NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.
Inactivation of the retinoblastoma protein (pRB) by mutations or abnormal phosphorylation is a mechanism by which tumour cells can subdue normal growth control. Among molecules involved in control of pRB phosphorylation, cyclin D1 and E have been found to be deregulated and overexpressed in various types of cancers. In order to study the cell cycle regulatory mechanisms in breast cancer, we have analysed the protein expression of cyclin D1 and E in 114 tumour specimens from patients with primary breast cancer using Western blotting. Twenty-®ve out of 34 tumours with overexpression of cyclin E showed uniform low cyclin D1 expression, and by immunohistochemical analysis of pRB we present evidence for the existence of pRB defects in approximately 40% of these tumours in contrast to no pRB defects in the other group of tumours. This result was supported by a high protein expression of the cyclindependent kinase inhibitor p16 in 44% of the tumours with high cyclin E and low D1 expression, and all immunohistochemical pRB defect tumours showed a high p16 protein level. Additionally, an abnormal low pRB phosphorylation in relation to a high proliferative activity and loss of heterozygosity of the retinoblastoma susceptibility gene locus were found in all but one tumour with immunohistochemical defect pRB. Interestingly, tumours with high cyclin E and low D1 expression were generally oestrogen receptor negative suggesting a role for cell cycle regulators in the mechanisms leading to oestrogen independent tumour growth. Furthermore, the prognosis di ered markedly for the patients in the various groups of tumours, indicating that the heterogeneous nature of breast cancer pathogenesis and the clinical course in part could be explained by di erent and distinctive sets of cell cycle defects.
In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1 high tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E high tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E high tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1high and E high tumours. Using transfected cell lines overexpressing cyclin E, cyclin E high and D1 high tumours were mimicked and the cyclin D1 high cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E high cell lines obtained increased kinase activity without redirection of inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1 high and cyclin E high tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer. Oncogene (2002Oncogene ( ) 21, 4680 -4690. doi:10.1038 Keywords: breast cancer; cell cycle; cyclins; cdkinhibitors; pRb pathway; proliferation IntroductionThe G1/S transition in normal cells is a thoroughly controlled checkpoint where the important decision to initiate DNA-replication or not is taken (Draetta, 1994;Weinberg, 1995). As has been obvious the last couple of years, aberrations in G1/S regulatory proteins are common in various tumours and aberrant expression of cyclin E and D1, downregulation of p16 and p27 as well as mutation of the retinoblastoma gene (Rb) has frequently been observed in several cancers and it can be hypothesized that G1/S defects might be obligatory in tumour development (Landberg and Roos, 1997;Sandhu and Slingerland, 2000).Cyclin D1 links mitogenic signals to cell cycle progression through increased phosphorylation of pRb (Lukas et al., 1996). Amplification of the encoding cyclin D1 gene, CCND1, resulting in high cyclin D1 protein content, has been observed in a significant numbers of breast cancers and together with impaired cyclin D1 protein degradation potentially cause unbalanced phosphorylation of pRb (Sherr, 1996;Russell et al., 1999). The relation between cyclin D1 and in vivo pRb phosphorylation in primary breast cancer has nevertheless not been investigated. Overexpression of cyclin D1 has been associated with ERpositivity (Michalides et al., 1996;van Diest et al., 1997), while the relation to proliferation and survival has been without consensus (Jares et al., 1997;Barnes and Gillett, 1998). Nevertheless, simila...
Angiogenesis is a prognostic indicator in primary breast cancer regulated by specific angiogenic factors and their receptors. Vascular endothelial growth factor-A (VEGF-A), so far considered the most important, acts through dimerization of the receptor VEGFR2/KDR within the receptor tyrosine kinase family of VEGF receptors. In order to study the interplay between VEGF-A and VEGFR2/KDR in breast cancer we evaluated their expression by immunohistochemistry in 102 breast cancers organized in a tumor tissue array system allowing semi-quantitative evaluation of cytoplasmatic staining intensity. In addition, VEGF-A165 was analyzed by an enzyme immuno assay (ELISA) in protein extracts prepared from frozen tissue from 98 of 102 tumors included in the array. Cytoplasmatic staining of VEGF of varying intensity was observed in all samples and correlated with the ELISA results of VEGF content (p = 0.007). Interestingly, VEGFR2/KDR expression correlated with VEGF expression using immunohistochemistry, indicating that VEGF and VEGFR2/KDR may be co-expressed in breast cancer. Furthermore, high levels of VEGF-A165 in the protein extracts was associated with impaired short time survival but not long term survival whereas immunohistochemically assessed VEGF and VEGFR2/KDR were not significantly associated with survival. In summary, immunohistochemically based analysis of VEGF using a tumor tissue array system seems to be a useful method for VEGF quantification in breast cancer here validated using an ELISA based method. The tumor tissue array system enables opportunities of simultaneous analysis of markers engaged in angiogenesis justifying further studies using larger series of tumors.
The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could a ect tumor growth and survival thereby in¯uencing both tumor aggressiveness and potential response to treatments. We have previously identi®ed the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a di erentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly di erentiated tumors and higher stage. There was a signi®cantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway. Oncogene (2001) 20, 3497 ± 3505.
Cell cycle deregulation is frequently observed in tumors and has moreover been proposed to be a requirement for tumor development. By analyzing the expression of p27 by immunohistochemistry in 100 primary breast tumors and combining the analyses with our earlier characterization of cyclin E, D1, p16, and the retinoblastoma protein (pRB), we have been able to cover the majority of potential G1-S transition defects and observed that 90% of the tumors had alterations in one or several cell cycle regulatory proteins. Considerable variations in protein levels were found among tumors, with low p16 expression as the most common alteration followed by cyclin E or cyclin D1 overexpression, low p27 expression or pRB inactivation in decreasing prevalence. Tumors were grouped according to observed combinations of defects and the proliferative capacity was determined for each group by analyzing Ki-67 labeling index. Low proliferation was observed in tumors with: low p16; high cyclin D1 with normal or high p16 expression; and in tumors without cell cycle defects. Tumors with high cyclin E/low p27 or pRB defects showed higher proliferation. The survival differed noticeably for patients with various combinations of cell cycle defects, and four distinctive clusters were identified showing significantly different breast cancer specific survival (p<0.0001) for both node-positive (p = 0.0006) and node-negative patients (p<0.0001). In summary, we have shown that G1-S transition defects are nearly obligatory in breast tumors and that the specific type of cell cycle defect influences the clinical behavior of the tumor.
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