Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors.

Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m2 on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4. Once the RP2D was defined, patients with advanced ovarian carcinoma were treated at this dose level in an expansion phase. Biomarkers of Hh signaling were assessed by immunohistochemistry in archival tissue and antitumor activity evaluated using RECIST 1.1. Results 18 patients were treated: 3 at 400 mg, 3 at 600 mg and 12 at 800 mg sonidegib. Only one patient treated at 800 mg presented a DLT (prolonged neutropenia resulting in failure to receive 75% of the planned sonidegib dose). However, 4 of 12 patients treated at 800 mg had their sonidegib dose reduced for toxicity after cycle 1. Hh biomarker (SHH, Patched, SMO and GLI1) staining did not correlate with clinical activity. Best response was partial response in 3 patients (2 ovarian, 1 breast cancer) and stable disease >4 cycles in 3 patients (2 ovarian, 1 anal cancer). Conclusions The combination of sonidegib and paclitaxel is tolerable and evidence of antitumor activity was identified. The RP2D of sonidegib was 800 mg in combination with paclitaxel 80mg/m2.

Effect of front-line chemotherapy on circulating CK-19 mRNA-positive cells in patients with metastatic breast cancer.

PURPOSE: To evaluate the effect of front-line chemotherapy on CK-19mRNA+ circulating tumor cells (CTCs) and their relevance in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: The presence of CK-19mRNA+ CTCs was assessed using a real-time RT-PCR assay in 298 previously untreated patients with MBC before and after the administration of front-line chemotherapy. RESULTS: CK-19mRNA+ CTCs were detected in the blood of 199 (66.8 %) and 148 (49.7 %) patients before and after chemotherapy, respectively. There was no correlation between the detection of CK-19mRNA+ CTCs after chemotherapy and the various known clinicopathologic parameters except with HER2 status. The incidence of detection of CK-19mRNA+ CTCs was significantly decreased after the administration of 3 (47.8 %; p < 0.001) or 6 (44.3 %; p = 0.001) chemotherapy cycles. The persistent detection of >2.25 CK-19mRNA+ CTCs both before and after chemotherapy (persistently high group) was associated with a significantly (p = 0.003) decreased overall survival. In addition, chemotherapy-induced decrease of CK-19mRNA+ CTCs (≤2.25 CTCs) was associated with a better survival (47 vs 34 months; p < 0.001). Failure of chemotherapy to decrease the CK-19mRNA+ CTCs ≤2.25 was associated with decreased overall survival (HR 1.405, 95 % CI 1.044-1.891; p = 0.025) whereas in multivariate analysis the persistence of >2.25 CTCs both before and after chemotherapy was emerged as an independent prognostic factor (HR 1.661, 95 % CI 1.070-2.579; p = 0.024). CONCLUSION: Detection of CK-19mRNA+ CTCs after the completion of front-line chemotherapy in patients with MBC is associated with poor survival and may be a useful tool for the evaluation of front-line chemotherapy.

Predictive and prognostic vaue of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer

OBJECTIVE: Cancer patients usually develop malnutrition which may alter their innate immune system integrity. The aim of this study was to investigate the clinical relevance of chemokine response after lipopolysaccharide (LPS)-stimulation in metastatic non-small cell lung cancer (NSCLC). METHODS: Blood samples from metastatic NSCLC patients were incubated with LPS before the onset of systemic therapy. Interleukin (IL)-6 and IL-8 levels at baseline and after LPS-stimulation were measured and the fold change compared to baseline levels was evaluated as the stimulation index for each cytokine per patient. Results were correlated with sex, age, smoking status, histologic subtype, performance status (PS), albumin, Mini Nutritional Assessment (MNA) status and clinical outcomes. RESULTS: Totally 103 patients were evaluated. Mean (±SD) stimulation index was 37.6 (±57.8) for IL-6 and 76.7 (±133.4) for IL-8. The disease control rate after first-line chemotherapy was 44/80 (55 %) and the mean (±SD) progression-free survival (PFS) and overall survival (OS) were 4.2 (±3.9) and 9.2 (±1.1) months, respectively. MNA, PS, albumin, IL-6 and IL-8 stimulation indices were univariately associated with PFS and OS. IL-8 stimulation index emerged as an independent predictor of both PFS and OS, along with PS, and albumin levels. CONCLUSION: The extent of IL-6 and IL-8 stimulation after ex vivo induction with LPS is an important predictor of clinical outcome in metastatic NSCLC patients (AU)

Predictive and prognostic value of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer.

