To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).
Two trials of SBRT for patients with active HCC unsuitable for standard ...locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors).
A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio HR = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis.
These results provide strong rationale for studying SBRT for HCC in a randomized trial.
Patients with early-stage non–small-cell lung carcinoma (NSCLC) may benefit from treatments based on more accurate prognosis. A 15-gene prognostic classifier for NSCLC was identified from mRNA ...expression profiling of tumor samples from the NCIC CTG JBR.10 trial. In this study, we assessed its value in an independent set of cases.
Expression profiling was performed on RNA from frozen, resected tumor tissues corresponding to 181 stage I and II NSCLC cases collected at University Health Network (UHN181). Kaplan–Meier methodology was used to estimate 5-year overall survival probabilities, and the prognostic effect of the classifier was assessed using the log-rank test. A Cox proportional hazards model evaluated the signature’s effect adjusting for clinical prognostic factors.
Expression data of the 15-gene classifier stratified UHN181 cases into high- and low-risk subgroups with significantly different overall survival (hazard ratio HR = 1.92; 95% confidence interval CI, 1.15–3.23; p = 0.012). In a subgroup analysis, this classifier predicted survival in 127 stage I patients (HR = 2.17; 95% CI, 1.12–4.20; p = 0.018) and the smaller subgroup of 48 stage IA patients (HR = 5.61; 95% CI, 1.19–26.45; p = 0.014). The signature was prognostic for both adenocarcinoma and squamous cell carcinoma cases (HR = 1.76, p = 0.058; HR = 4.19, p = 0.045, respectively).
The prognostic accuracy of a 15-gene classifier was validated in an independent cohort of 181 early-stage NSCLC samples including stage IA cases and in different NSCLC histologic subtypes.
Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially ...determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.
Tumor hypoxia is an important determinant of outcome in many human malignancies and is associated with treatment resistance and metastases. The aim of this study was to determine the effect of ...hypoxia in patients with prostate cancer treated with radiotherapy.
Tumor hypoxia was measured in 247 patients with clinically localized prostate cancer before radiotherapy, with or without hormonal therapy. The median pO(2) was 6.8 mm Hg and the median hypoxic percentage less than 10 mm Hg (HP(10)) was 63%. The median follow-up was 6.6 years.
The 5-year biochemical relapse-free rate (bRFR) was 78%. Prostrate-specific antigen and Gleason score were both associated with biochemical relapse and formed a baseline clinical model. The effect of hypoxia was found to vary with the duration of patient follow-up. HP(10), when added to the clinical model, was an independent predictor of early bRFR (P = 0.019). The relationship between hypoxia and early bRFR was more pronounced when the analysis was restricted to 142 patients with bulk tumor at the site of the oxygen measurements (P = 0.004). Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during follow-up (P = 0.043), again with the effect being greatest early after completing treatment.
This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It shows that hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland.
Abstract Background Intraductal carcinoma (IDC) of prostate is a distinct entity associated with higher Gleason score and poor prognosis. The prognostic significance of large cribriform Gleason ...pattern 4 (LC) in conjunction with IDC has not been previously investigated. The aim of our study was to determine the impact of IDC and LC on biochemical recurrence-free rate (bRFR) in a contemporary prostatectomy cohort. Methods Prostate cancers of 246 prostatectomies, median follow-up 130.6 months, were graded with the International Society of Urological Pathology (ISUP) 2005 modified Gleason score (GS) and assessed for the presence of LC and/or IDC. In 57 cases with LC and/or IDC, immunostaining was performed to distinguish LC and IDC. The Kaplan–Meier (KM) method was used to estimate 5-year bRFR probabilities. Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Multivariable analysis showed that the presence of any amount of LC or IDC had a highly significant prognostic effect on bRFR (HR 2.98, 95% CI: 1.68–5.28, p = 0.0002) after adjusting for GS, surgical margin status and pathological stage. Although IDC alone tended to be associated with a worse prognosis, LC and IDC did not appear to be associated with a difference in bRFR when analysed separately. Conclusion We demonstrate that the presence of any amount of LC/IDC is a significant prognostic factor after adjusting for Gleason score and T stage in determining patient outcome and we advocate including the presence of either in routine pathology reporting.
Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been ...implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses.
Summary Background Clinical prognostic groupings for localised prostate cancers are imprecise, with 30–50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to ...test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. Methods We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort MSKCC cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. Findings Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio HR 4·5 95% CI 2·1–9·8; p=0·00013; area under the receiver operator curve AUC 0·70 95% CI 0·65–0·76) and radical prostatectomy (4·0 1·6–9·7; p=0·0024; AUC 0·57 0·52–0·61) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 1·2–12; p=0·019; AUC 0·67 0·61–0·73). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 95% CI 2·0–19; p=0·0015; AUC 0·74 95% CI 0·65–0·83). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 95% CI 1·4–6·0; p=0·0039; AUC 0·68 95% CI 0·63–0·73), and was better at predicting biochemical relapse than 23 previously published RNA signatures. Interpretation This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. Funding Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.
Contemporary studies evaluating post-transplant survival are limited and often include data from single centers or selected sub-groups. The purpose of this study was to evaluate overall transplant ...survival and to identify risk factors associated with death after transplant.
The Canadian Cystic Fibrosis Registry, a population-based cohort, was used to describe survival after lung transplant. Pre-transplant factors associated with post-transplant survival were estimated using Cox proportional hazards models.
Between 1988 and 2012, 580 patients received a lung transplant. In the entire cohort, post-lung transplant 1-year survival was 87.8%, 5-year survival was 66.7%, and 10-year survival was 50.2%. Median post-transplant survival was 3.3 years (95% confidence interval CI = 2.13-6.56) in patients infected with Burkholderia cepacia complex compared with 12.36 years (95% CI = 10.34-17.96) in patients without B cepacia infection (hazard ratio HR = 2.63, 95% CI = 2.0-3.44). After adjustment, there was a non-significant trend toward better post-transplant survival with increasing year of transplant (HR = 0.98, 95% CI = 0.96-1.00). Pancreatic sufficiency (HR = 2.13, 95% CI = 1.41-3.20) and age at transplant such that youngest and oldest had the poorest survival (p < 0.001) were significant negative predictors of survival. The risk of death after transplant for patients infected with B cepacia was highest within the first year (HR = 6.29, 95% CI = 3.87-10.21) but remained elevated >1 year after transplant (HR = 1.92, 95% CI = 1.33-2.77) compared with patients without B cepacia infection.
After lung transplantation, 5-year survival in Canadians with CF is 67%, and 50% of patients live >10 years. Despite these impressive probabilities, age at transplant, pancreatic sufficiency and B cepacia infection remain important determinants of survival after lung transplantation.
Hypoxic cells have been linked to genetic instability and tumor progression. However, little is known about the exact relationship between DNA repair and genetic instability in hypoxic cells. We ...therefore tested whether the sensing and repair of DNA double-strand breaks (DNA-dsbs) is altered in irradiated cells kept under continual oxic, hypoxic or anoxic conditions. Synchronized G0-G1 human fibroblasts were irradiated (0-10 Gy) after initial gassing with 0% O(2) (anoxia), 0.2% O(2) (hypoxia) or 21% O(2) (oxia) for 16 hours. The response of phosphorylated histone H2AX (γ-H2AX), phosphorylated ataxia telangiectasia mutated ATM(Ser1981), and the p53 binding protein 1 (53BP1) was quantified by intranuclear DNA repair foci and western blotting. At 24 hours following DNA damage, residual γ-H2AX, ATM(Ser1981) and 53BP1 foci were observed in hypoxic cells. This increase in residual DNA-dsbs under hypoxic conditions was confirmed using neutral comet assays. Clonogenic survival was also reduced in chronically hypoxic cells, which is consistent with the observation of elevated G1-associated residual DNA-dsbs. We also observed an increase in the frequency of chromosomal aberrations in chronically hypoxic cells. We conclude that DNA repair under continued hypoxia leads to decreased repair of G1-associated DNA-dsbs, resulting in increased chromosomal instability. Our findings suggest that aberrant DNA-dsb repair under hypoxia is a potential factor in hypoxia-mediated genetic instability.
Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. ...Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies.
Surgically resected early-stage non-small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 μL. Gene expression analysis was performed using a microarray platform.
Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs.
PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.
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