A preliminary report of head-to-head comparison of 18-gene-based clinical-genomic model and oncotype DX 21-gene assay for predicting recurrence of early-stage breast cancer.

BACKGROUND: The information of Oncotype DX applied in Asian breast cancer patients is limited. A recurrence index for distant recurrence (RI-DR) has been developed for early-stage breast cancer (EBC) from tumor samples in Chinese patients. In this study, we compared the prognostic performance of the Oncotype DX (ODx) recurrence score (RS) with the RI-DR for any recurrence risk type. MATERIALS AND METHODS: One hundred thirty-eight (138) patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative EBC who were previously tested with ODx were included for testing with the RI-DR. The cutoff score to partition the low- and high-risk patients was 26 for RS and 36 for RI-DR. The primary endpoint was recurrence-free survival (RFS). RESULTS: The concordance between the RI-DR and RS was 83% in N0 patients and 81% in node-positive patients when the RS score cutoff was set at 26. With a median follow-up interval of 36.8 months, the 4-year RFS for the high- and low-risk groups categorized by the RS were 61.9% and 95.0%, respectively (hazard ratio: 10.6, 95.0% confidence interval [CI]: 1.8-62.9). The 4-year RFS in the high- and low-risk groups categorized by the RI-DR were 72.6% and 98.5%, respectively (hazard ratio: 18.9, 95% CI: 1.8-138.8). CONCLUSION: This paper illustrated the performance of RI-DR and ODx RS in breast cancer women in Taiwan. There was high concordance between the RI-DR and RS. The RI-DR is not inferior to the RS in predicting RFS in EBC patients. This study will fill the gap between the current and best practice in Chinese patients.

Is quality of colorectal cancer care good enough? Core measures development and its application for comparing hospitals in Taiwan.

BACKGROUND: Although performance measurement for assessing care quality is an emerging area, a system for measuring the quality of cancer care at the hospital level has not been well developed. The purpose of this study was to develop organization-based core measures for colorectal cancer patient care and apply these measures to compare hospital performance. METHODS: The development of core measures for colorectal cancer has undergone three stages including a modified Delphi method. The study sample originated from 2004 data in the Taiwan Cancer Database, a national cancer data registry. Eighteen hospitals and 5585 newly diagnosed colorectal cancer patients were enrolled in this study. We used indicator-based and case-based approaches to examine adherences simultaneously. RESULTS: The final core measure set included seventeen indicators (1 pre-treatment, 11 treatment-related and 5 monitoring-related). There were data available for ten indicators. Indicator-based adherence possesses more meaningful application than case-based adherence for hospital comparisons. Mean adherence was 85.8% (79.8% to 91%) for indicator-based and 82.8% (77.6% to 88.9%) for case-based approaches. Hospitals performed well (>90%) for five out of eleven indicators. Still, the performance across hospitals varied for many indicators. The best and poorest system performance was reflected in indicators T5-negative surgical margin (99.3%, 97.2%-100.0%) and T7-lymph nodes harvest more than twelve(62.7%, 27.6%-92.2%), both of which related to surgical specimens. CONCLUSIONS: In this nationwide study, quality of colorectal cancer care still shows room for improvement. These preliminary results indicate that core measures for cancer can be developed systematically and applied for internal quality improvement.

Adherence to quality indicators and survival in patients with breast cancer.

BACKGROUND: International initiatives increasingly advocate physician adherence to clinical protocols that have been shown to improve outcomes, yet the process-outcome relationship for adhering to breast cancer care protocol is unknown. OBJECTIVE: This study explores whether 100% adherence to a set of quality indicators applied to individuals with breast cancer is associated with better survival. RESEARCH DESIGN AND SUBJECTS: Ten quality indicators (4 diagnosis-related and 6 treatment-related indicators) were used to measure the quality of care in 1378 breast cancer patients treated from 1995 to 2001. Adherence to each indicator was based on the number of procedures performed divided by the number of patients eligible for that procedure. The main analysis of adherence was dichotomous (ie, 100% adherence vs. <100% adherence). MEASURES: The outcome measures studied were 5-year overall survival and progression-free survival, calculated using the Kaplan-Meier method. The Cox's proportional hazard regression model was used for univariate and multivariate analyses. RESULTS: Most patients received care that demonstrated good adherence to the quality indicators. Multivariate analysis revealed that 100% adherence to entire set of quality indicators was significantly associated with better overall survival [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.33-0.63] and progression-free survival (HR 0.51; 95% CI, 0.39-0.67). One hundred percent adherence to treatment indicators alone was also associated with statistically significant improvements in overall and progression-free survivals. CONCLUSIONS: Our study strongly supports that 100% adherence to evidence supported quality-of-care indicators is associated with better survival rates for breast cancer patients and should be a priority for practitioners.

