An expression signature at diagnosis to estimate prostate cancer patients' overall survival.

BACKGROUND: This study aimed to identify biomarkers for estimating the overall and prostate cancer (PCa)-specific survival in PCa patients at diagnosis. METHODS: To explore the importance of embryonic stem cell (ESC) gene signatures, we identified 641 ESC gene predictors (ESCGPs) using published microarray data sets. ESCGPs were selected in a stepwise manner, and were combined with reported genes. Selected genes were analyzed by multiplex quantitative polymerase chain reaction using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 PCa patients diagnosed between 1986 and 2001. Of these patients, there was overall and PCa-specific survival data available for 97.9%, and 77.9% were primarily treated by hormone therapy only. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis, and a k-nearest neighbor (kNN) algorithm for estimating overall survival. RESULTS: An expression signature of VGLL3, IGFBP3 and F3 was shown sufficient to categorize the patients into high-, intermediate- and low-risk subtypes. The median overall survival times of the subtypes were 3.23, 4.00 and 9.85 years, respectively. The difference corresponded to hazard ratios of 5.86 (95% confidence interval (CI): 2.91-11.78, P<0.001) for the high-risk subtype and 3.45 (95% CI: 1.79-6.66, P<0.001) for the intermediate-risk compared with the low-risk subtype. The kNN models that included the gene expression signature outperformed the one designed on clinical parameters alone. CONCLUSIONS: The expression signature can potentially be used to estimate overall survival time. When validated in future studies, it could be integrated in the routine clinical diagnostic and prognostic procedure of PCa for an optimal treatment decision based on the estimated survival benefit.

Epidemiology and prognosis of ovarian metastases in colorectal cancer.

BACKGROUND: National guidelines for prophylactic oophorectomy in women with colorectal cancer are lacking. The aim of this population-based cohort study was to report on the prevalence, incidence and prognosis of ovarian metastases from colorectal cancer, providing information relevant to the discussion of prophylactic oophorectomy. METHODS: All 4566 women with colorectal cancer in Stockholm County during 1995-2006 were included and followed until 2008. Prospectively collected data regarding clinical characteristics, treatment and outcome were obtained from the Regional Quality Registry. RESULTS: The prevalence of ovarian metastases at the time of diagnosis of colorectal cancer was 1.1 per cent (34 of 3172) among women with colonic cancer and 0.6 per cent (8 of 1394) among those with rectal cancer (P = 0.105). After radical resection of stage I-III colorectal cancer, metachronous ovarian metastases were found during follow-up in 1.1 per cent (22 of 1971) with colonic cancer and 0.1 per cent (1 of 881) with rectal cancer (P = 0.006). Survival in patients with ovarian metastases was poor. CONCLUSION: Ovarian metastases from colorectal cancer are uncommon.

Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) lacking expression of steroid receptors and human epidermal growth factor receptor 2, having chemotherapy as the only therapeutic option, is characterised by early relapses and poor outcome. We investigated intratumoural (i.t.) levels of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF) and survival in patients with TNBC compared with non-TNBC. PATIENTS AND METHODS: VEGF levels were determined by an enzyme immunosorbent assay in a retrospective series consisting of 679 consecutive primary breast cancer patients. RESULTS: Eighty-seven patients (13%) were classified as TNBC and had significantly higher VEGF levels; median value in TNBC was 8.2 pg/microg DNA compared with 2.7 pg/microg DNA in non-TNBC (P < 0.001). Patients with TNBC had statistically significant shorter recurrence-free survival [hazard ratio (HR) = 1.8; P = 0.0023], breast cancer-corrected survival (HR = 2.2; P = 0.004) and overall survival (HR = 1.8; P = 0.005) compared with non-TNBC. Patients with TNBC relapsed earlier than non-TNBC; mean time from diagnosis to first relapse was 18.8 and 30.7 months, respectively. The time between first relapse and death was also shorter in TNBC: 7.5 months versus 17.5 months in non-TNBC (P = 0.087). CONCLUSIONS: Our results show that TNBC have higher i.t. VEGF levels compared with non-TNBC. Ongoing clinical trials will answer if therapy directed towards angiogenesis may be an alternative way to improve outcome in this poor prognosis group.

Shorter survival-times following adjuvant endocrine therapy in oestrogen- and progesterone-receptor positive breast cancer overexpressing HER2 and/or with an increased expression of vascular endothelial growth factor.

