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2.  Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study 
British Journal of Cancer  2013;108(5):1195-1208.
We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries.
We analysed the data on 257 362 women diagnosed with breast cancer during 2000–7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis.
Age-standardised 3-year net survival was 87–89% in the UK and Denmark, and 91–94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42–45% elsewhere. Women in the UK had low survival for TNM stage III–IV disease compared with other countries.
International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.
PMCID: PMC3619080  PMID: 23449362
breast cancer; survival; stage; population-based
3.  Mammographic density and molecular subtypes of breast cancer 
British Journal of Cancer  2012;107(1):18-23.
Gene expression profiling has led to a subclassification of breast cancers independent of established clinical parameters, such as the Sorlie–Perou subtypes. Mammographic density (MD) is one of the strongest risk factors for breast cancer, but it is unknown if MD is associated with molecular subtypes of this carcinoma.
We investigated whether MD was associated with breast cancer subtypes in 110 women with breast cancer, operated in Stockholm, Sweden, during 1994 to 1996. Subtypes were defined using expression data from HGU133A+B chips. The MD of the unaffected breast was measured using the Cumulus software. We used multinomial logistic models to investigate the relationship between MD and Sorlie–Perou subtypes.
Although the distribution of molecular subtypes differed in women with high vs low MD, this was statistically non-significant (P=0.249), and further analyses revealed no association between the MD and Sorlie–Perou subtypes as a whole, nor with individual subtypes.
These findings suggest that although MD is one of the strongest risk factors for breast cancer, it does not seem to be differentially associated with breast cancer molecular subtypes. However, larger studies with more comprehensive covariate information are needed to confirm these results.
PMCID: PMC3389424  PMID: 22644308
breast cancer; mammographic density; molecular subtypes
4.  Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen 
Annals of Oncology  2012;23(11):2866-2873.
ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.
Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.
All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).
Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.
PMCID: PMC3477878  PMID: 22532584
breast cancer; genomics; luminal; mammaprint; oncotype; PAM50
5.  Impact of tumour size on axillary involvement and distant dissemination in breast cancer 
British Journal of Cancer  2009;101(6):902-907.
Tumour size and nodal involvement are the two main prognostic factors in breast cancer (BC). Their impact on the natural history of BC is not fully captured by analyses that ignore their quantitative nature.
Data pertaining to 18 159 patients treated with primary surgery: 3661 at the Institut Gustave-Roussy (IGR, France) between 1954 and 1983, and 14 498 in the breast cancer registry in the Stockholm–Gotland Health Care region (SG, Sweden) between 1976 and 1999, were collected. The risks of distant metastases (DMs) and of nodal involvement were analysed according to tumour size with parametric models.
Using SG 1976–1990 as the reference group, relative risks (RRs) for DM were equal to 1.42 (95% CI: 1.29–1.56; P<10−10) in IGR and 0.61 (95% CI: 0.55–0.67; P<10−10) in SG 1991–1999. Differences in tumour size explained the increased risk in IGR (RR adjusted for tumour size 1.09; 95% CI: 0.99–1.20; P=0.07), but not the decreased risk in SG 1991–1999 (adjusted RR: 0.63; 95% CI: 0.57–0.69; P<10−10). The relationship between tumour size and DM risk changed significantly during the 1990s.
Early diagnosis is sufficient to explain differences in the prognosis before 1990. After 1990, the use of adjuvant systemic therapies is the main reason for the reduction in DM.
PMCID: PMC2743352  PMID: 19690546
breast cancer; prognosis; tumour size; parametric models
6.  No link between viral findings in the prostate and subsequent cancer development 
British Journal of Cancer  2006;96(1):137-139.
In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA.
PMCID: PMC2360195  PMID: 17117176
DNA virus; C. albicans; prostate, benign prostate hyperplasia
11.  Practice, efficacy and cost of staging suspected non-small cell lung cancer: a retrospective study in two Dutch hospitals 
Thorax  2002;57(1):11-14.
Background: A study was undertaken to investigate the clinical practice, yield, and costs of preoperative staging in patients with suspected NSCLC and to obtain baseline data for prospective studies on the cost effectiveness of 18F-fluorodeoxyglucose positron emission tomography in the management of these patients.
Methods: A retrospective study of the medical records of all patients with suspected NSCLC was performed during a 2 year interval (1993–4) in an academic and a large community hospital.
Results: Three hundred and ninety five patients with suspected NSCLC were identified; 58 were deemed to be medically inoperable and 337 patients proceeded to the staging process. Staging required a mean (SD) of 5.1 (1.5) diagnostic tests per patient (excluding thoracotomy) carried out over a median period of 20 days (IQR 10–31). Many of the tests (including both invasive and non-invasive) were done because previous imaging tests had suggested metastases, and in most cases the results of initial tests proved to be false positives. After clinical staging, 168 patients were considered to be resectable (stage I/II) and 144 patients underwent surgery with curative intent. At surgery 33 patients (23% of those who underwent surgery) were found to have irresectable lesions and 19 (13%) had a benign lesion. Surgery was also considered to be futile in 22 patients (15%) who developed metastases or local recurrence within 12 months following radical surgery. Hospital admission was responsible for most of the costs.