Association of a Bundled-Payment Program With Cost and Outcomes in Full-Cycle Breast Cancer Care.

IMPORTANCE: Value-driven payment system reform is a potential tool for aligning economic incentives with the improvement of quality and efficiency of health care and containment of cost. Such a payment system has not been researched satisfactorily in full-cycle cancer care. OBJECTIVE: To examine the association of outcomes and medical expenditures with a bundled-payment pay-for-performance program for breast cancer in Taiwan compared with a fee-for-service (FFS) program. DESIGN, SETTING, AND PARTICIPANTS: Data were obtained from the Taiwan Cancer Database, National Health Insurance Claims Data, the National Death Registry, and the bundled-payment enrollment file. Women with newly diagnosed breast cancer and a documented first cancer treatment from January 1, 2004, to December 31, 2008, were selected from the Taiwan Cancer Database and followed up for 5 years, with the last follow-up data available on December 31, 2013. Patients in the bundled-payment program were matched at a ratio of 1:3 with control individuals in an FFS program using a propensity score method. The final sample of 17 940 patients included 4485 (25%) in the bundled-payment group and 13 455 (75%) in the FFS group. MAIN OUTCOMES AND MEASURES: Rates of adherence to quality indicators, survival rates, and medical payments (excluding bonuses paid in the bundled-payment group). The Kaplan-Meier method was used to calculate 5-year overall and event-free survival rates by cancer stage, and the Cox proportional hazards regression model was used to examine the effect of the bundled-payment program on overall and event-free survival. Sensitivity analysis for bonus payments in the bundled-payment group was also performed. RESULTS: The study population included 17 940 women (mean [SD] age, 52.2 [10.3] years). In the bundled-payment group, 1473 of 4215 patients (34.9%) with applicable quality indicators had full (100%) adherence to quality indicators compared with 3438 of 12 506 patients (27.5%) with applicable quality indicators in the FFS group (P < .001). The 5-year event-free survival rates for patients with stages 0 to III breast cancer were 84.48% for the bundled-payment group and 80.88% for the FFS group (P < .01). Although the 5-year medical payments of the bundled-payment group remained stable, the cumulative medical payments for the FFS group steadily increased from $16 000 to $19 230 and exceeded pay-for-performance bundled payments starting in 2008. CONCLUSIONS AND RELEVANCE: In Taiwan, compared with the regular FFS program, bundled payment may lead to better adherence to quality indicators, better outcomes, and more effective cost-control over time.

Prevertebral muscle involvement in nasopharyngeal carcinoma.

PURPOSE: The purpose of this study is to evaluate the prevalence and prognostic significance of prevertebral muscle involvement in patients with nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Between July 1990 and December 2001, 521 newly diagnosed patients with NPC treated at Koo Foundation Sun Yat-Sen Cancer Center (KF-SYSCC) were examined with magnetic resonance imaging (MRI) for evidence of prevertebral muscle involvement before treatment. Patients were staged according to the 1997 American Joint Committee on Cancer staging classification of NPC based on the physical exams and MRI findings. All patients received radiotherapy with or without chemotherapy. The association between clinical prevertebral muscle involvement and posttreatment outcomes (overall survival, locoregional recurrence, and distant metastasis) were evaluated using Cox regression model to adjust for other prognostic factors. RESULTS: Of 521 patients treated at KF-SYSCC, 181 (35%) patients were found to have prevertebral muscle involvement, one-third in those with Stage II/III tumors and two-thirds in those with Stage IV tumor. In multivariate analysis accounting for all previously known prognostic factors, prevertebral muscle invasion was associated with an increased risk for any recurrence (adjusted relative risk, 2.01; p<0.001), locoregional recurrence (adjusted relative risk, 2.69; p<0.001), and distant metastasis (adjusted relative risk, 2.25; p<0.001), and with a borderline significant increased risk for overall survival (adjusted relative risk, 1.44; p=0.10). CONCLUSIONS: Prevertebral muscle involvement is an independent prognostic factor for NPC recurrence.

