Background: Breast cancer (BC) patients receiving anthracycline-cyclophosphamide (AC) chemotherapy (CT) are at risk for developing CINV due not only to the emetogenicity of the CT but also to young age and gender. As recommended by international antiemetic guidelines, targeting multiple molecular pathways involved in emesis related to AC is important for maximizing control of CINV and improving the functional status of BC patients during CT. NEPA is a fixed-dose combination of netupitant (NETU), a highly-selective NK1 receptor antagonist (RA), and palonosetron (PALO), a pharmacologically distinct 5-HT3 RA, that targets dual antiemetic pathways with a convenient single day dose. Methods: This was a multinational, randomized, double-blind, phase 3 study evaluating the efficacy and safety of a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naïve patients receiving AC. All patients received oral dexamethasone (DEX) on day 1 (12 mg NEPA arm; 20 mg PALO arm). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) in the delayed phase, 25-120h after CT. The Functional Living Index-Emesis (FLIE) questionnaire with a 5-day recall period was used to assess the impact of CINV on patients’ daily lives as a secondary endpoint. The FLIE consists of 9 nausea-specific (nausea domain) and 9 vomiting-specific (vomiting domain) items that address the effect of nausea and vomiting on daily life. Each item is scored on a 7-point 100 mm visual analog scale with anchors of “none/not at all” and “a great deal”. The proportion of patients with an average item score >6 reflecting “no impact on daily life” (NIDL) (ie, total FLIE score >108, nausea/vomiting domain score >54) was compared for NEPA vs PALO using a Cochran-Maentel-Haenszel test stratified by age class and region. Results: 1455 patients with a mean age of 54 were randomized to receive NEPA or PALO. Treatment groups were similar; 98% were females with BC (97%). As previously reported (ASCO 2013), NEPA showed superior CR rates compared to PALO for the acute 0-24h (88% vs 85%; p = 0.047), delayed (77% vs 70%; p = 0.001) and overall 0-120h (74% vs 67%; p = 0.001) phases. A greater proportion of NEPA-treated patients reported NIDL for nausea, vomiting and combined domains compared to PALO. % Patients with NIDL (Overall 0-120h)NEPA (N = 724)PALO (N = 725)p-valueNausea domain72%66%0.015Vomiting domain90%84%0.001Overall combined79%72%0.0056 patients excluded who did not receive AC or study drug The adverse event (AE) profile was comparable between groups. Most frequently reported treatment-related AEs for NEPA and PALO, respectively, were headache (3.3%, 3.0%) and constipation (2.1%, 2.1%). Conclusions: In this large Phase 3 study of predominantly females with BC receiving AC, NEPA was superior to PALO in preventing CINV and reducing the negative impact of CINV on patients’ daily lives. As a fixed-dose antiemetic drug combination including an NK1 RA and 5-HT3 RA, NEPA offers improved efficacy over PALO alone, with a convenient single-day dose, and oral DEX only on day 1. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-01.
Background: Clinical studies have demonstrated the prognostic and predictive value of the number of CTCs in metastatic breast cancer. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment. Methods: Ten to twenty mLs of blood from 32 metastatic breast cancer patients with poor prognosis (≥5 CTCs in 7.5mLs blood) were subjected to immunomagnetic enrichment. Pools of ∼20 CTCs [EpCAM+, CD45-, nucleated] were isolated via fluorescence activated cell sorting, FACS. Genomic DNA was subjected to whole genome amplification followed by array comparative genomic hybridization (CGH) analysis. Serial genomic profiling was performed in three patients. Genomic profiles from archival primary tumor available from 4 patients were compared to matched CTCs. Copy number analysis was performed using the Nexus® Copy Number. Genomic alterations with p ≥0.05 were considered significant. Results: Genomic profiling of CTCs revealed significant recurrent (≥35%) genomic alterations including gains in 8q12.1, 8q24 and losses in 1p36, 4p16, 5q21, 10q22, 11q24-25, and 13q34. Good concordance of CGH profiles obtained from CTCs isolated from serial blood samples attested to the reproducibility of the assay. Furthermore, comparisons of CTCs with matched archival primary tumors confirmed shared lineage with some divergence. Conclusions: Copy number analysis revealed common genomic alterations in CTCs as well as shared aberrations with matched primary tumor. In addition, we demonstrated the feasibility of serial genomic profiling of CTCs. Future work will determine associations between genomic aberrations in CTCs and clinicopathological parameters. Uncovering genomic alterations in CTCs may lead to the discovery of therapeutic biomarkers to specifically target these cells in breast cancer patients who respond poorly to current aggressive therapies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-10.
In patients with breast cancer, the risk of developing chemotherapy-induced nausea and vomiting (CINV) is particularly high due to the common use of highly emetogenic chemotherapy coupled with pt-related risk factors including female gender and young age. Despite prophylactic antiemetics, controlling CINV is difficult in this high risk population, particularly in the delayed phase following CT. Palonosetron, a potent 5-HT3 receptor antagonist (RA) with a distinctly different pharmacokinetic and receptor binding profile, has demonstrated improved CINV protection compared to older 5-HT3 RAs in phase 3 and 4 clinical trials in a variety of settings and tumor types. We conducted a retrospective subset analysis of pts with breast cancer, the majority of whom (89%) received anthracycline combination chemotherapy (doxorubicin or epirubicin and cyclophosphamide, AC/EC) from four phase 3, randomized, double-blind, parallel group studies to assess the comparative effectiveness and safety of single IV doses of palonosetron (0.25 or 0.75 mg) versus older 5HT3-RAs (ondansetron 32 mg, dolasetron 100 mg, and granisetron 3 mg) in preventing CINV in pts receiving this highly emetogenic chemotherapy. The primary efficacy evaluation was for complete response (CR), defined as the proportion of patients with no emetic episodes & no use of rescue medication during 0–24hrs (acute), >24-120hrs (delayed), & 0–120hrs (overall) using a logistic regression model. A comparative descriptive safety assessment was also performed. A total of 1197 patients with breast cancer were included in this analysis (palonosetron n=714; older 5HT3-RAs n=483). Higher CR rates were seen for palonosetron vs. older 5HT3-RAs during the acute (63.4% vs 59.4%, p= 0.08), delayed (59.2% vs. 44.9%, p<0.0001) and overall (50.7% vs.38.5%, p<0.0001) phases. Rates for CR were similarly higher for palonosetron-treated patients in the large subgroup of patients receiving AC/EC based chemotherapy. Consistent improvements associated with palonosetron were seen for secondary endpoints of complete control (CR + no more than mild nausea), no emesis, and severity of nausea. The adverse event (AE) profile for palonosetron was similar to older 5HT3-RAs, with headache and constipation being the most commonly reported treatment-related AEs with similar incidences for all 5-HT3 RAs. This retrospective analysis of patients with breast cancer, including a large subgroup receiving anthracycline-based highly emetogenic chemotherapy, demonstrated significantly improved CINV prevention with palonosetron compared to older 5HT3-RAs, particularly in the delayed phase. Safety was comparable. This data has important implications for current CINV prevention guidelines. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-13-03.
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