PURPOSE: To investigate the possible correlation between expression of HER2 and vascular endothelial growth factor (VEGF), and to determine the predictive value of these factors in patients receiving adjuvant endocrine therapy including the group with a breast cancer (BC) positive for both oestrogen receptor (ER) and progesterone receptor (PgR). MATERIAL AND METHODS: By enzyme immuno-sorbent assays (ELISA) tumour levels of HER2 and VEGF proteins were determined in 679 consecutive primary BC patients, median age 63 years, median follow-up time 92 months. A total of 404 patients received adjuvant endocrine therapy, mainly tamoxifen, out of them 295 had an ER and PgR positive BC. In 160 patients, HER2 status was also determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. RESULTS: Overexpression of HER2 by IHC was found in 15% of the patients. Overexpression of HER2 by ELISA correlated with HER2 by IHC (P < 0.001) and a higher VEGF expression (P = 0.004). Patients receiving adjuvant endocrine therapy with high VEGF (RFS P = 0.0087, BCCS P = 0.0012) or over-expressing HER2 (RFS P = 0.0116, BCCS P = 0.0036) had significantly shorter survival. Factors retaining statistical significance in multivariate analyses for recurrence-free survival (RFS) were nodal status (P < 0.001), tumour size (P = 0.005) and VEGF (P = 0.032) and for breast cancer corrected survival (BCCS) nodal status (P < 0.001), tumour size (P = 0.001), ER status (P = 0.022), and VEGF (P = 0.016). Both factors were significantly correlated with survival in the group with a BC positive for both ER and PgR; VEGF (RFS P = 0.0177, BCCS P = 0.0321) and HER2 (RFS P = 0.0143, BCCS P = 0.0311). In multivariate analyses, nodal status (P < 0.001) and VEGF (P = 0.021) were independent factors for RFS. Nodal status (P < 0.001) and tumour size (P = 0.016) retained independent factors for BCCS. Combined analysis identified a high-risk group (HER2 positive and high VEGF) with significantly reduced survival. CONCLUSION: The results from this retrospective analysis suggest that overexpression of HER2 and higher VEGF expression may add information on patient's outcome after adjuvant endocrine therapy in ER and PgR positive BC.

Differences in multidisciplinary team assessment and treatment between patients with stage IV colon and rectal cancer.

OBJECTIVE: At diagnosis, 14-27% of patients with colorectal cancer (CRC) have distant metastases (stage IV) and a poor prognosis. Today, treatment decisions for CRC patients are often made at multidisciplinary team (MDT) conferences. The aim of this study was to evaluate the effects of development and implementation of MDT assessment and treatment in patients with stage IV colon cancer (CC) and rectal cancer (RC) in a large population. METHOD: All 1449 patients who had stage IV CRC at the time of diagnosis and were registered in the regional quality registry of Stockholm from 1995 to 2004 were included. Patients with CC and RC were grouped according to treatment and their characteristics were analysed separately. RESULTS: In total, 1000 patients with CC and 449 patients with RC had stage IV disease. Of these, 689 (68.9%) CC patients and 352 (78.4%) RC patients were assessed by a MDT and the proportion increased over the study period (P < 0.001). Surgery for metastases was undertaken on 39 (3.9%) CC patients and 38 (8.5%) RC patients (P < 0.001). CRC patients selected for metastasis surgery had 37% 5-year survival when compared with 2% in patients who were not selected for metastasis surgery (P < 0.001). CONCLUSION: Patients with CC were less often assessed by a MDT and less often had metastasis surgery than RC patients. The proportion of patients with CC and RC assessed by a MDT increased during the study period, as did the proportion who had surgery for metastases. MDT assessment opens up the opportunity for more aggressive treatment with better outcomes.

Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.

BACKGROUND: Our aim was to use quantitative real-time PCR (Q-PCR) and RNA expression profiles (RNA-EPs) to investigate HER2 status in relation to outcome. PATIENTS AND METHODS: Cut-off levels for Q-PCR and RNA-EP were established in relation to immunohistochemistry (IHC) validated by FISH in a test set of frozen tissue samples from 40 primary breast cancers. The HER2 status was subsequently studied in another validation set of 306 tumors, where Q-PCR and RNA-EP results were compared with previously carried out IHC that we had validated by chromogenic in situ hybridization (CISH). RESULTS: Q-PCR and RNA-EP offered similar sensitivity (90% versus 77%), specificity (93% versus 95%), and negative (99% versus 98%) and positive (63% versus 61%) predictive values for HER2 determinations. Analyses of relapse-free survival (RFS) and overall survival on the basis of 5 and 10 years of follow-up indicated equivalent hazard ratios for all three techniques. In contrast to IHC/CISH, both Q-PCR and RNA-EP analyses of HER2 also gave statistically significant results regarding RFS and breast cancer-corrected survival after 10 years of follow-up. CONCLUSION: The use of RNA-EP and Q-PCR to analyze HER2 in frozen and formalin-fixed breast cancer samples may be an alternate approach to IHC in combination with FISH/CISH.