Shorter Progression-free Time Research Articles

Pegvisomant and Pasireotide LAR as second line therapy in acromegaly: clinical effectiveness and predictors of response

The treatment of acromegaly resistant to first-generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR. Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (i) resistant to high dose first-generation SRLs and (ii) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded. Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4%) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P = 0.004, HR: 1.6, 95%CI: 1.2-4.6), with a Ki67-Li >4% (P = 0.004, HR: 3.49, 95%CI: 1.4-4.0) and with pre-treatment IGF-I >3.3×ULN (P=0.03, HR: 1.3, 95%CI: 1.1-6.0). A poor Pasireotide LAR response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P=0.025, HR: 1.6 95%CI: 1.4-3.4), pre-treatment IGF-I >2.3×ULN (P=0.049, HR: 2.4, 95%CI: 1.4-8.0), absent/low SST5 membranous expression (P=0.023 HR: 4.56 95%CI: 1.3-6.4) and in patients carried the d3-delated GHR isoform (P=0.005, HR: 11.37, 95%CI: 1.3-20.0). Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR.

Criteria for Responses of Renal Cancer Metastases to Targeted and Immunotherapy

Objective : to compare the criteria for tumor response to targeted therapy and immunotherapy for metastatic kidney cancer. Subjects and methods. The paper presents the results of diagnosis and treatment in 20 patients with metastatic renal cell carcinoma. Of these, 10 patients took interferon- α as immunotherapy, 10 patients received sorafenib as targeted therapy. The response of targeted foci was assessed using computed tomography according to the RECIST 1.1, Choi, mChoi, and SACT criteria. Control CTs were performed every 3 months until the disease progressed. The progression-free time was calculated using the Kaplan-Meier method. Results. The investigation revealed the coincidence according to the RECIST 1.1, Choi, mChoi and SACT criteria in terms of progression in all assessed cases; that according to the partial response criterion in 50% of cases, and that according to the stability criterion in 8.7%. Other cases displayed a discrepancy in the interpretation of the results. The progression-free time for patients receiving immunotherapy according to the RECIST 1.1 criteria, the Choi and mChoi criteria, and the SACT criteria was 6.3 ± 0.7, 4.3 ± 0.6, and 4.5 ± 0.7 months, respectively. The progression-free time for patients receiving targeted therapy according to the above criteria was 10.3 ± 1.2, 6.4 ± 1.2, and 6.7 ± 1.3 months. Conclusion. Tumor response to therapy is critical in evaluating the efficiency of anticancer treatment. Targeted and immunological drugs cause not only a tumor size change, but also necrosis and cystic degeneration. The criteria based not only on changes in size, but also on those in the density of tumor foci have a shorter progression-free time and make it possible to identify patients with disease progression at an earlier date.

CT Imaging Biomarkers Predict Clinical Outcomes After Pancreatic Cancer Surgery.

This study aimed to determine whether changes in contrast-enhanced computed tomography (CT) parameters could predict postsurgery overall and progression-free survival (PFS) in pancreatic cancer patients. Seventy-nine patients with a final pathological diagnosis of pancreatic adenocarcinoma were included in this study from June 2008 to August 2012. Dynamic contrast-enhanced (DCE) CT of tumors was obtained before curative-intent surgery. Absolute enhancement change (AEC) and relative enhancement change (REC) were evaluated on DCE-CT. PFS and overall survival (OS) were compared based on CT enhancement patterns. The markers of fibrogenic alpha-smooth muscle antigen (α-SMA) and periostin in tumor specimens were evaluated by immunohistochemical staining. The χ2 test was performed to determine whether CT enhancement patterns were associated with α-SMA-periostin expression levels (recorded as positive or negative). Lower REC (<0.9) was associated with shorter PFS (HR 0.51, 95% CI: 0.31–0.89) and OS (HR 0.44, 95% CI: 0.25–0.78). The α-SMA and periostin expression level were negatively correlated with REC (both P = 0). Among several CT enhancement parameters, REC was the best predictor of patient postsurgery survival. Low REC was associated with a short progression-free time and poor survival. The pathological studies suggested that REC might be a reflection of cancer fibrogenic potential.

