B1 Field Correction of T1 Estimation Should Be Considered for Breast Dynamic Contrast-enhanced MR Imaging Even at 1.5 T.

Purpose To prospectively quantify the effect of T1 estimation in fat by B1 correction in breast magnetic resonance (MR) imaging at 1.5 T and to examine the subsequent quantitative dynamic contrast material-enhanced parameters in breast cancer with and without B1 correction. Materials and Methods This study had institutional review board approval, and informed consent was obtained from 72 patients with breast cancer before breast MR imaging studies were performed between January and July 2015. B1+ field and variable flip angle (FA) mapping were included in the dynamic contrast-enhanced breast MR imaging protocol with a 1.5-T MR imaging system. Precontrast T1 relaxation in fat and breast tumors was computed with and without B1 correction. The pharmacokinetic parameters of breast cancer were calculated by using the Tofts model with T1 values before and after B1 correction. The Mann-Whitney U test and linear regression model were used for statistical analysis. Results The FA was 19% higher in the left breast and 3% lower in the right breast than the prescribed value. This 22% average FA difference created a 43% T1 estimation bias in fat between the breasts. The T1 variation in fat was reduced to 0.96% after B1 correction. There was a 50% overestimation and a 7% underestimation of tumor T1 in the left breast and the right, respectively, associated with B1 error. Assuming T1 after B1 correction represents the true tumor T1, 41% underestimation in the left breast and 10% overestimation in the right without B1 correction were seen in the dynamic contrast-enhanced parameters (including the volume transfer constant, or Ktrans, fraction of extracellular extravascular space, or ve, and blood normalized initial area under the gadolinium concentration curve to 90 seconds, or IAUGCBN90). Conclusion B1 correction for more accurate T1 values should be considered for quantitative dynamic contrast-enhanced breast MR imaging, even at 1.5 T, to offset significant systemic error. © RSNA, 2016.

The learning curve of laparoscopic liver resection after the Louisville statement 2008: Will it be more effective and smooth?

BACKGROUND: Laparoscopic liver resection (LLR) has been proven to be feasible and safe. However, it is a difficult and complex procedure with a steep learning curve. The aim of this study was to evaluate the learning curve of LLR at our institutions since 2008. METHODS: One hundred and twenty-six consecutive LLRs were included from May 2008 to December 2014. Patient characteristics, operative data, and surgical outcomes were collected prospectively and analyzed. RESULTS: The median tumor size was 25 mm (range 5-90 mm), and 96 % of the resected tumors were malignant. 41.3 % (52/126) of patients had pathologically proven liver cirrhosis. The median operation time was 216 min (range 40-602 min) with a median blood loss of 100 ml (range 20-2300 ml). The median length of hospital stay was 4 days (range 2-10 days). Six major postoperative complications occurred in this series, and there was no 90-day postoperative mortality. Regarding the incidence of major operative events including operation time longer than 300 min, perioperative blood loss above 500 ml, and major postoperative complications, the learning curve [as evaluated by the cumulative sum (CUSUM) technique] showed its first reverse after 22 cases. The indication of laparoscopic resection in this series extended after 60 cases to include tumors located in difficult locations (segments 4a, 7, 8) and major hepatectomy. CUSUM showed that the incidence of major operative events proceeded to increase again, and the second reverse was noted after an additional 40 cases of experience. Location of the tumor in a difficult area emerged as a significant predictor of major operative events. CONCLUSIONS: In carefully selected patients, CUSUM analysis showed 22 cases were needed to overcome the learning curve for minor LLR.

Risk factors associated with conversion from nonmalignant to malignant diagnosis after surgical excision of breast papillary lesions.