An Eighteen-Gene Classifier Predicts Locoregional Recurrence in Post-Mastectomy Breast Cancer Patients.

We previously identified 34 genes of interest (GOI) in 2006 to aid the oncologists to determine whether post-mastectomy radiotherapy (PMRT) is indicated for certain patients with breast cancer. At this time, an independent cohort of 135 patients having DNA microarray study available from the primary tumor tissue samples was chosen. Inclusion criteria were 1) mastectomy as the first treatment, 2) pathology stages I-III, 3) any locoregional recurrence (LRR) and 4) no PMRT. After inter-platform data integration of Affymetrix U95 and U133 Plus 2.0 arrays and quantile normalization, in this paper we used 18 of 34 GOI to divide the mastectomy patients into high and low risk groups. The 5-year rate of freedom from LRR in the high-risk group was 30%. In contrast, in the low-risk group it was 99% (p < 0.0001). Multivariate analysis revealed that the 18-gene classifier independently predicts rates of LRR regardless of nodal status or cancer subtype.

Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description.

Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6+/-4.3Gy, in a daily fraction of 1.8-2.0Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30Gy, prediction score, and normal tissue complication probability, failed to differentiate the fatality and clinical types of this complication. Elevated transaminases are more frequently seen than ascites and elevated alkaline phosphamide are seen in patients with RILD.

Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and TP53 mutations.

Nearly 30% of the breast cancer patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset breast cancer counterparts. Genomic abnormalities between these two breast cancer age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset breast tumors. In addition, more profound chromosomal changes were consistently associated with the more advanced-stage tumors, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the breast cancers examined carried a TP53 mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these TP53 mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no TP53 mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset breast tumor formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes.

Colorectal cancer screening in asymptomaic adults: comparison of colonoscopy, sigmoidoscopy and fecal occult blood tests.

BACKGROUND AND PURPOSE: Fecal occult blood tests (FOBT) and flexible sigmoidoscopy have previously been recommended for colon cancer screening. More recently, studies have recommended colonoscopy due to the high rates of advanced neoplasm not detected by FOBT and sigmoidoscopy. Previous studies of the effectiveness of colonoscopic screening in Taiwan were limited to families of patients with colorectal cancer. This study compared colonoscopy, sigmoidoscopy and FOBT for colorectal cancer screening in asymptomatic adults. METHODS: Screening colonoscopies and FOBT were performed in asymptomatic adults enrolled in our health-screening program between January 1997 and December 2000. Advanced neoplasm was defined as the presence of a polyp larger than 1 cm, polyps with villous or severe dysplastic features, or cancer. The junction of the splenic flexure and descending colon was defined as the boundary of the proximal and distal colon, and it was presumed that the distal colon would be examined using sigmoidoscopy in all patients. Data on the prevalence of polyps, advanced neoplasm, and cancer among different age groups were obtained. The results of chemical and immunologic FOBT were compared. The anatomic distributions of advanced neoplasm and cancer were analyzed. RESULTS: A total of 7,411 colonoscopic examinations were included in the analysis. Advanced neoplasms were present in 93 examinations (1.3%), including 16 cancers (0.2%). Chemical FOBT detected 20.2% of advanced neoplasms and 37.5% of cancers. Immunologic FOBT detected 48.3% of advanced neoplasms and 87.5% of cancers. If sigmoidoscopy had been performed in place of colonoscopy, 26.9% of advanced neoplasms and 12.5% of cancers would not have been detected. CONCLUSIONS: Colonoscopy can detect neoplastic lesions undetectable by FOBT and sigmoidoscopy in asymptomatic subjects. These results suggest that colonoscopy should be the method of choice in colon cancer screening.

