Safety and dose modification for patients receiving niraparib

Background: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the United States and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to TEAE was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was performed to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were performed on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (ie, as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cutoff points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL in effect received an average daily dose approximating 200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 mg or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of < 77 kg or baseline platelets of < 150,000/μL may benefit from a starting dose of 200 mg per day. (ClinicalTrials.gov ID: NCT01847274)

The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study

Abstract Background To date, there is no consensus on the utility of screening procedures for the early detection of endometrial cancer. The value of transvaginal ultrasound for screening of asymptomatic endometrial cancer has been discussed controversially. This study was conducted to evaluate whether asymptomatic patients with endometrial cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed after postmenopausal bleeding. Methods In the present multi-center study, the effect of the presence of postmenopausal bleeding on prognosis was evaluated retrospectively in 605 patients with endometrial cancer using patients' files. 543 patients (133 patients were asymptomatic, 410 patients were symptomatic) with endometrioid endometrial cancer were enrolled in all further analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were used were appropriate. Results Presence/absence of a postmenopausal bleeding was not associated with tumor stage (p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer had a significantly higher rate of well and moderate-differentiated tumors compared to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis, tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence of a postmenopausal bleeding, were associated with disease free and overall survival. Conclusion Asymptomatic patients with endometrial cancer have a higher rate of well differentiated tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients was similar.</p

The prognostic value of estrogen receptor beta and proline-, glutamic acid- and leucine-rich protein 1 (PELP1) expression in ovarian cancer

Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a coregulator of the estrogen receptors (ERs) alpha and beta, is a potential proto-oncogene in hormone dependent gynecological malignancies. To better understand the role of PELP1 in epithelial ovarian cancer (EOC), the protein expression and prognostic significance of PELP1 was evaluated together with ERalpha and ERbeta in EOC tissues. Methods: The expression of PELP1, ERalpha, and ERbeta was characterized in tumor tissues of 63 EOC patients. The prognostic value was calculated performing log-rank tests and multivariate Cox-Regression analysis. In a second step, validation analysis in an independent set of 86 serous EOC patients was performed. Results: Nuclear PELP1 expression was present in 76.2% of the samples. Prevalence of PELP1 expression in mucinous tumors was significantly lower (37.5%) compared to serous (85.7%) and endometrioid tumors (86.7%). A significant association between PELP1 expression and nuclear ERbeta staining was found (p=0.01). Positive PELP1 expression was associated with better disease-free survival (DFS) (p=0.004) and overall survival (OS) (p=0.04). The combined expression of ERbeta+/PELP1+ revealed an independent association with better DFS (HR 0.3 [0.1-0.7], p=0.004) and OS (HR 0.3 [0.1-0.7], p=0.005). In the validation set, the combined expression of ERbeta+/PELP1+ was not associated with DFS (HR 0.7 [0.4-1.3], p=0.3) and OS (HR 0.7 [0.3-1.4], p=0.3). Conclusion: Positive immunohistochemical staining for the ER coregulator PELP1, alone and in combination with ERbeta, might be of prognostic relevance in EOC.Stefanie Aust, Peter Horak, Dietmar Pils, Sophie Pils, Christoph Grimm, Reinhard Horvat, Dan Tong, Bernd Schmid, Paul Speiser, Alexander Reinthaller, and Stephan Polteraue

In ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway

HER2/neu overexpression is a driving force in the carcinogenesis of several human cancers. In breast cancer the prognostic influence of HER2/neu was shown to be at least partly based on increased metastatic potential mediated by the chemokine–chemokine receptor pair SDF-1(CXCL12)/CXCR4. We wanted to evaluate the influence of HER2/neu on ovarian cancer prognosis and to investigate whether compromised survival would correlate with CXCR4 expression and/or SDF-1 abundance. Therefore, we analysed HER2/neu, CXCR4, and SDF-1 in 148 ovarian tumour samples by means of immunohistochemistry on tissue microarrays. Overexpression of HER2/neu was found in 27.6% of ovarian cancer tissues and in 15% of ovarian borderline tumours. In ovarian cancer patients, overexpression of HER2/neu correlated closely with overall survival (univariate hazard ratio (HR) 2.59, P=0.005; multiple corrected HR 1.92, P=0.074). In contrast, CXCR4 expression and SDF-1 abundance had no impact on overall survival, and both parameters were not correlated with HER2/neu expression. As expected, cytoplasmic CXCR4 expression and SDF-1 abundance correlated closely (P<0.0001). Our results confirm a univariate influence of HER2/neu expression on overall survival, which was completely independent of the expression of CXCR4 and the abundance of SDF-1, implying significant differences between the HER2/neu downstream pathways in ovarian cancer compared with breast cancer

Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients

The chemokine monocyte chemoattractant protein (MCP)-1 is an important mediator of monocyte infiltration in various solid tumours of epithelial origin. The aim of the present study was to evaluate the role of MCP-1 in the natural history of ovarian cancer and to determine its value as differentiation marker and prognostic marker regarding disease free and overall survival. This retrospective study comprises 86 patients with ovarian cancer, 48 with primary ovarian cancer and 38 with recurrent ovarian cancer, 67 patients with benign ovarian cysts and 42 healthy women. Median serum levels in patients with primary ovarian cancer, recurrent ovarian cancer, benign ovarian cysts and in healthy women were 535.6 (range 129.6–1200) pg ml–1, 427.3 (range 193.4–1101) pg ml–1, 371.2 (range 222–986.8) pg ml–1 and 318.7 (range 241.3–681.4) pg ml–1 respectively (Mann–Whitney U-test, P < 0.001). Univariate logistic regression models revealed a significant influence of MCP-1 serum levels on the odds of presenting with primary ovarian cancer versus benign cysts and versus healthy women respectively (univariate logistic regression, P < 0.001 and P < 0.001 respectively). In a multivariate logistic regression model considering MCP-1 and CA 125 serum levels simultaneously, both MCP-1 and CA 125 revealed statistical significance on the odds of presenting with primary ovarian cancer versus benign cysts (multivariate logistic regression, P = 0.05 and P < 0.001 respectively). In ovarian cancer patients, MCP-1 serum levels showed a statistically significant correlation with histological grade (Mann–Whitney U-test, P = 0.02) and age at the time of diagnosis (Mann–Whitney U-test, P = 0.03). Elevated MCP-1 serum levels prior to therapy were not associated with disease-free and overall survival (log-rank test, P = 0.2 and P = 0.7 respectively). In summary these data indicate that MCP-1 might play a functional role in the natural history of ovarian cancer and might serve as differentiation marker between benign ovarian cysts and ovarian cancer, providing additional information to the established tumour marker CA 125. © 1999 Cancer Research Campaig