PURPOSE: Management of papillary lesions of the breast identified during preoperative tissue diagnosis remains controversial. This study was designed to analyze the clinical factors associated with under-diagnosis of malignancy in breast papillary lesions. METHODS: Patients with a preoperative tissue diagnosis of benign or atypical papillary lesions, who received surgical excision between 1991 and 2005, were identified. Age of diagnosis, family history of breast cancer, presentation of nipple discharge, palpable mass, mammogram grading, size of lesion, and final pathological diagnosis were analyzed. Tissue sections were reviewed to confirm the diagnosis of malignancy and reasons of discrepancy. RESULTS: A total of 205 women with 228 papillary lesions were studied. The median age was 42 (range, 12-83) years. Malignancies were diagnosed after surgery in 21 cases (9.2%). Patients aged 45 years or older and atypical lesions according to fine needle aspiration cytology (FNAC) or core needle biopsy (CNB) were associated with higher risk for postoperative malignant diagnosis with P values of 0.0008 and < 0.0001, respectively. Pathology review of 19 lesions with malignancy revealed that reasons for preoperative nonmalignant diagnosis were borderline lesions in nine (47.3%), sampling problem in six (31.5%), interpretation error in three (15.7%) and uninterpretable sample in one (5.2%). CONCLUSIONS: In this cohort, 9.21% of preoperative nonmalignant papillary lesions were converted to malignant diagnosis after surgery. Atypical lesions and patients aged 45 years or older were significant factors associated with such conversion. Surgical excision should be considered for papillary lesions of breast, especially for patients with the identified risk factors.

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.

Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients.

PURPOSE: To develop clinical prediction models for local regional recurrence (LRR) of breast carcinoma after mastectomy that will be superior to the conventional measures of tumor size and nodal status. METHODS AND MATERIALS: Clinical information from 1,010 invasive breast cancer patients who had primary modified radical mastectomy formed the database of the training and testing of clinical prognostic and prediction models of LRR. Cox proportional hazards analysis and Bayesian tree analysis were the core methodologies from which these models were built. To generate a prognostic index model, 15 clinical variables were examined for their impact on LRR. Patients were stratified by lymph node involvement (<4 vs. >or =4) and local regional status (recurrent vs. control) and then, within strata, randomly split into training and test data sets of equal size. To establish prediction tree models, 255 patients were selected by the criteria of having had LRR (53 patients) or no evidence of LRR without postmastectomy radiotherapy (PMRT) (202 patients). RESULTS: With these models, patients can be divided into low-, intermediate-, and high-risk groups on the basis of axillary nodal status, estrogen receptor status, lymphovascular invasion, and age at diagnosis. In the low-risk group, there is no influence of PMRT on either LRR or survival. For intermediate-risk patients, PMRT improves LR control but not metastases-free or overall survival. For the high-risk patients, however, PMRT improves both LR control and metastasis-free and overall survival. CONCLUSION: The prognostic score and predictive index are useful methods to estimate the risk of LRR in breast cancer patients after mastectomy and for estimating the potential benefits of PMRT. These models provide additional information criteria for selection of patients for PMRT, compared with the traditional selection criteria of nodal status and tumor size.

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.

Better Overall Survival for Breast Cancer Patients by Adding Breast Ultrasound to Follow-Up Examinations for Early Detection of Locoregional Recurrence-A Survival Impact Study.

We retrospectively reviewed patient records to evaluate the effectiveness of our 15 y of ultrasound (US) surveillance of recurrent breast disease in comparison with mammography (MM) and clinical examination. From 4796 stage 0-III breast cancer patients who had received surgical treatment, we identified locoregional recurrence (LRR) in 161 patients. The mean age of the 161 patients was 48 y (27-82 y), and the mean follow-up interval was 77.2 mo (11-167 mo). The methods of LRR detection, sites of LRR and overall survival (OS) were examined. Multivariate Cox survival analysis showed significantly better survival in groups detected by US (hazard ratio = 0.6, p = 0.042). The 10-y LRR OS by detection types for US (n = 69), clinical examination (n = 78) and MM (n = 8) were 58.5%, 33.1% and 100%, respectively (p = 0.0004). US was seen with better OS associated with the effective early detection of non-palpable LRR breast cancer, which is mostly not detectable on MM.

Transanal local wide excision for rectal adenocarcinoma.

