Comparison of prognostic gene expression signatures for breast cancer

<p>Abstract</p> <p>Background</p> <p>During the last years, several groups have identified prognostic gene expression signatures with apparently similar performances. However, signatures were never compared on an independent population of untreated breast cancer patients, where risk assessment was computed using the original algorithms and microarray platforms.</p> <p>Results</p> <p>We compared three gene expression signatures, the 70-gene, the 76-gene and the Gene expression Grade Index (GGI) signatures, in terms of predicting distant metastasis free survival (DMFS) for the individual patient. To this end, we used the previously published TRANSBIG independent validation series of node-negative untreated primary breast cancer patients. We observed agreement in prediction for 135 of 198 patients (68%) when considering the three signatures. When comparing the signatures two by two, the agreement in prediction was 71% for the 70- and 76-gene signatures, 76% for the 76-gene signature and the GGI, and 88% for the 70-gene signature and the GGI. The three signatures had similar capabilities of predicting DMFS and added significant prognostic information to that provided by the classical parameters.</p> <p>Conclusion</p> <p>Despite the difference in development of these signatures and the limited overlap in gene identity, they showed similar prognostic performance, adding to the growing evidence that these prognostic signatures are of clinical relevance.</p

Study protocol for THINK : a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

Introduction: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3 zeta signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. Methods and analysis: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3x10(8), 1x10(9) and 3x10(9) NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. Ethics approval and dissemination: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals

Validation and Clinical Utility of a 70-Gene Prognostic Signature for Women With Node-Negative Breast Cancer

Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. Conclusions: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cance

Fecal immunological blood test is more appealing than the guaiac-based test for colorectal cancer screening

International audienceBACKGROUND: The reasons for participation in fecal immunological testing (FIT) of subjects who were previously non-respondents to guaiac fecal occult blood testing (g-FOBT) have not been assessed. POPULATION AND METHODS: We aimed to determine the reasons for current compliance with FIT among non-responders to g-FOBT, termed "converts‿, in a French district. A questionnaire was returned by 170 converts aged from 55 to 75 years (response rate 75.2% after exclusions). RESULTS: The major barriers to participation in screening with g-FOBT were test-related: the test was perceived as complicated (24%) and it required three consecutive stools (28%). Among the test-related major determinants of FIT compliance was the perception that the test was less complicated than previous test (30%) and that a unique stool sample was required (29%). Among the non-test related major determinants of FIT compliance were the perception that the general practitioner was more convincing (31%) and the feeling to be more concerned because of age (21%). The reasons for compliance among converts did not differ according to age, sex, and rural or urban residence. CONCLUSIONS: Our study demonstrated that the simplicity of FIT and the endorsement of practitioners were both major motivations for FIT compliance among non-respondents in at least two previous consecutive campaigns

Is genomic grading killing histological grading ?

Communication on the European breast cancer conference, 2006 Presidential sessioninfo:eu-repo/semantics/publishe

Quantitation of HER2 expression or HER2:HER2 dimers and differential survival in a cohort of metastatic breast cancer patients carefully selected for trastuzumab treatment primarily by FISH.

The selection of patients with HER2-positive breast cancer for treatment with trastuzumab is based on the measurement of HER2 protein expression by immunohistochemistry, or the presence of HER2 gene amplification by fluorescence in situ hybridization (FISH). By using multivariate analyses, we investigate the relationship between quantitative measurements of HER2 expression or HER2:HER2 dimers and objective response (Response Evaluation Criteria in Solid Tumors), time to progression, and breast cancer survival after trastuzumab treatment in a cohort of patients with metastatic breast cancer who were primarily selected for treatment by FISH. The VeraTag assay, a proximity-based assay designed to quantitate protein expression and dimerization in formalin-fixed, paraffin-embedded tissue specimens, was used to measure HER2 protein expression and HER2:HER2 dimer levels. In a Cox proportional hazards analysis, higher HER2 expression or HER2:HER2 dimer levels were both correlated with longer survival (P=0.0058 and P=0.016, respectively) after treatment with trastuzumab in a population of patients that were either FISH-positive (90%) or immunohistochemistry 3+ (10%). Patients with higher levels of HER2 expression or HER2:HER2 dimers seemed to derive little benefit from the addition of concomitant chemotherapy to trastuzumab, whereas those with lower levels benefited significantly [interaction test P=0.43 (HER2 expression), P=0.27 (HER2:HER2 dimers)]. These data suggest that more quantitative or functional measurements of HER2 status may facilitate the development of more personalized treatment strategies for patients with metastatic breast cancer.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.

Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes.Clinical Trial, Phase IIIComparative StudyJournal ArticleRandomized Controlled TrialResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

TRANSBIG multi-centre independent validation of the Rotterdam 76-gene prognostic signature for patients with node-negative breast cancer

Presidential sessioninfo:eu-repo/semantics/nonPublishe

Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.

BACKGROUND: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. METHODS: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. RESULTS: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. CONCLUSIONS: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tValidation Studiesinfo:eu-repo/semantics/publishe