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Background: PELICAN is a phase III trial of pegylated liposomal doxorubicin (PLD) vs capecitabine (CAP) as first-line therapy of patients (pts) with MBC. In the elderly pts, a CGA and analyses on biologic parameters on inflammation and nutrition, incorporated in the Prognostic Inflammatory and Nutritional Index (PINI) and Glasgow Prognostic Scale (GPS), were performed and results correlated to time to progression (TTP), overall survival (OS), time to treatment failure (TTF), and toxicity. Methods: CGA comprised data on activities of daily living (ADL), instrumental activities of daily living (IADL), ECOG and Karnofsky performance score (KPS), comorbidity (CIRS-G), and comedication. According to CGA, pts were classified into groups 1-3, ranging from fit to frail (Balducci 2000). For biologic assessment, blood samples of 86 pts were collected and centrally analysed. PINI was defined as [(CRP (mg/L) x A1GP (mg/L)]/[albumin (g/L) x prealbumin (mg/L)]. For GPS: pts were allocated a score of 2 if CRP >10mg/L and albumin Results: 210 pts (PLD:105; CAP:105) were randomized, stratified by age & prior anthracycline. Median age was 62y (22-85). Pts received a median of 5 cycles each of PLD and CAP. Median TTP was comparable in both arms (6.7mo PLD vs 7.1mo CAP, p=0.346). There was an insignificant trend for higher GPS and PINI in pts ≥65y. According to CGA, 102 pts were considered fit (group 1, 72%), 21 compromised (group 2, 15%), and 19 frail (group 3, 13%). CGA did not correlate with therapy efficacy. Pts with good KPS of ≥90% (n=46) had a significantly longer TTP vs pts with a worse KPS (n=44) (median KPS 100%: 8.7mo; 90%: 8.6mo; ≥90%: 3.8mo; p=0.0027). Pts with GPS of 0 or 1 had a significantly longer TTP and TTF vs pts with a GPS of 2 (median TTP score 0: 8.3mo, score 1: 9.2mo, score 2: 2.8mo, p=0.0002). Grouping of pts by PINI values (10) showed no correlation with TTP or TTF, and a nonsignificant trend for shorter OS for pts with PINI >10 (p=0.056). Among the analyzed laboratory parameters as single values, CRP showed a significant correlation with TTP (median TTP ≥5mg/L: 10.4mo, > 5 mg/l: 6.2mo, p=0.031) as did serum amyloid A (SAA, median TTP ≥6.8mg/L: 10.4mo, >6.8mg/L: 6.0mo, p=0.026) and serum albumin (median TTP ≥35g/L: 8.3mo, Conclusions: First-line chemotherapy of MBC pts using PLD or CAP showed similar efficacy with respect to TTP. Incorporation of CGA into a phase III trial is feasible and yields information that would otherwise have been missed. Prospective analyses of parameters of systemic inflammation and nutrition may have prognostic significance regarding TTP, TTF, and potentially OS in pts with breast cancer. Results of CGA, PINI and GPS need to be validated prospectively in treatment algorithms for this population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-06.

Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblastoma, seminomas/germinoma/dysgerminoma, and embryonal carcinoma but not in the various types of differentiated nonseminomas. Multitumor tissue microarray analysis covering100 different tumor categories and 3600 individual cancers verified that POU5F1 expression is specific for particular subtypes of GCT of adults. No protein was observed in GCT of newborn and infants, spermatocytic seminomas, and the various tumors of nongerm cell origin. In addition, no difference in staining pattern was found in chemosensitive and chemoresistant GCT of adults. These results indicate preservation of the link between POU5F1 and pluripotency, as reported during normal development, after malignant transformation. Therefore, POU5F1 immunohistochemistry is an informative diagnostic tool for pluripotent GCT and offers new insights into the histological heterogeneity of this cancer.

Differences in the global methylation pattern, i.e. hyper- as well as hypomethylation, are observed in cancer, including germ cell tumors (GCTs). Related to their precursor cells, GCT methylation status differs according to histology. We investigated the methylation pattern of normal fetal, infantile, and adult germ cells (n=103) and GCTs (n=251) by immunohistochemical staining for 5-mCytidine. The global methylation pattern of male germ cells changes from hypomethylation to hypermethylation, while female germ cells remain unmethylated at all stages. Undifferentiated GCTs (seminomas, carcinoma in situ and gonadoblastomas) are hypomethylated, whereas more differentiated GCTs (teratomas, yolk sac tumors, choriocarcinomas) show a higher degree of methylation. Embryonal carcinomas show an intermediate pattern. Resistance to cisplatin was assessed in the seminomatous cell line TCam-2 before and after demethylation using 5-azacytidine. Exposure to 5-azacytidine resulted in decreased resistance to cisplatin. Furthermore, after demethylation, the stem cell markers NANOG and POU5F1 (OCT3/4), as well as the germ cell specific marker VASA showed increased expression. Upon treatment with 5-azacytidine, TCam-2 cells were analyzed by high throughput methylation screen for changes in methylation sites of 14,000 genes. Among the genes revealing changes, interesting targets were identified, i.e. demethylation of KLF11, a putative tumor suppressor gene, and hypermethylation of CFLAR, a gene previously described in treatment resistance in GCTs. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-67.