Abstract. In vivo, recombinant human interleukin la (rHuIL-la) + recombinant human macrophage colony-stimulating factor (rHuM- Moreover, sequencing studies provided data suggesting that the dampening effects of IL-3 on the synergistic interaction of IL-1 + M-CSF resulted from both an enhanced differentiation of the more primitive HSC subpopulations and a signifcant, but preferential, mobilization of the more mature 8 d CFU-S and CFU-M to extramedullary organs and that the mobilization of these more mature HSC subpopulations was temporally linked to their generation from the recovering HPP-CFC and 12 d CFU-S subpopulations.CSF
Background: We have previously demonstrated how transcriptional pathway activity and the molecular subtypes of breast cancer metastases significantly influence patient post-relapse survival. Here we extend our analysis to determine whether the prognostic information provided by gene expression signatures in primary breast tumours is also relevant in the metastatic setting. Specifically, we test the research versions of the Genomic Grade Index (GGI), Mammaprint, Recurrence score (RS) and PAM50 gene signatures along with our own cell-cycle based classifier (CCS).
Methods: 287 patients with morphologically confirmed loco-regional or distant breast cancer relapse were enrolled in the Swedish multicenter TEX trial from December 2002 until June 2007. Of these, sufficient tumour RNA for gene expression profiling was obtained from metastatic tissue by fine needle aspiration from 111 patients (totalling 120 relapse biopsies). Gene signatures were applied as described in the original research articles and their relationship to short (1.5 year) and long-term (5 year) post-relapse survival was assessed using likelihood ratio, Kaplan-Meier and Cox regression analysis.
Results: As anticipated from an aggressive metastatic cohort, the majority of samples (> 70%) were classified into intermediate or high risk groups by all signatures. In both short and long-term survival analysis only PAM50 provided statistically significant prognostic information (short: LRχ2 = 14.7, p = 0.005 and long: LRχ2 = 13.2, p = 0.010), with the cell cycle score signature displaying a prognostic trend in long-term survival only (LRχ2 = 5.2, p = 0.074). Kaplan-Meier curves and Cox regression analysis suggest that the strength of both signatures resides in their ability to select a group of low-risk patients with better long-term survival.
Conclusions: Our findings demonstrate the prognostic utility of the multi-level PAM50 and to a lesser extent, cell cycle score signatures in predicting survival of patients with metastatic breast cancer. Simpler binary gene expression signatures (GGI and Mammaprint) do not appear to capture the same prognostic information and as such may have limited utility in a metastatic setting.
Short and long term survival Likehood Ratios for five gene expression signatures in metastatic breast cancer Short term survival (1.5 year)Long term survival (5 year)Gene SignatureLRχ2P-valueLRχ2P-valueGGI1.30.2510.50.500Mammaprint1.70.1900.60.427RS3.90.1434.40.110CCS2.80.2425.20.074PAM5014.70.00513.20.010GGI: Genomic grade index; RS: Recurrence score; CCS: Cell cycle score
Citation Format: Tobin NP, Lundberg A, Lindström LS, Harrell JC, Egyhazi Brage S, Frostvik Stolt M, Einbeigi Z, Loman N, Malmberg M, Perou CM, Bergh J, Hatschek T. Multi-level gene expression signatures provide significant prognostic information in metastatic breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-16.
Recombinant human interleukin 1 (IL-1) administered as a "priming" agent 24 h prior to hematopoietically lethal doses of total body irradiation (TBI) confers radioprotection to normal C57B1/6 (B6) mice, but not to B6 tumor-bearing animals (TBAs) known to have altered hematopoietic steady states. Using the Lewis lung tumor (LLca) in the B6 mouse, studies were carried out to determine whether the failure of IL-1 to radioprotect the LLca TBA was related to a preexisting "primed" hematopoietic state in the TBA or resulted from inhibition of myelopoietic activity associated with the production of prostaglandin E (PGE) by, or in response to, the tumor. Both normal B6 and LLca B6 TBAs were injected (every 24 h x 1-5) with 100 micrograms of indomethacin (IND) prior to the administration of IL-1. A single treatment with IND was sufficient to reduce the elevated levels of PGE found in the plasma of the TBAs. After five treatments, IND reduced the PGE level to below that of controls. Neither the acute nor the protracted IND treatment, however, affected the expansion of the stem and progenitor cell compartments of the marrow in the LLca TBA. Furthermore, no evidence of restoration of the radioprotective properties of IL-1 was observed in TBAs pretreated with IND. Collectively, these data suggest that the failure of IL-1 to provide radioprotection to the LLca TBA is not a direct result of the elevated plasma PGE levels associated with growth of the LLca tumor. In addition, these studies provide insight into the importance of examining in vivo effects of biological molecules in altered, as well as normal, physiological states.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.