Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking.
We thus ...analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe.
PTEN deletions were detected in 19% of no special type, 9% of lobular, 4% of tubular cancers and 46% in carcinomas with medullary features. 98.7% of deletions were heterozygous and only 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high-grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity; p<0.0001 each, and CCND1 amplification; p=0.0020). PTEN deletions were also strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, CCND1 and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. While cancers with one of these aberrations behaved only marginally different from cancers with none, disease outcome was markedly worse in cancers with two or more aberrations as compared to those with only one aberration (p=0.0002). In addition, the particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy.
PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumor behavior. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells.
Epithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No ...predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC.
In the European multicentric project "OVCAD", 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively.
Median age at first diagnosis was 58 years (range 18-85 years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II-III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p<0.001) and platinum-resistance (p=0.009). Plasma CA125 and the risk index (HE4 and CA125) were independent predictive factors for surgical outcome (p=0.001, OR=3.37, 95% CI=1.61-7.06 and p<0.001, OR=6,041, 95% CI=2.33-15.65, respectively). FIGO stage III was an independent predictive factor for platinum response (p=0.039, OR=0.436, 95% CI=0.198-0.960).
The presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS.
Overexpression of L1-cell adhesion molecule (L1CAM) has been observed for various carcinomas and correlates with poor prognosis and late-stage disease. In vitro, L1CAM enhances proliferation, cell ...migration, adhesion and chemoresistance. We tested L1CAM and interleukin-1 beta (IL-1β) expression in tumor samples and ascitic fluid from ovarian carcinoma patients to examine its role as a prognostic marker.
We investigated tumor samples and ascitic fluid from 232 serous ovarian carcinoma patients for L1CAM by enzyme-linked immunosorbent assay. L1CAM expression was correlated with pathoclinical parameters and patients' outcome. IL-1β levels were measured in tumor cell lysates. Ovarian cancer cell lines were analyzed for the contribution of L1CAM to IL-1β production and nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB) activation.
We observed that L1CAM-expressing tumors show a highly invasive phenotype associated with restricted tumor resectability at primary debulking surgery and increased lymphogenic spread. Soluble L1CAM proved to be a marker for poor progression-free survival and chemoresistance. In ovarian carcinoma cell lines, the specific knock-down of L1CAM reduces IL-1β expression and NF-κB activity.
L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1β production and NF-κB activation.
Purpose
The objective was to compare the prognostic factors and outcomes among primary ovarian cancer (OC), fallopian tube cancer (FC), and peritoneal cancer (PC) patients in a population-based ...setting.
Methods
We analysed 5399 OC, 327 FC, and 416 PC patients diagnosed between 1998 and 2014 in the catchment area of the Munich Cancer Registry (meanwhile 4.8 million inhabitants). Tumour site differences were examined by comparing prognostic factors, treatments, the time to progression, and survival. The effect of the tumour site was additionally analysed by a Cox regression model.
Results
The median age at diagnosis, histology, and FIGO stage significantly differed among the tumour sites (
p
< 0.001); PC patients were older, more often diagnosed with a serous subtype, and in FIGO stage III or IV. The time to progression and survival significantly differed among the tumour sites. When stratified by FIGO stage, the differences in time to progression disappeared, and the differences in survival considerably weakened. The differences in the multivariate survival analysis showed an almost identical outcome in PC patients (HR 1.07 0.91–1.25) and an improved survival of FC patients (HR 0.63 0.49–0.81) compared to that of OC patients.
Conclusion
The comparison of OC, FC, and PC patients in this large-scale population-based study showed differences in the prognostic factors. These differences primarily account for the inferior outcome of PC patients, and for the improved survival of FC compared to OC patients.
Despite the recent publication of two randomized controlled phase III trials addressing neoadjuvant chemotherapy in advanced ovarian cancer, the optimal timing of multimodal management in primary ...therapy is still under debate. As both studies met their primary end point by demonstrating non-inferiority, neoadjuvant chemotherapy followed by interval debulking surgery has been proposed to be an alternative standard for primary ovarian cancer treatment. Nevertheless, significant questions remain unanswered in both trials. Especially, the radicality of surgical therapy was below expectation with the median operating times of <3 h and complete gross resection in <20% of the patients. Consecutively, survival rates of patients undergoing primary debulking surgery were low. Since the primarily surgical question of 'primary versus interval-surgery' can only be answered if the key criteria 'complete gross resection' are present in a considerable percentage of patients, additional studies are needed and neoadjuvant chemotherapy should not be used to reduce surgical radicality for ovarian cancer treatment.
To perform a subset analysis of patients with partially platinum-sensitive recurrent ovarian cancer (ROC) who received either CD carboplatin–pegylated liposomal doxorubicin (PLD) or CP ...(carboplatin–paclitaxel) in the CALYPSO trial.
CALYPSO, an international phase III, non-inferiority trial, enrolled women with ROC that relapsed >6 months following first- or second-line therapy. Patients were randomized to CD or CP. Patients with a treatment-free interval of >6 and ≤12 months were evaluated for progression-free survival (PFS), the primary end point of CALYPSO trial, and safety.
A total of 344 partially platinum-sensitive patients were included (N = 161, CD and N = 183, CP). The hazard ratio for PFS was 0.73 (95% confidence interval: 0.58–0.90; P = 0.004 for superiority) in favor of CD. Median PFS times were 9.4 months (CD) and 8.8 months (CP). Toxicities more common with CP versus CD included grade 3/4 neutropenia (50% versus 39%; P = 0.015), grade 2 alopecia (86% versus 9%; P < 0.001), neuropathy and hypersensitivity reactions. Hand-foot syndrome was more common with CD; however, grade 3/4 reactions were low (one patient in each arm).
Carboplatin–PLD has a more favorable risk-benefit profile than CP in patients with partially platinum-sensitive ROC and should be considered an effective treatment option for these patients.
The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.
...Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC).
Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes (PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points.
A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months 95% confidence interval (CI) 9.4–10.6 and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4–27.6 resp. 26.0–36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia.
The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.
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