International study on inter-reader variability for circulating tumor cells in breast cancer

Introduction Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. Methods CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. Results For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90). Conclusions The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are require

Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide.

PURPOSE: We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide. RESULTS: In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (</= 720 mg/m(2) and </= 6,300 mg/m(2), respectively) had an 8-year cumulative probability of developing AML/MDS of 0.37% (95% CI, 0.13% to 0.61%) compared with 4.97% (95% CI, 2.06% to 7.87%) for patients administered higher cumulative doses of both epirubicin and cyclophosphamide. CONCLUSION: Patients treated with standard cumulative doses of adjuvant epirubicin (</= 720 mg/m(2)) and cyclophosphamide (</= 6,300 mg/m(2)) for early breast cancer have a lower probability of secondary leukemia than patients treated with higher cumulative doses. Increased risk of secondary leukemia must be considered when assessing the potential benefit to risk ratio of higher than standard doses.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial.

We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy.Clinical Trial, Phase IIIJournal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group.

Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the co-chairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.Journal ArticlePractice GuidelineResearch Support, Non-U.S. Gov'tSCOPUS: re.jinfo:eu-repo/semantics/publishe