Uwe Gueth

Epithelial growth factor receptor status in primary and recurrent ovarian cancer

Success of epidermal growth factor receptor (EGFR) targeting agents in different cancer types is related to EGFR gene mutations and/or copy number gains. We investigated the EGFR gene status and protein expression by DNA mutational analysis, fluorescence in situ hybridization (FISH), and immunohistochemistry in tumor tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas. The patients were classified into six groups with ascending EGFR gene copy numbers. EGFR amplification and high polysomy (FISH+) was present in a significant fraction of the primary (20%) and recurrent (22%) ovarian carcinomas. On mutational analysis, only one tumor with a silent EGFR mutation was observed, and this was the only carcinoma with high-level amplification. EGFR protein immunoexpression was seen in 28% of primary and 33% of recurrent carcinomas and correlated to amplification in the primary tumors (P=0.003). In recurrent carcinoma, moderate and strong EGFR expression was associated with amplification (P=0.034). These molecular events potentially have impact on the responsiveness to EGFR targeting agents in ovarian cancer.

Glypican-3 expression in primary and recurrent ovarian carcinomas.

Summary: The identification of glypican-3 (GPC3) expression in malignant neoplasms is potentially of interest because GPC3 might represent a therapeutic target. Tissue microarrays containing tissue cylinders from 308 patients with ovarian carcinomas were used for an immunohistochemical study. There were 255 serous, 38 endometrioid, and 15 clear-cell carcinomas included. From 76 patients, paired tissue samples of primary serous ovarian carcinomas and their corresponding recurrences after platinum-based chemotherapy were available. Glypican-3 was expressed in a total of 17.9% of ovarian carcinomas and was strongly associated with the clear-cell histotype (P = 0.0001). Glypican-3 expression was not associated with tumor stage. Positive staining for GPC3 was also observed in a significant fraction of recurrent carcinomas but was not particularly associated with chemoresponse. In conclusion, our data show that GPC3 is observed in a significant fraction of primary and corresponding recurrent ovarian carcinomas. Glypican-3 may therefore represent a potential target for (second-line) therapy in ovarian cancer.

Expression of peroxisome proliferator activated receptor γ and cyclo-oxygenase 2 in primary and recurrent ovarian carcinoma

Aim: Peroxisome proliferator-activated receptor γ (PPARγ) has emerged as a potential therapeutic target in several types of cancer. In ovarian carcinomas, limited and conflicting data on PPARγ protein expression have been reported. Methods: The immunoexpression of PPARγ and its putative target cyclo-oxygenase 2 (COX2) was investigated in tumour tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas after conventional platinum-based chemotherapy. Results: PPARγ expression was observed in 29% of primary and recurrent carcinomas. In the recurrent tumours, PPARγ expression inversely correlated with COX2 overexpression in both chemosensitive (p = 0.02) and chemoresistant (p = 0.04) carcinomas. Conclusions: The data indicate that PPARγ may represent a potential target for second-line treatment in ovarian cancers.

Systemic therapy of metastatic breast cancer: the truth beyond the clinical trials.

Objective: To depict a clear and coherent picture of the overall course of palliative treatment in an unselected study cohort over the course of time. Methods: We compared therapy type and course of 242 women whose distant metastatic disease was diagnosed from 1990 to 2006 and who ultimately died of the disease. We divided the patients into two subgroups depending on the year of diagnosis of metastases (group A: 1998–2006 vs. group B: 1990–1997). Results: In both subgroups, there were no significant differences in the general type of treatment and the number of administered therapy lines (no systemic therapy: 12.9 vs.13.7%, p = 0.848; endocrine therapy only: 20.4 vs. 25.2%, p = 0.430; chemotherapy only: 18.4 vs.16.9%, p = 0.735; sequential combination regimen including endocrine therapy/chemotherapy/trastuzumab: 46.9 vs. 44.2%, p = 0.694; median: 2 lines). In the cases where chemotherapy was administered, there were no differences between the number of lines among older and younger patients (median: two lines; ≥70 years vs. <70 years: p = 0.269). The median metastatic disease-specific survival increased from 16 months in the period from 1990 to 1997, to 21 months in the period from 1998 to 2000 (p = 0.062). Conclusion: The number of patients who died from metastatic breast cancer without receiving any antineoplastic therapy was surprisingly high. The use of newer agents and regimens in the treatment of metastatic breast cancer was associated with an improved survival over time. Chemotherapy is a feasible option also among older patients.