BACKGROUND/AIMS: Abdominoperineal resection is associated with high morbidity and mortality, and sphincter preservation is the aim for the patient. Transanal local wide excision of highly selected rectal cancers is an acceptable alternative to radical surgery. METHODOLOGY: This retrospective study of 18 patients with rectal cancer treated with transanal local wide excision at our hospital during a 6-year period (from 1995 to 2001) is discussed. RESULTS: Tumor size ranged from 1 to 6 cm (mean, 2.23 cm). All resection margins were free of tumors. There was no surgical mortality or morbidity. Median follow-up period was 17.9 months. Among 18 patients, 12 patients received radiotherapy and chemoradiotherapy as a postoperative adjuvant treatment. There was one local recurrence with liver metastasis noted within one year after the operation. The 1-yr, 2-yr and 5-yr disease-free survival rate was 92%. CONCLUSIONS: Transanal local wide excision for rectal cancer, when combined with selected chemotherapy or radiotherapy, results in good local-regional control in our series. A Good long-term survival rate was also proven by presented articles. This approach can be safely applied to more advanced tumors (T3 lesion) under accurate pre-op staging, aggressive postoperative adjuvant therapy and careful regular follow-up.

Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy.

PURPOSE: To analyze the incidence and risk factors for locoregional recurrence (LRR) in patients with breast cancer who had T1 or T2 primary tumor and 1-3 histologically involved axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy (RT). MATERIALS AND METHODS: Between April 1991 and December 1998, 125 patients with invasive breast cancer were treated with modified radical mastectomy and were found to have 1-3 positive axillary nodes. The median number of nodes examined was 17 (range 7-33). Of the 125 patients, 110, who had no adjuvant RT and had a minimum follow-up of 25 months, were included in this study. Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. Patient-related characteristics (age, menopausal status, medial/lateral quadrant of tumor location, T stage, tumor size, estrogen/progesterone receptor protein status, nuclear grade, extracapsular extension, lymphovascular invasion, and number of involved axillary nodes) and treatment-related factors (chemotherapy and hormonal therapy) were analyzed for their impact on LRR. The median follow-up was 54 months. RESULTS: Of 110 patients without RT, 17 had LRR during follow-up. The 4-year LRR rate was 16.1% (95% confidence interval [CI] 9.1-23.1%). All but one LRR were isolated LRR without preceding or simultaneous distant metastasis. According to univariate analysis, age <40 years (p = 0.006), T2 classification (p = 0.04), tumor size >==3 cm (p = 0.002), negative estrogen receptor protein status (p = 0.02), presence of lymphovascular invasion (p = 0.02), and no tamoxifen therapy (p = 0.0006) were associated with a significantly higher rate of LRR. Tumor size (p = 0.006) was the only risk factor for LRR with statistical significance in the multivariate analysis. On the basis of the 4 patient-related factors (age <40 years, tumor >==3 cm, negative estrogen receptor protein, and lymphovascular invasion), the high-risk group (with 3 or 4 factors) had a 4-year LRR rate of 66.7% (95% CI 42.8-90.5%) compared with 7.8% (95% CI 2.2-13.3%) for the low-risk group (with 0-2 factors; p = 0.0001). For the 110 patients who received no adjuvant RT, LRR was associated with a 4-year distant metastasis rate of 49.0% (9 of 17, 95% CI 24.6-73.4%). For patients without LRR, it was 13.3% (15 of 93, 95% CI 6.3-20.3%; p = 0.0001). The 4-year survival rate for patients with and without LRR was 75.1% (95% CI 53.8-96.4%) and 88.7% (95% CI 82.1-95.4%; p = 0.049), respectively. LRR was independently associated with a higher risk of distant metastasis and worse survival in multivariate analysis. CONCLUSION: LRR after mastectomy is not only a substantial clinical problem, but has a significant impact on the outcome of patients with T1 or T2 primary tumor and 1-3 positive axillary nodes. Patients with risk factors for LRR may need adjuvant RT. Randomized trials are warranted to determine the potential benefit of postmastectomy RT on the survival of patients with a T1 or T2 primary tumor and 1-3 positive nodes.

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.

Sonographic elastography improves the sensitivity and specificity of axilla sampling in breast cancer: a prospective study.