Abstract A9: Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

Abstract The androgen receptor (AR) signaling pathway is central to the emergence of castration-resistant prostate cancer (CRPC). We set out to identify androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. We found miR-32 to be an androgen regulated miRNA which is differentially expressed in CRPC compared to benign prostate hyperplasia (BPH) according to microarray analyses. qRT-PCR analyses confirmed that miR-32 expression increases in CRPC compared to BPH, and that in untreated prostate cancer (PC) miR-32 expression is higher in tumors of stage pT3 compared to pT2. Transfection of pre-miR-32 to prostate cancer cell line LNCaP provided a significant growth advantage to the cells, and miR-32 was further demonstrated to reduce apoptosis. To identify target genes for miR-32, an mRNA microarray analysis was performed with LNCaP cells transfected with pre-miR-32. In this assay, B cell translocation gene 2 (BTG2) was identified as a novel putative target for miR-32. BTG2 was reduced both at mRNA and protein level in the cells transfected with pre-miR-32, and BTG2 was confirmed to be a miR-32 target by 3′-UTR-luciferase assay. Furthermore, BTG2 was able to partially rescue the growth advantage of miR-32 in LNCaP cells. Immunostainings of prostate cancer patient material showed a statistically significant (p &amp;lt; 0.0001) reduction of BTG2 protein in CRPCs compared to PC. The lack of BTG2 staining was also associated (p=0.0021) with a short progression-free time in patients who underwent prostatectomy and inversely correlated to miR-32 expression levels. In conclusion, we find that miR-32 is an androgen-regulated miRNA targeting BTG2 and overexpressed in CRPC. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC. Citation Format: Sanni E. Jalava, Leena Latonen, Mauro Scaravilli, Kati K. Waltering, Janne Seppälä, Harri Lähdesmäki, Teuvo L.J. Tammela, Tapio Visakorpi. Androgen-regulated miR-32 targets BTG2 and is overexpressed in castrationresistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A9.

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Here, we identified several androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. Seven miRNAs, miR-21, miR-32, miR-99a, miR-99b, miR-148a, miR-221 and miR-590-5p, were found to be differentially expressed in CRPC compared with benign prostate hyperplasia (BPH) according to microarray analyses. Significant growth advantage for LNCaP cells transfected with pre-miR-32 and pre-miR-148a was found. miR-32 was demonstrated to reduce apoptosis, whereas miR-148a enhanced proliferation. Androgen regulation of miR-32 and miR-148a was confirmed by androgen stimulation of the LNCaP cells followed by expression analyses. The AR-binding sites in proximity of these miRNAs were demonstrated with chromatin immunoprecipitation (ChIP). To identify target genes for the miRNAs, mRNA microarray analyses were performed with LNCaP cells transfected with pre-miR-32 and pre-miR-148a. Expression of BTG2 and PIK3IP1 was reduced in the cells transfected with pre-miR-32 and pre-miR-148a, respectively. Also, the protein expression was reduced according to western blot analysis. BTG2 and PIK3IP1 were confirmed to be targets by 3'UTR-luciferase assays. Finally, immunostainings showed a statistically significant (P<0.0001) reduction of BTG2 protein in CRPCs compared with untreated prostate cancer (PC). The lack of BTG2 staining was also associated (P<0.01) with a short progression-free time in patients who underwent prostatectomy. In conclusion, androgen-regulated miR-32 is overexpressed in CRPC, leading to reduced expression of BTG2. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC.

ABCC2 (MRP2, cMOAT) Localized in the Nuclear Envelope of Breast Carcinoma Cells Correlates with Poor Clinical Outcome

Nuclear expression of ABCC2 can be specific for lower differentiated cells and stem cells. The study aimed at examination of ABCC2 expression in breast cancers. The immunohistochemical analyses were performed on 70 samples of breast cancer. We have also studied prognostic value of the ABCC2 mRNA expression using the KM plotter which assessed the effect of 22,277 genes on survival in 1809 breast cancer patients. Immunohistochemical studies demonstrated that ABCC2 expression may be manifested in nuclear envelope of neoplastic cells (ABCC2n) as well as in their cell membrane and cytoplasm (ABCC2c). The univariate and multivariate analyses showed that higher expression of ABCC2n and ABCC2c was typical for cases of a shorter overall survival time. Higher ABBC2n expression was also typical for cases of a shorter disease-free survival and a shorter progression-free time. The KM plotter analysis of the prognostic value of ABCC2 mRNA expression showed that elevated ABCC2 expression was specific for cases of a shorter relapse-free survival only in the estrogen receptor-negative subgroup. The study demonstrated hat breast cancers manifest ABCC2 expression and that it is linked to a less favourable prognosis. Our results suggested that immunohistochemical tests represent a reliable way to detect prognostic value of ABCC2 expression, allowing to demonstrate differences related to subcellular localization of the protein. Cases with nuclear expression of ABCC2 manifested a more aggressive clinical course, which might reflect a less advanced differentiation of neplastic cells, resistance to the applied cytostatic drugs and tamoxifen.

Topoisomerase 1A, HER/2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples.