Impact of hormone replacement therapy on the histologic subtype of breast cancer

ObjectivePostmenopausal hormone replacement therapy (HRT) is associated with an increase in breast cancer risk, which correlates to the duration of HRT use. We wanted to investigate a possible association between HRT use and the risk of a histologic subtype of breast cancer.Patients and methodsFrom 1995 until 2004, 497 cases of primary ductal, lobular or ductulolobular breast cancer in postmenopausal women were diagnosed at the Department of Gynecology and Obstetrics, University Hospital Basel, Switzerland. The data was derived from patient’s records. HRT ever use was defined as HRT use for ≥6 months.ResultsOf the 99 cases of lobular cancer 72.7% were invasive lobular cancers, 21.2% were invasive ductulolobular cancers and 6.1% were lobular cancers in situ. Of the 398 cases of ductal cancer, 90.5% were invasive ductal cancers and 9.5% were ductal cancers in situ. Totally 144 women were HRT ever users, and 341 women were HRT never users. HRT status could not be defined in 12 women. HRT ever use was associated with an increased risk for lobular cancer (OR 1.67; 95% CI 1.02–2.73). Also, menopause due to bilateral oophorectomy was associated with an increased risk for lobular cancer (OR 2.42; 95% CI 1.06–5.54).ConclusionsThere is evidence that HRT as well as menopause due to bilateral oophorectomy may be associated with an increased risk for lobular cancer. This association is of major clinical relevance, since lobular breast cancer is more difficult to diagnose clinically and radiologically than ductal breast cancer.

Eligibility, Compliance and Persistence of Sequential Therapy with Aromatase Inhibitors following 2–3 Years of Tamoxifen in Endocrine Adjuvant Breast Cancer Therapy

Objective: This study evaluated the eligibility, compliance and persistence of sequential therapy, i.e. a switch to an aromatase inhibitor (AI) following 2–3 years of tamoxifen, in adjuvant endocrine breast cancer (BC) treatment. Methods: Data concerning 388 BC patients (age ≤70 years) who started endocrine adjuvant therapy between 1998 and 2008 were analyzed. Results: From the 263 patients who started therapy with tamoxifen, 167 (63.5%) were eligible for a sequential therapy. Fifty-nine patients (35.3%) were offered a switch by their physicians; women who had their follow-up at oncological units received the offer more often when compared to those treated by general practitioners (p < 0.001). Out of these 59 patients, 50 followed the proposal (compliance 84.7%). Of those who agreed to a sequential therapy, 2 (4%) were non-persistent to endocrine therapy; in 9 cases (18.0%), a re-switch to tamoxifen was done due to AI-related adverse side effects. Conclusions: Only a minority of the patients who started an endocrine adjuvant BC therapy was eligible for sequential therapy. Patients who underwent a switch had a high rate of persistence. Efforts should be made to make sure that all physicians, above all general practitioners, who are involved in the treatment of BC patients, are provided with current therapy guidelines.

Abstract 5540: Non malignant breast cancer tissue identification scoring system

Abstract: Introduction. Molecular pathology tools are increasingly important in routine diagnostic. Histological determination remains mandatory, while gene expression profiles (GEP) are successfully classifying breast cancer specimens also when minimal amount of tissue, such as core biopsies (CB), is available. The limit of this application resides however in the fact that the part of material used for RNA extraction could not represent the entire biopsy. To overcome this problem in the present work we calculated an algorithm for the identification of malignant cells in a giving CB. Patients and methods. The quantitative expression levels of 60 selected genes representative for relevant pathways in breast cancer (BC) oncogenesis were assessed by real time PCR in a total of 106 CB samples obtained from patients with neoplasia or invasive BC and in 12 biopsies with known good differentiation grade (Grade 1). The GEP of 48 CBs and of the 12 Grade 1 specimens were used as training set to build the scoring system based on the Welsh variant of t-test and best-fit logistic curves. The remaining GEPs were used as validation set. Results. A 15-genes classifier was built and cross-validated with 1000 iterations of a leave −10% out in which each of the 10 subset is used. The 15 genes were representative for proliferation (thymidine phosphorylase and E2F1), cell matrix degradation (CTSD, MMP1, MMP11, PLAU, PLAUR, SERPINE1), as well as angiogenesis (VEGFA, VEGFD, TGFbeta1). EGFR and GSTP1 were also part of this classifier able to discriminate non-malignant from malignant breast tissue with an accuracy of almost 90%. Discussion. The calculated classifier, which could also be reduced to only six genes, is robust and useful in the discrimination of malignant from non-malignant breast cancer tissue. Such an algorithm identifying normal proliferation rate and inability of invasion should be integrated in the evaluation of GEP data from microarrays before using them for other predictive purposes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5540. doi:1538-7445.AM2012-5540