Abstract Background Bone is the commonest site of metastasis in breast cancer and bone metastasis is associated with skeletal complications and reduced quality of life. Adjuvant use of zoledronic acid (ZA) has been explored to prevent or reduce development of bone metastases. In the large international AZURE trial (N = 3360), early stage (II/III) breast cancer patients were randomised to standard therapy (control arm) or to standard therapy + ZA. There is an unmet need for biomarkers to identify early stage patients at high risk of developing bone metastasis so that therapy can be appropriately targeted. We report a study using proteomics and primary tumour tissue microarrays (TMAs) from patients in the AZURE trial to address this need. Methods Bone- and lung-homed variants of the MDA-MB-231 cell line were compared to the parental (non-bone homing) cell type using proteomics (difference gel electrophoresis and mass spectrometry) to identify differentially regulated proteins for clinical validation using TMAs from the AZURE trial. Following characterisation on breast cancer TMAs of different grade, protein expression of candidate biomarkers on AZURE TMAs was assessed semi-quantitatively (low, medium, or high) based on immunohistochemical staining intensity. Statistical analysis investigated associations between protein expression, clinical variables (e.g. ER/PR/HER2 status) and time to local and distant recurrence events (updated to 59 months follow-up). Results Over 140 proteins were differentially expressed and two were chosen for validation based on fold change, biological relevance and antibody availability: Macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1. Cox proportional hazards regression analysis of 378 AZURE breast tumour samples showed that patients who did not receive ZA were 4.5-fold more likely to develop bone-only metastasis (p = 0.006) if both proteins were highly expressed in the primary tumour (adjusted for systemic therapy plan, ER status, lymph node involvement, Table 1). This effect was not seen in patients who received ZA. Kaplan-Meier analysis indicated that the effect was not linked to menopausal status. Discussion We have identified two proteins expressed in primary breast tumours of patients which are significantly associated with subsequent development of bone-only metastases and appear to predict for benefit from ZA. Biologically, the two proteins are reported to be involved in cellular structures and signalling, and are implicated in cancers, but their association with breast cancer bone metastasis appears to be novel. Ongoing analysis will extend validation in a further AZURE TMA sample set. These proteins have potential as biomarkers to predict development of bone metastasis. Table 1: Cox proportional hazards regressions for breast cancer patients with high expression of CAPG and GIPC1 protein in primary tumour cells ArmN (events)HR95% CIp OV691.4520.673-3.1330.342Any distant recurrenceC341.2110.542-2.7040.641 ZA351.2400.468-3.2870.665 OV313.0361.150-8.0170.025Skeletal and other distant metastasesC172.9721.119-7.8890.029 ZA140.9780.214-4.4700.977 OV214.4461.547-12.7800.006Skeletal metastases onlyC144.4491.545-12.8080.006 ZA71.0560.122-9.1540.961Arm: OV, Overall, n = 378; C, Control, n = 191; ZA, n = 187 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-07.
Although approximately 50% of patients with non‐invasive (T a ) papillary transitional cell carcinoma show no recurrence of their disease, current histopathological approaches cannot distinguish this sub‐group from those patients in whom the disease will recur. In this 5 year retrospective study, we have shown that cytokeratin 20 (CK20) was expressed in 19 of 29 (65.5%) of non‐invasive papillary tumours of grades 1 or 2. CK20 expression patterns were predictive of disease non‐recurrence in a sub‐group of eight patients, representing 51.7% of patients with non‐recurrent disease. In normal bladder mucosa, CK20 expression was restricted to the terminally‐differentiated superficial cell. In eight CK20‐positive tumours which showed no recurrence at 5 years, CK20 expression was either restricted to, or most intense in, the luminal cells of the papillae. This pattern of expression was not seen in any of the 15 tumours from the recurrent group. Disruption of normal CK20 expression was highly significantly correlated with recurrent tumours. These results suggest that changes in the expression of differentiation‐associated antigens, such as CK20, may be useful in predicting benign versus malignant behaviour and may, therefore, be useful in defining treatment strategies.
BMJ 1992;304:1621-3 Biological therapy for cancer may be defined as a treatment that uses biological materials, usually cells or cell products, which either have direct effects on tumour cell proliferation or differentiation or modify the host biological response to the malignant disease.1 The subject has a long history, extending back to the last century when patients were treated with extracts of infectious organisms or tumours, with occasional success claimed. In the 1970s immunotherapy with BCG and allogeneic or autologous tumour cells was widely investigated, but carefully performed clinical studies failed to show consistent success. However, in the past few years there has been increasing interest in biological therapy for cancer and considerable research activity. In this article we will try to explain the reasons for the increasing current interest and try to discern whether there is really promise of progress.
Summary Myeloma colonies (MY‐CFU c ) from 7/24 patients undergoing treatment with VAMP (vincristine, adriamycin and methyl prednisolone) and high dose melphalan (HDM) were melphalan‐resistant. It was not possible to conclude that VAMP induced melphalan resistance in MY‐CFU c , but that resistance is endogenous in some myeloma cell populations. In 12/13 of the same patients of whom four had MY‐CFU c which were melphalan resistant, the sensitivity of MY‐CFU c and GM‐CFU c to busulphan was similar. Thus resistance of MY‐CFU c to melphalan did not confer resistance to busulphan. MY‐CFU c from 1/7 of a second group of patients were adriamycin‐resistant. This resistance was removed when the cells were treated with a combination of verapamil (3 μg/ml) and adriamycin. Verapamil also enhanced the toxicity of adriamycin to MY‐CFU c , from two patients where there was no evidence for adriamycin resistance. In these three patients the sensitivity of both MY‐CFU c and GM‐CFU c was similar after treatment with verapamil. Verapamil did not affect the uptake or efflux of 3 H‐daunorubicin in sensitive and resistant RPMI‐8226 cells (myeloma) and peripheral blood mononuclear cells from a normal donor; neither did it affect the binding of 3 H‐daunorubicin to nucleic acid. It is concluded that verapamil may be a useful adjuvant to VAMP chemotherapy and that busulphan may provide an alternative to melphalan in patients whose myeloma cells are melphalan resistant.
Four girls born to second cousin parents developed chronic chest infection and bronchiectasis in infancy. Three were studied in detail: they all had the same HLA haplotype, all showed random orientation of cilia or compound cilia in the respiratory tract, and all had low levels of the C1 and C2 components of the complement system. Although the cause of the respiratory disease in this family remains unclear, it is suggested that the low C1 levels may have contributed to the disease in two of the children while the low C2 levels were artefacts and the ciliary abnormalities were secondary to chronic chest infection.
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