We describe a study to determine whether elastography of axillary lymph nodes (LNs) combined with B-mode ultrasound (US) is capable of differentiating the benign from the metastatic state in patients with breast cancer. B-mode US, elastography and fine-needle aspiration of 90 axillary lymph nodes from 89 female patients with breast cancer are described in this report. Five elastographic patterns were observed as defined by the percentages of high elasticity according to pattern of distribution and degree of hardness of the target LNs. B-mode US and elastography scores were combined to give the final scores. Sensitivity and specificity were 80% and 88%, respectively, for B-mode US alone, 86% and 90% for elastography alone and 84% and 98% for the combined assessment to differentiate the benign from the malignant state. The combination of B-mode US and elastography is capable of identifying metastatic axillary LNs from benign enlargement in patients with breast cancer.

Locoregional therapy in luminal-like and HER2-enriched patients with de novo stage IV breast cancer.

BACKGROUND: Locoregional therapy is rarely the standard of care for De Novo stage IV breast cancer but usually used for palliation of symptoms. This retrospective study aimed to determine whether surgery or radiation would contribute to survival benefit for this group of patients by examining the survival outcome through the disease molecular subtypes. MATERIALS AND METHODS: We reviewed 246 patients with de novo stage IV (M1) breast cancer treated at our hospital between 1990 and 2009. Multivariable Cox Analysis was used to evaluate the survival association with subtypes and clinicopathologic factors. RESULTS: Patients with luminal-like subtype are mostly premonopausal (66.9%, P = 0.0002), with abnormal CA 15-3 level at initial diagnosis (58.7%, P = 0.01), a higher rate of bony metastases (78.5%, P = 0.02), and a lower rate of liver metastases (22.3%, P < 0.0001). Patients with HER2-enriched and triple negative showed higher rate of nuclear grade III, up to 35% and 40%, respectively (P = 0.01). There is no difference in treatment options patient received: systemic chemotherapy up to 82.2 ~ 95% (p = 0.0705), locoregional treatment up to 40.0 ~ 51.2% (P-0.2571). The median overall survival was 23.1 months: luminal-like subtype 39.6 months, HER2-enriched subtype 17.9 months, and triple negative subtype 13.3 months, respectively (P < 0.0001). In multivariate analysis, poor prognostic factors included HER2-enriched (HR 2.2, P < 0.0001) and triple negative subtype (HR 4.3, P < 0.0001), liver metastasis (HR 1.9, P < 0.0001), lung metastasis (HR 1.4, P = 0.0153), and bone metastasis (HR 1.8, P = 0.0007). Subgroup analysis revealed that local treatments (surgery or radiotherapy) to primary/regional tumors achieved better survival in patients with luminal-like (3-year survival 66.4% vs. 34.4%, p = 0.0001) and HER2-enriched (3-year survival 41.6% vs. 8.8%, p = 0.0012) subtypes, but not in triple negative subtype (P = 0.9575). CONCLUSIONS: For better survival outcome, De Novo Stage IV breast cancer patients with luminal-like or HER2-enriched subtype should be offered local treatments when surgery and/or radiotherapy presents an option for proper control of the primary and regional tumors.

Feasibility of combined paravertebral block and subcostal transversus abdominis plane block in postoperative pain control after minimally invasive esophagectomy.

OBJECTIVES: Subcostal transversus abdominis plane (TAP) block and paravertebral block (PVB) offer postoperative analgesia for laparoscopic and thoracoscopic surgery, respectively. We investigated the early postoperative analgesic effects of PVB in combination with subcostal TAP block in patients undergoing minimally invasive esophagectomy (MIE) for esophageal cancer. METHODS: Seventeen patients undergoing MIE without nerve block for postoperative analgesia and 16 patients undergoing MIE with PVB and subcostal TAP block for postoperative analgesia were enrolled for the study. The surgeon performed PVB with bupivacaine at T4, T6, and T8 levels under video-assisted thoracoscopy at the end of the thoracoscopic stage. The anesthesiologist responsible for the anesthesia performed ultrasound-guided bilateral subcostal TAP with bupivacaine at the end of the surgery. Postoperative morphine consumption, pain severity, vital capacity, intensive care unit (ICU) stay, and complication rate were compared between groups. RESULTS: The group receiving nerve blocks consumed less morphine on postoperative Day 0 (p = 0.016), experienced lower levels of pain at postoperative 0 hour (p = 0.005) and 2 hours (p = 0.049), and had a shorter ICU stay (p = 0.02). No between-group differences in postoperative vital capacity and respiratory complications were observed. CONCLUSION: PVB in combination with subcostal TAP block could reduce morphine consumption and pain severity in the early postoperative period but did not offer other clinical benefits in MIE.