Conclusion: In many patients staging involved considerable effort in terms of the number of diagnostic tests, the duration of the staging period and the cost, with limited success in preventing futile surgery. Failures relate to the quality of diagnostic preparation at every level of the TNM staging system.
PMCID: PMC1746187  PMID: 11809983
12.  Subclinical cardiotoxicity following adjuvant dose-escalated FEC, high-dose chemotherapy, or CMF in breast cancer 
British Journal of Cancer  2000;82(4):777-781.
We compared adjuvant chemotherapy-related myocardial damage by antimyosin scintigraphy in patients who received either nine cycles of FEC (fluorouracil, epirubicin and cyclophosphamide) where the doses of epirubicin and cyclophosphamide were escalated according to the leucocyte nadir (group I, n = 14), three cycles of FEC followed by high-dose chemotherapy with alkylating agents (CTCb) given with the support of peripheral blood stem cell transplantation (group II, n = 14), or six cycles of standard intravenous CMF (cyclophosphamide, methotrexate and fluorouracil; group III, n = 8). The cardiac uptake of In-111-antimyosin-Fab (R11D10) antibody was measured and the heart-to-lung ratio (HLR) calculated 8–36 months after the last dose of chemotherapy. Cardiac antimyosin antibody uptake was considerably higher among patients treated with nine cycles of dose-escalated FEC than among those who were treated with three cycles of FEC and high-dose CTCb (HLR, median 1.98; range 1.36–2.24 vs median 1.51; range 1.20–1.82;P< 0.001), or those treated with CMF (median 1.44; range 1.15–1.68;P< 0.001). The difference between groups II and III was not significant (P> 0.1). A linear association was found between the cumulative dose of epirubicin and the cardiac antimyosin uptake (P< 0.001). We conclude that subclinical cardiac damage caused by three cycles of conventional-dose FEC followed by one cycle of high-dose CTCb chemotherapy is small as compared with the damage caused by dose-escalated FEC. © 2000 Cancer Research Campaign
PMCID: PMC2374396  PMID: 10732745
breast cancer; chemotherapy; adverse effects; high-dose therapy; epirubicin; antimyosin scintigraphy
13.  Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors. 
British Journal of Cancer  1997;75(6):816-821.
We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.
PMCID: PMC2063389  PMID: 9062401
14.  The cytotoxic activity of Taxol in primary cultures of tumour cells from patients is partly mediated by Cremophor EL. 
British Journal of Cancer  1995;71(3):478-481.
In patient tumour samples the activity in vitro of Taxol corresponded fairly well to the known clinical activity and Taxol showed low cross-resistance to standard cytotoxic drugs. However, the Taxol solvent Cremophor EL--ethanol was considerably active alone, whereas paclitaxel formulated in ethanol was less active. Taxol thus seems to contain two components active against patient tumour cells in vitro.
PMCID: PMC2033622  PMID: 7880727
15.  Activity of cyclosporins as resistance modifiers in primary cultures of human haematological and solid tumours. 
British Journal of Cancer  1994;70(1):11-17.
The semiautomated fluorimetric microculture cytotoxicity assay (FMCA) was used for evaluation of the ability of cyclosporin A (CsA) and its novel non-immunosuppressive derivative SDZ PSC 833 (PSC) to modify the response to doxorubicin or vincristine in vitro in different haematological and solid human tumour types. Primary cultures of 322 tumour samples were analysed. Both cyclosporins showed resistance-modifying activity in all haematological tumours tested, and in solid tumours activity was observed in ovarian carcinoma and childhood tumours. Little or no effect was found in the remaining tumour types, including breast, renal and adrenal cortical carcinomas and adult sarcomas. In most of the responsive cases the interaction between the modifier and the cytotoxic drug was synergistic. There was a tendency to higher activity in samples from previously treated patients, and an inverse relationship between degree of cytotoxic drug resistance and resistance-modifying activity was noted. No difference in potency between CsA and PSC could be discerned. The results indicate differential in vitro resistance-modifying activity of the cyclosporins depending on tumour type. The results also suggest that treatment with resistance modifiers should be considered also for primary therapy of drug-sensitive tumours. Drug resistance assays such as the FMCA may become useful in preclinical evaluation of resistance modifiers.
PMCID: PMC2033318  PMID: 8018519
16.  Differential expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human lung carcinoma cell lines. 
British Journal of Cancer  1993;68(4):708-711.