In the present study we examined prognostic value of immunohistochemical estimation of topoisomerase 1A (TOP 1A) and HER-2/neu expression in ovarian cancers treated with platinum-based drugs but not with topotecan and the relation between expression of these proteins on the one hand and intensity of proliferation (Ki67) on the other. The analyses were performed on 73 samples of ovarian carcinoma originating from 43 first-look laparotomies (FLL) and, in 30 cases, from secondary cytoreductions (SCR)(after chemotherapy) from the same patients. In paraffin sections immunohistochemical reactions were performed using antibodies directed to HER-2/neu, TOP 1A and Ki67. Kaplan-Meier's analysis disclosed a shorter overall survival time in cases with augmented expression of TOP 1A at FLL and with higher expression of Ki67 at SCR. A shorter progression-free time was detected in cases with higher proportion of Ki67 positive cells at FLL. No relationship could be disclosed between HER-2/neu expression and the studied clinicopathological parameters. The studies confirmed high value of Ki67 estimation. The augmented expression of TOP 1A was demonstrated to represent an unfavourable prognostic factor. Thus, in cases with elevated expression of TOP 1A application of topotecan-based therapeutic schemes should be considered.

Relationship between the expression of cyclooxygenase 2 and MDR1/P-glycoprotein in invasive breast cancers and their prognostic significance

IntroductionRecent reports suggest that expression of the cyclooxygenase 2 (COX-2) enzyme may up-regulate expression of MDR1/P-glycoprotein (MDR1/P-gp), an exponent of resistance to cytostatic drugs. The present study aimed at examining the relationship between the expression of COX-2 and of MDR1/P-gp in a group of breast cancer cases.MethodsImmunohistochemical reactions were performed using monoclonal antibodies against COX-2 and MDR1/P-gp on samples originating from 104 cases of primary invasive breast cancer.ResultsCOX-2-positive cases were shown to demonstrate higher expression of MDR1/P-gp (P < 0.0001). The studies also demonstrate that COX-2 expression was typical for cases of a higher grade (P = 0.01), a shorter overall survival time (P < 0.0001) and a shorter progression-free time (P < 0.0001). In the case of MDR1/P-gp, its higher expression characterised cases of a higher grade (P < 0001), with lymph node involvement (P < 0001), and shorter overall survival (P < 0.0001) and progression-free time (P < 0.0001).ConclusionOur studies confirmed the unfavourable prognostic significance of COX-2 and MDR1/P-gp. We also document a relationship between COX-2 and MDR1/P-gp, which suggests that COX-2 inhibitors should be investigated in trials as a treatment supplementary to chemotherapy of breast cancers.

Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients

Resistance to cis- or carboplatin represents the principal cause of therapeutic failures in ovarian carcinoma. The phenomenon of resistance to platinum-based drugs is partly related to expression of metallothionein (MT) and of glutathione S-transferase pi (GST-pi), but opinion on the subject is discordant. Documentation of a negative predictive effect of MT and GST-pi expression for the therapy employing platinum-based drugs would permit to select resistant cases in which other therapeutic approaches could be employed. The present study aimed at examining the relation between intensities of MT and GST-pi expressions in ovarian carcinomas and dynamics of the clinical course in the neoplastic disease in a group of cisplatin-treated patients. The analyses were performed on samples of ovarian carcinoma originating from 43 first-look laparotomies (FLLs) and, in 30 cases, from second-look laparotomies (SLL) from the same patients. Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies to MT and GST-pi. The calculations showed that in cases with augmented expression of MT, mortality was higher. On the other hand, augmented expression of GST-pi predisposed to more frequent relapses, deaths and progression of the tumor. Kaplan-Meier analysis showed that a significantly shorter survival time was linked to cases of higher expression of MT at FLL and of higher expression of GST-pi at FLL, whereas a shorter progression-free time was manifested by cases with higher expression of GST-pi at FLL. The performed investigations indicate that augmented expressions of MT at FLL and GST-pi at FLL in ovarian cancer represent an unfavourable predictive factor in cisplatin-treated patients.

Significance of cyclooxygenase 2 and MDR1/P-glycoprotein coexpression in ovarian cancers

Immunohistochemical analysis of prognostic significance of COX-2 and P-gp expression in ovarian cancers was performed on samples originating from 73 tumors. COX-2-positive cases were shown to demonstrate higher expression of P-gp. The studies demonstrated also that, higher P-gp expression was typical for cases which responded poorly to chemotherapy and for cases with shorter progression-free time. Expression of COX-2 predisposed to a more rapid disease progression. The study documented a relationship between COX-2 and P-gp suggesting that COX-2 inhibitors might investigated in clinical trials as a treatment supplementary to chemotherapy of ovarian cancers.