Genomic prediction of locoregional recurrence after mastectomy in breast cancer.

PURPOSE: This study aims to explore gene expression profiles that are associated with locoregional (LR) recurrence in breast cancer after mastectomy. PATIENTS AND METHODS: A total of 94 breast cancer patients who underwent mastectomy between 1990 and 2001 and had DNA microarray study on the primary tumor tissues were chosen for this study. Eligible patient should have no evidence of LR recurrence without postmastectomy radiotherapy (PMRT) after a minimum of 3-year follow-up (n = 67) and any LR recurrence (n = 27). They were randomly split into training and validation sets. Statistical classification tree analysis and proportional hazards models were developed to identify and validate gene expression profiles that relate to LR recurrence. RESULTS: Our study demonstrates two sets of gene expression profiles (one with 258 genes and the other 34 genes) to be of predictive value with respect to LR recurrence. The overall accuracy of the prediction tree model in validation sets is estimated 75% to 78%. Of patients in validation data set, the 3-year LR control rate with predictive index more than 0.8 derived from 34-gene prediction models is 91%, and predictive index 0.8 or less is 40% (P = .008). Multivariate analysis of all patients reveals that estrogen receptor and genomic predictive index are independent prognostic factors that affect LR control. CONCLUSION: Using gene expression profiles to develop prediction tree models effectively identifies breast cancer patients who are at higher risk for LR recurrence. This gene expression-based predictive index can be used to select patients for PMRT.

Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes.

We describe a comprehensive modeling approach to combining genomic and clinical data for personalized prediction in disease outcome studies. This integrated clinicogenomic modeling framework is based on statistical classification tree models that evaluate the contributions of multiple forms of data, both clinical and genomic, to define interactions of multiple risk factors that associate with the clinical outcome and derive predictions customized to the individual patient level. Gene expression data from DNA microarrays is represented by multiple, summary measures that we term metagenes; each metagene characterizes the dominant common expression pattern within a cluster of genes. A case study of primary breast cancer recurrence demonstrates that models using multiple metagenes combined with traditional clinical risk factors improve prediction accuracy at the individual patient level, delivering predictions more accurate than those made by using a single genomic predictor or clinical data alone. The analysis also highlights issues of communicating uncertainty in prediction and identifies combinations of clinical and genomic risk factors playing predictive roles. Implicated metagenes identify gene subsets with the potential to aid biological interpretation. This framework will extend to incorporate any form of data, including emerging forms of genomic data, and provides a platform for development of models for personalized prognosis.

Gene expression predictors of breast cancer outcomes.

BACKGROUND: Correlation of risk factors with genomic data promises to provide specific treatment for individual patients, and needs interpretation of complex, multivariate patterns in gene expression data, as well as assessment of their ability to improve clinical predictions. We aimed to predict nodal metastatic states and relapse for breast cancer patients. METHODS: We analysed DNA microarray data from samples of primary breast tumours, using non-linear statistical analyses to assess multiple patterns of interactions of groups of genes that have predictive value for the individual patient, with respect to lymph node metastasis and cancer recurrence. FINDINGS: We identified aggregate patterns of gene expression (metagenes) that associate with lymph node status and recurrence, and that are capable of predicting outcomes in individual patients with about 90% accuracy. The metagenes defined distinct groups of genes, suggesting different biological processes underlying these two characteristics of breast cancer. Initial external validation came from similarly accurate predictions of nodal status of a small sample in a distinct population. INTERPRETATION: Multiple aggregate measures of profiles of gene expression define valuable predictive associations with lymph node metastasis and disease recurrence for individual patients. Gene expression data have the potential to aid accurate, individualised, prognosis. Importantly, these data are assessed in terms of precise numerical predictions, with ranges of probabilities of outcome. Precise and statistically valid assessments of risks specific for patients, will ultimately be of most value to clinicians faced with treatment decisions.