Treatment of operable breast cancer in the elderly: A randomised clinical trial EORTC 10850 comparing modified radical mastectomy with tumorectomy plus tamoxifen

We have examined the outcome of older patients with operable breast cancer treated in a randomised trial by either standard surgery or less extensive surgery and tamoxifen. There were 236 participants aged ≥70 years, randomised to either modified radical mastectomy MRM (n=120) or wide local excision (WLE) and tamoxifen (T) 20 mg daily (n=116). Survival curves were estimated using the Kaplan-Meier method and multivariate analyses were performed using Cox's proportional hazards model. Endpoints were survival and time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. No significant difference was seen in terms of progression-free survival, but there were significantly more loco-regional relapses in the WLE+T group. In contrast, there were more distant metastases in the MRM group, but with a similar overall survival in both groups. The results of this trial give cautious support for the use of WLE+T for selected older women. © 2003 Elsevier Science Ltd. All rights reserved.Articl

Hypoxic activation of the PERK/eIF2alpha arm of the unfolded protein response promotes metastasis through induction of LAMP3

Item does not contain fulltextPURPOSE: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2alpha signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated. EXPERIMENTAL DESIGN: Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis. RESULTS: We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration. CONCLUSION: These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3. Clin Cancer Res; 19(22); 6126-37. (c)2013 AACR