Validating a prognostic scoring system for postmastectomy locoregional recurrence in breast cancer.

PURPOSE: This study is designed to validate a previously developed locoregional recurrence risk (LRR) scoring system and further define which groups of patients with breast cancer would benefit from postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An LRR risk scoring system was developed previously at our institution using breast cancer patients initially treated with modified radical mastectomy between 1990 and 2001. The LRR score comprised 4 factors: patient age, lymphovascular invasion, estrogen receptor negativity, and number of involved lymph nodes. We sought to validate the original study by examining a new dataset of 1545 patients treated between 2002 and 2007. RESULTS: The 1545 patients were scored according to the previously developed criteria: 920 (59.6%) were low risk (score 0-1), 493 (31.9%) intermediate risk (score 2-3), and 132 (8.5%) were high risk (score ≥4). The 5-year locoregional control rates with and without PMRT in low-risk, intermediate-risk, and high-risk groups were 98% versus 97% (P=.41), 97% versus 91% (P=.0005), and 89% versus 50% (P=.0002) respectively. CONCLUSIONS: This analysis of an additional 1545 patients treated between 2002 and 2007 validates our previously reported LRR scoring system and suggests appropriate patients for whom PMRT will be beneficial. Independent validation of this scoring system by other institutions is recommended.

The effect on improvement of recovery and pain scores of paravertebral block immediately before breast surgery.

OBJECTIVES: Paravertebral block (PVB) has the potential to reduce postoperative pain after breast surgery. The aim of the study was to investigate whether PVB performed immediately before surgery could affect the postoperative morbidities in terms of pain and emesis, and improve the quality of recovery (QoR) in patients after surgery for breast cancer. METHODS: Postoperative data were collected prospectively from two groups of patients undergoing unilateral breast surgery during the study period of 1 month. Forty consecutive patients received either solely general anesthesia (GA group, n=25) or GA plus ultrasound-guided PVB (GA+PVB group, n=15) for the surgery. Pain scores and areal distribution of pain were compared between the two groups 1 hour and 6 hours postoperatively and on the midmorning of postoperative Day 1 (POD1). The QoR scores were compared between the two groups 6 hours postoperatively and on the midmorning of POD1. Incidence of postoperative nausea and vomiting and doses of analgesics and narcotics given were also compared. RESULTS: Pain scores at rest were significantly lower in the GA+PVB group at all designated time points [1 hour (p<0.0001), 6 hours (p<0.0001), and on midmorning of POD1 (p=0.041)]. Pain scores with movements was also significantly lower at all time points in the GA+PVB group (1 hour, p<0.0001; 6 hours, p<0.0001; midmorning of POD1, p=0.0012). Areal distribution of pain at rest and with movement was wider in the GA group 1 hour and 6 hours postoperately but was identical to that of GA+ PVB group on the mid-morning of POD1 [1 hour postoperatively at rest (p<0.0001), with movement (p<0.0001); 6 hours postoperatively at rest (p=0.0018), with movement (p=0.0048)]. The QoR scores were significantly higher in the GA+PVB group at 6 hours (p<0.0001) and on midmorning of POD1 (p=0.0079). The incidences of postoperative nausea and vomiting were significantly lower in the GA+PVB group (p=0.0004). Doses of postoperative analgesics and narcotics were significantly less in the GA+PVB group (p<0.0001 and p=0.001, respectively). Time to first request for analgesics was significantly longer in the GA+PVB group (p=0.0002). CONCLUSIONS: PVB given before surgery in combination with GA could provide better postoperative analgesia and better QoR than did GA alone in patients undergoing surgery for unilateral breast cancer.

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.