In the present investigation we have studied the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) in ten different human lung carcinoma cell lines, four small cell carcinomas and six non-small cell carcinomas. None of the small-cell lung carcinoma cell lines demonstrated expression of PD-ECGF/TP mRNA. However, four of six of the non-small cell carcinoma cell lines expressed the 1.8 kb PD-ECGF/TP transcript. The cell lines derived from the single squamous cell carcinoma and the two adenocarcinomas expressed the PD-ECGF/TP mRNA, and were found to have the corresponding protein both in cell lysates and conditioned media as determined both by immunoblotting and measurement of thymidine phosphorylase activity. Only one of three studied large cell carcinoma cell lines expressed low levels of PD-ECGF/TP mRNA, but the corresponding PD-ECGF/TP protein was not demonstrated by immunoblotting.
PMCID: PMC1968610  PMID: 8398697
17.  Doxorubicin selected multidrug-resistant small cell lung cancer cell lines characterised by elevated cytoplasmic Ca2+ and resistance modulation by verapamil in absence of P-glycoprotein overexpression. 
British Journal of Cancer  1991;64(6):1011-1018.
Sublines from the small cell lung cancer (SCLC) cell lines U1285 and U1690, denoted U1285-100, U1285-250, U1690-40 and U1690-150, were adapted to grow in the continuous presence of 100, 250, 40 and 150 ng ml-1 doxorubicin (Dox), respectively. The Dox resistance was accompanied by cross-resistance to vincristine (Vcr), Vp-16 and for U1285-100 also to cisplatinum. Sublines of U1690-40 and U1285-100, cultured in absence of Dox for 4 months were only partially reversed with respect to Dox resistance. Neither the parental nor the most Dox resistance sublines had detectable levels of mdr 1 RNA but a small fraction of cells in all cell lines stained weakly positive for P-glycoprotein (P-gp). Verapamil (Ver) at 5 microM reversed the Dox resistance completely and partly in the U1690 and U1285 sublines, respectively, but did not increase the cellular accumulation of Dox. The cytoplasmic free Ca2+ concentration (Ca2+i) was close to 100 nM in both parental cell lines but elevated in the U1285-100 and U1690-40 sublines by 21 and 44%, respectively, and in U1285-250 and U1690-150 by 51 and 91%, respectively. The partly reverted sublines still showed significant but smaller elevations in Ca2+i of 10-30%. Ver was without acute or long term effects of Ca2+i in the U1285-100 and U1690-40 sublines. Selection for Dox resistance in SCLC may thus result in atypical multidrug-resistance characterised by absence of P-gp overexpression and atypical cross-resistance. Although Ver did not seem to affect Dox accumulation it may still work as a resistance modulator.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1977853  PMID: 1684906
18.  Estramustine binding protein and anti-proliferative effect of estramustine in human glioma cell lines. 
British Journal of Cancer  1988;58(3):326-329.
Four human cell lines derived from malignant gliomas were immunohistochemically examined for their content of estramustine-binding protein (EMBP). EMBP was detected in a large amount in all glioma cells during the entire cell cycle. EMBP has previously been demonstrated to be the major receptor protein in prostatic cancers for the cytostatic drug estramustine-phosphate (EMP). EMP caused a dose-dependent inhibition of exponentially growing cells by increasing the number of cells in G2/M stage of the cell cycle as monitored by flow cytofluorometry. The effect may be coupled to arrest of the glioma cells at metaphase. The presence of EMBP may suggest a selective binding and effect of EMP in glioma cells.
PMCID: PMC2246581  PMID: 3052561
19.  Neurone specific enolase: a useful diagnostic serum marker for small cell carcinoma of the lung. 
Thorax  1985;40(2):85-90.
Among lung cancers small cell carcinoma is the most sensitive to chemotherapy and radiation. This has emphasised the importance of an accurate diagnosis of this cell type, and the present study examined the use of serum neurone specific enolase (NSE) as a diagnostic marker for small cell carcinoma. NSE was measured in pretreatment sera from 103 patients with small cell carcinoma and in sera from relevant controls, including patients with other lung cancers, non-malignant lung diseases, and healthy adults. Serum NSE concentration was raised (greater than 25 ng/ml) in 72% of patients with small cell carcinoma. Ninety one per cent of patients with extensive disease and 50% of patients with limited disease were serum NSE positive. Patients with extensive disease in general had higher serum NSE concentrations than patients with limited disease. No definite difference in serum NSE positivity could be shown between oat cell and intermediate cell subtypes. Out of 51 patients with other lung cancers, four (8%) had a raised serum concentration, whereas all patients with non-malignant diseases and healthy individuals had normal serum NSE concentrations. Serum NSE determination seems to be a valuable tool for the diagnosis of small cell carcinoma.
PMCID: PMC459994  PMID: 2983452

Results 1-21 (21)