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Background: The optimal treatment sequence for patients with rectal cancer and synchronous liver metastases remains unclear. The aim of this study was to evaluate the feasibility and effectiveness of short‐course pelvic radiotherapy (5 × 5 Gy) followed by systemic therapy and local treatment of all tumour sites in patients with potentially curable stage IV rectal cancer in daily practice. Methods: This was a retrospective study performed in eight tertiary referral centres in the Netherlands. Patients aged 18 years or above with rectal cancer and potentially resectable liver ± extrahepatic metastases, treated between 2010 and 2015, were eligible. Main outcomes included full completion of treatment schedule, symptom control and survival. Results: In total, 169 patients were included with a median follow‐up of 49·5 (95 pr cent c.i. 43·6 to 55·6) months. The completion rate for the entire treatment schedule was 65·7 per cent. Three‐year progression‐free survival and overall survival (OS) rates were 24·2 (95 per cent c.i. 16·6 to 31·6) and 48·8 (40·4 to 57·2) per cent respectively. Median OS of patients who responded well and completed the treatment schedule was 51·5 months, compared with 15·1 months for patients who did not complete the treatment (P < 0·001). Adequate symptom control of the primary tumour was achieved in 87·0 per cent of all patients. Conclusion: Multimodal treatment leads to relief of symptoms in most patients, and is associated with good survival rates in those able to complete the schedule. [Correction added on 12 February 2020, after first online publication: the Conclusion has been reworded for clarity] [ABSTRACT FROM AUTHOR]

Background: The product of the Bcar1/p130Cas (breast cancer resistance/p130Crk-associated substrate) gene causes resistance to antiestrogen drugs in human breast cancer cells in vitro. To investigate its role in clinical breast cancer, we determined the levels of Bcar1/p130Cas protein in a large series of primary breast carcinomas.Methods: We measured Bcar1/p130Cas protein in cytosol extracts from 937 primary breast carcinomas by western blot analysis. The levels of Bcar1/p130Cas protein were tested for associations and trends against clinicopathologic and patient characteristics, the lengths of relapse-free survival and overall survival (n = 775), and the efficacy of first-line treatment with tamoxifen for recurrent or metastatic disease (n = 268).Results: Bcar1/p130Cas levels in primary tumors were associated with age/menopausal status and the levels of estrogen receptor and progesterone receptor. In univariate survival analysis, higher Bcar1/p130Cas levels were associated with poor relapse-free survival and overall survival (both two-sided P =.04; log-rank test for trend). In multivariate analysis, a high level of Bcar1/p130Cas was independently associated with poor relapse-free survival and overall survival. The response to tamoxifen therapy in patients with recurrent disease was reduced in patients with primary tumors that expressed high levels of Bcar1/p130Cas. In multivariate analysis for response, Bcar1/p130Cas was independent of classical predictive factors, such as estrogen receptor status, age/menopausal status, disease-free interval, and dominant site of relapse.Conclusion: Patients with primary breast tumors expressing a high level of Bcar1/p130Cas protein appear to experience more rapid disease recurrence and have a greater risk of (intrinsic) resistance to tamoxifen therapy. Thus, measurement of Bcar1/p130Cas may provide useful prognostic information for patients with primary or metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Treatment of breast cancer with the antiestrogen tamoxifen is effective in approximately one half of the patients with estrogen receptor-positive disease, but tumors recur frequently because of the development of metastases that are resistant to tamoxifen. We have previously shown that mutagenesis of human estrogen-dependent ZR-75-1 breast cancer cells by insertion of a defective retrovirus genome caused the cells to become antiestrogen resistant. In this study, we isolated and characterized the crucial gene at the breast cancer antiestrogen resistance 1 (BCAR1) locus.Methods/results: Transfer of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen-resistant phenotype on the recipient cells. The complete coding sequence of BCAR1 was isolated by use of exon-trapping and complementary DNA (cDNA) library screening. Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino acids that was strongly homologous to rat p130Cas-adapter protein. Genomic analysis revealed that BCAR1 consists of seven exons and is located at chromosome 16q23.1. BCAR1 transcripts were detected in multiple human tissues and were similar in size to transcripts produced by retrovirus-mutated ZR-75-1 cells. Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell proliferation in the presence of antiestrogens, confirming that BCAR1 was the responsible gene in the locus.Conclusions: Overexpression of the BCAR1 gene confers antiestrogen resistance on human ZR-75-1 breast cancer cells. Overexpression of BCAR1 in retrovirus-mutated cells appears to result from activation of the gene's promoter. The isolation and characterization of this gene open new avenues to elucidating mechanisms by which the growth of human breast cancer becomes independent of estrogen. [ABSTRACT FROM AUTHOR]