.1%, >10 cm:21.1%; stages:I/II:21.0%, III:43.4%, IV:35.6%. To assess the impact of NISI on axillary lymph node involvement (ALNI), we analyzed a sub-group of 50 patients with tumours < or =5 cm and compared them with a matched control group. NISI was found to be associated with increased ALNI (HR, 2.66; 95%CI, 1.59-4.63; p<0.0001). According to the inherent rules of tumour classification, only tumours with similar morphologic extent and prognostic significance should be combined. Since there is a high grade of heterogeneity, this basic tenet is clearly violated regarding breast cancer with NISI. Our proposal is to eliminate these tumours from the T4 category and to classify them simply by size (T1-3). Due to its prognostic significance, NISI should be indicated by an optional descriptor (e.g. S1).

Suicide in breast cancer patients: An individual-centered approach provides insight beyond epidemiology

Abstract Background. Epidemiologic studies have identified increased suicide rates among breast cancer (BC) patients. The population-based approach, however, has considerable methodic shortcomings. None of the studies have been carried out in a prospective manner and none reported suicide rates from a country in which physician-assisted suicide (PAS) is legal. Patients and methods. All cases recorded by a prospective Swiss BC database during a 17-year period (1990–2006; n = 1165) were analyzed. Using an individual-centered approach, the cases of women who committed suicide are reported according to the psychological autopsy method. Results. In six patients (0.5%; 5.1/1.000 patients), suicidal death was identified. In four patients, suicide was committed during late stages of metastatic BC. In two cases, comorbid conditions were associated with suicide. Three women chose PAS. Conclusion. The individual-centered approach is a well-suited innovative concept to increase the knowledge regarding the relationship between cancer and suicide. We found a two to seven times higher suicide rate than those reported in epidemiologic studies. The population-based approach can barely elucidate the immense variety of one of the most personal decisions: the act of intentionally ending ones own life. These studies suffer from systematic failure of analysis since they did not a) consider the potential confounding role of comorbid medical and/or psychiatric conditions, and b) report in which disease stage suicide was committed, since the decisive disease-related event whether and when metastatic disease occurred was not recorded. Furthermore, epidemiologic data stems from countries in which PAS is prohibited and therefore not included in official statistics. This grey area of medicine accounts for a greater scope of underreporting than had previously been assumed.

Trastuzumab treatment beyond progression in advanced breast cancer: patterns of care in six Swiss breast cancer centers.

Background: Trastuzumab is an established treatment for HER2-positive breast cancer (BC). We analyzed Swiss patterns of care in patients with HER2-positive BC after disease progression on trastuzumab-containing therapy for metastatic BC (MBC). Patients and Methods: A retrospective analysis was performed in six Swiss BC centers. Patients with HER2-positive MBC treated with at least one infusion of trastuzumab for advanced disease between January 2006 and December 2007 were identified. Treatment patterns in first and further lines were analyzed. Results: All of the 72 identified patients received trastuzumab as their first palliative anti-HER2 therapy, either as monotherapy (n = 23) or in combination with chemotherapy (typically taxane or vinorelbine; n = 49). Median time to progression was 8.1, 8.0 and 7.9 months in the monotherapy, trastuzumab-taxane and trastuzumab-vinorelbine cohorts, respectively. After progression on first-line anti-HER2 therapy, trastuzumab was continued in 67 of 68 patients who received further therapy. One patient received second-line lapatinib plus capecitabine. The median duration of anti-HER2 therapy was 20 months. Patients received a median of 4 lines of anti-HER2 therapy. Conclusions: Durable responses were achieved with repeated exposure to anti-HER2 therapy. In a selected patient population, trastuzumab monotherapy appears to be a reasonable first-line treatment option.

Overweight, obesity, and breast cancer screening: results from the 2012 Swiss Health Survey.

Obesity is associated with poor breast cancer (BC) prognosis. Larger tumor size and more advanced disease stage at diagnosis could partly explain this outcome and nonadherence of obese women to BC screening may play a role. We examined the relationship between BMI (kg/m2) and the use of mammography in Switzerland as well as separately in the German-speaking part with mainly opportunistic screening and in the French-speaking part with organized programs. We analyzed the data of 50–69-year-old women (n=3121) of the Swiss Health Survey 2012. Study participants were classified as underweight (BMI<18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29), or obese (BMI≥30). Outcome measures were dichotomized into 2 years or less since most recent mammography versus more than 2 years or never. We carried out multivariable logistic regression analyses, adjusting for sociodemographics, lifestyle, and self-perceived health. In Switzerland, 47% of women aged 50–69 years had had BC screening within the last 2 years, 35% of women in the German-speaking and 78% of women in the French-speaking part. In the total group, mammography use was higher in overweight than in normal-weight women (adjusted odds ratio 1.21, 95% confidence interval 0.98–1.49). Stratified by region, this effect was only maintained in women of the German-speaking part (adjusted odds ratio 1.41, 95% confidence interval 1.08–1.85; P-interaction<0.001). There were no differences in mammography attendance between normal-weight and obese and underweight women. In the 2012 Swiss Health Survey, overweight, obesity, and underweight were no barriers to mammography. In the German-speaking part, overweight women even attended mammography screening more often than normal-weight women.