Background: Immunohistochemical (IHC) assessment of the proportion of cells staining for the KI67 nuclear antigen is being increasing utilized in the management of patients with early-stage breast cancer (ESBC). A comprehensive systematic review and evidence synthesis of biomarkers potentially predictive of response to systemic therapy was initiated as a part of an NCI-funded comparative effectiveness research program. Methods: Studies of chemotherapy response prediction based on baseline IHC assessment of Ki67 in patients with ESBC receiving neoadjuvant systemic therapy were identified. Response was specified as pathologic complete response (pCR) or clinical response (ClinR). Assay predictive performance for response was assessed on the basis of sensitivity, specificity, predictive value and predictive odds ratio (POR±95%CLs) utilizing mixed effects models. Study results were fitted in an ROC analysis based on the method of DerSimonian and Laird. Publication bias was evaluated on the basis of funnel plot asymmetry assessed by Egger's regression intercept and Begg and Mazumdar's rank correlation. Results: Of 469 potentially eligible studies, dual blind full text review identified 42 eligible studies reporting 44 independent cohorts with 6,716 patients (21–979). While Ki67 cutpoints varied considerably, they were most commonly between 10%–30% (median 20%, range 1–50%). The analysis prsented here is limited to the 30 studies of ESBC patients (N = 3,343) receiving neoadjuvant therapy of which 14 reported fewer than 100 patients. The proportion of patients with elevated Ki67 across studies ranged from 0.20–0.92 (median = 0.54). Sensitivity and specificity for treatment response in patients with high vs. low baseline Ki67 was 0.65 [0.61, 0.68] and 0.52 [0.50, 0.54], respectively. Estimated response rates across studies in patients with high vs. low Ki67 were 31% [29%, 34%] and 19% [17%, 21%], respectively. The estimated POR for response across studies was 2.82 [2.14, 3.72; P < .001]. POR was significantly greater in studies of anthracycline-based [3.0] than non-anthracycline regimens [0.92](Pinteraction = .043) and of cyclophosphamide-based [3.41] compared to non-cyclophosphamide regimens [2.00](P interaction=.039) but was not associated with treatment based on other drug classes. Although Ki67 predictive performance was not significantly associated with the cutpoint utilized or the proportion of patients with ER or PR+, Her2+, or high grade tumors across studies, analysis based on individual patient data is needed to assess performance in specific clinical subgroups. No significant publication bias was found. Conclusions: A compelling need exists for larger studies with greater methodologic rigor and standardization to assess the clinical validity of Ki67 in ESBC as well its clinical utility in guiding neoadjuvant treatment decisions compared to the use of conventional predictive markers. Funding: NCI: RC2CA14041-01 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-07.
Background: Febrile neutropenia (FN) represents a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. Patients have the highest risk of the initial neutropenic event in cycle 1 when most patients receive full dose chemotherapy. This study evaluates time course of neutropenic events in patients receiving chemotherapy for early-stage breast cancer (ESBC) and supportive care interventions that modify FN risk in ESBC patients treated in actual oncology practice. Methods: A prospective cohort study of adult cancer patients with solid tumors or lymphoma starting a chemotherapy regimen was conducted at 115 U.S. sites. Toxicities associated with chemotherapy were recorded in up to 4 cycles including severe neutropenia (SN), FN, and infection. Documented clinical interventions included reductions in chemotherapy relative dose intensity (RDI), the use of colony-stimulating factors (CSFs), and antibiotics. Results: A total of 1202 ESBC patients starting chemotherapy were analyzed, of which 1154, 1099, and 896 reached the midcycle of cycles 2, 3, and 4, respectively. While the majority of neutropenic and infection events occurred in cycle 1, decreasing rates of FN and infection in later cycles correlated with increasing reductions in dose intensity and increased use of CSFs and antibiotics. The overall risk of FN in all patients combined was 16.3 %. It reached 21.1% for patients who started with planned RDI≥85% and without primary CSF prophylaxis. There was no significant difference in FN rates by menopausal status or hormone receptors. Conclusions: While the risk of neutropenic complications is highest during the first cycle of chemotherapy, reductions in neutropenic events during subsequent cycles are associated with reduced chemotherapy dose intensity or increased use of supportive care measures. Nevertheless, the cumulative risk of neutropenic events remains high in ESBC patients receiving full dose chemotherapy without prophylactic measures overall and across menopausal and hormone receptor subgroups. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-04.
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