Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?

Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. 'Prospective-retrospective' studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.

Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: further results from the prospective PANTHER study with focus on obese patients.

Background: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial. Patients and methods: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT. Results: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups. Conclusions: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies. ClinicalTrials.gov identifier: NCT00798070.

The role of docetaxel in the treatment of non-small cell lung cancer lung cancer: an update.

INTRODUCTION: Non-small cell lung cancer lung cancer (NSCLC) is a devastating disease, with poor prognosis for patients with metastatic disease. The management of these patients has evolved during the past decade, challenging the role of cytotoxic chemotherapy as the only available treatment option. Nevertheless, chemotherapy still retains a dominant position for the majority of both treatment naïve and pretreated patients. Among the chemotherapeutic agents, docetaxel is one of the most commonly used in 1st and subsequent treatment lines, even in the current era of precision medicine. Areas covered: We searched Medline, Embase, Scopus and Cochrane Library for randomized phase III trials that evaluated docetaxel in various clinical settings of NSCLC and for meta-analyses of such trials and we present all relevant data regarding the pharmacology and clinical use of docetaxel in NSCLC. Expert commentary: Despite its diminishing role, docetaxel in combination with novel targeted agents remains an important option of the therapeutic armamentarium in advanced NSCLC.

A multicentre phase II trial of cabazitaxel in patients with advanced non-small-cell lung cancer progressing after docetaxel-based chemotherapy.

BACKGROUND: Cabazitaxel, a semisynthetic microtubule inhibitor, has shown antitumour activity in models resistant to paclitaxel and docetaxel, and it has been approved for the treatment of docetaxel-resistant prostate cancer. We investigated its activity in patients with advanced non-small-cell lung cancer (NSCLC) progressing under or after docetaxel-based regimens. METHODS: Patients with locally advanced unresectable or metastatic NSCLC, with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled; patients had to have received up to two prior chemotherapy regimens for the treatment of advanced disease, including one docetaxel-containing regimen. Treatment consisted of cabazitaxel (25 mg m(-2) intravenously, every 21 days) until disease progression. The primary end point was the overall response rate. RESULTS: Among the 46 evaluable patients, 28.3% had squamous cell carcinoma and 54.3% had adenocarcinoma. Eight (17.4%) patients had received one and 38 (82.6%) two prior chemotherapy regimens. Treatment compliance was 95%; 26 (16%) cycles were delayed because of toxicity, (n=13) and dose reduction was required in 6 (13%) patients because of haematologic toxicity. Six (13%) patients achieved a partial response and 17 (37.0%) stable disease. The median progression-free survival and overall survival were 2.1 (95% confidence interval (CI): 1.0-3.2) and 7.4 (95% CI: 5.2-9.6) months, respectively. Grade 4 adverse events included neutropenia (n=8; 17%), febrile neutropenia (n=6; 13%) and thrombocytopenia (n=3; 6.5%). There was one treatment-related death. CONCLUSIONS: Cabazitaxel exhibits activity in NSCLC patients pre-treated with docetaxel-based chemotherapy with a substantial but manageable toxicity profile. The drug merits further evaluation in this indication.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).

BACKGROUND: Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. PATIENTS AND METHODS: In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. RESULTS: Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. CONCLUSIONS: This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. CLINICALTRIALSGOV: NCT01985724.

Efficacy and tolerance of frontline bevacizumab-based chemotherapy for advanced non-small cell lung cancer patients: a multicenter, phase IV study of the Hellenic Oncology Research Group (HORG).

INTRODUCTION: The addition of bevacizumab to the first-line chemotherapy of advanced non-small cell lung cancer (NSCLC) of non-squamous histology has been shown to improve survival. A multicenter, single-arm, phase IV study was conducted in order to evaluate the efficacy and toxicity of frontline bevacizumab-based chemotherapy regimens in real life. METHODS: Patients with previously untreated recurrent or metastatic non-squamous, NSCLC, with no contraindications for bevacizumab, were enrolled. Bevacizumab (15 mg/kg every 3 weeks) was administered in combination with both platinum- and non-platinum-based chemotherapy doublets or with single-agent chemotherapy plus bevacizumab. Treatment with bevacizumab was continued until disease progression. The primary end point of the study was the safety profile of bevacizumab regimens, whereas the secondary end points included overall survival, progression-free survival, and overall response rate. RESULTS: From February 2010 to April 2014, a total of 314 patients were enrolled in the study; the median age was 63, 74.8 % were men, 95.9 % had a performance status of 0-1, 90.4 % had metastatic disease, and 94.3 % had adenocarcinoma. Grade ≥3 neutropenia occurred in 11.5 % of the patients, 1.3 % experienced febrile neutropenia, 2.6 % grade ≥3 thrombocytopenia, 2.8 % thromboembolism, and 1.6 % severe bleeding. Treatment discontinuation occurred in 7.0 % of patients because of adverse events. There were three toxic deaths. Median progression-free survival was 7.7 months, and median overall survival was 17.6 months. CONCLUSION: The combination of bevacizumab with chemotherapy in the first-line setting of NSCLC is safe and active when used in appropriately selected patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01934465.