OBJECTIVE: Cancer patients usually develop malnutrition which may alter their innate immune system integrity. The aim of this study was to investigate the clinical relevance of chemokine response after lipopolysaccharide (LPS)-stimulation in metastatic non-small cell lung cancer (NSCLC). METHODS: Blood samples from metastatic NSCLC patients were incubated with LPS before the onset of systemic therapy. Interleukin (IL)-6 and IL-8 levels at baseline and after LPS-stimulation were measured and the fold change compared to baseline levels was evaluated as the stimulation index for each cytokine per patient. Results were correlated with sex, age, smoking status, histologic subtype, performance status (PS), albumin, Mini Nutritional Assessment (MNA) status and clinical outcomes. RESULTS: Totally 103 patients were evaluated. Mean (±SD) stimulation index was 37.6 (±57.8) for IL-6 and 76.7 (±133.4) for IL-8. The disease control rate after first-line chemotherapy was 44/80 (55 %) and the mean (±SD) progression-free survival (PFS) and overall survival (OS) were 4.2 (±3.9) and 9.2 (±1.1) months, respectively. MNA, PS, albumin, IL-6 and IL-8 stimulation indices were univariately associated with PFS and OS. IL-8 stimulation index emerged as an independent predictor of both PFS and OS, along with PS, and albumin levels. CONCLUSION: The extent of IL-6 and IL-8 stimulation after ex vivo induction with LPS is an important predictor of clinical outcome in metastatic NSCLC patients.

Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer.

BACKGROUND: To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer. METHODS: The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT-PCR assay, in a historical comparison of two cohorts of women with stage I-III breast cancer treated with adjuvant taxane-free (N=211; FE(75)C or E(75)C) and taxane-based (N=334; T/E(75)C or T/E(75)) chemotherapy. RESULTS: Taxane-based chemotherapy resulted in a higher incidence of CTCs' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20-3.34). CONCLUSION: Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.

Clinical relevance of circulating CK-19mRNA-positive tumour cells before front-line treatment in patients with metastatic breast cancer.

BACKGROUND: To investigate the clinical relevance of CK-19mRNA-positive circulating tumour cells (CTCs) detected before the initiation of front-line treatment in patients with metastatic breast cancer (MBC). METHODS: The presence of CTCs was detected in 298 patients with MBC using a real-time PCR (RT-PCR assay. In 44 patients, the detection of CTCs was evaluated by both the CellSearch and the RT-PCR assay. Interaction with known prognostic factors and association of CTCs with clinical outcome were investigated. RESULTS: There was a strong correlation between the detection of CTCs by both assays. CK-19mRNA-positive CTCs were detected in 201 (67%) patients and their detection was independent of various patients' clinico-pathological characteristics. The median progression-free survival (PFS; 9.2 vs 11.9 months (mo), P=0.003) and the overall survival (OS; 29.7 vs 38.9 mo, P=0.016) were significantly shorter in patients with detectable CK-19mRNA-positive CTCs compared with patients without detectable CTCs. Multivariate analysis demonstrated that oestrogen receptor status, performance status and detection of CTCs were emerged as independent prognostic factors associated with decreased PFS and OS. CONCLUSION: The detection of CK-19mRNA-positive CTCs in patients with MBC before front-line therapy could define a subgroup of patients with dismal clinical outcome.

Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study.

BACKGROUND: Since the detection of circulating tumor cells (CTCs) which express HER2 is an adverse prognostic factor in early breast cancer patients, we investigated the effect of trastuzumab on patients' clinical outcome. PATIENTS AND METHODS: Seventy five women with HER2 (-) breast cancer and detectable CK19 mRNA-positive CTCs before and after adjuvant chemotherapy, were randomized to receive either trastuzumab (n=36) or observation (n=39). CK19 mRNA-positive CTCs were detected by RT-PCR and double stained CK(+)/HER2(+) cells by immunofluorescence. The primary endpoint was the 3-year disease-free survival rate. RESULTS: Fifty-one (89%) of the 57 analyzed patients had HER2-expressing CTCs. After trastuzumab administration, 27 of 36 (75%) women became CK19 mRNA-negative compared to seven of 39 (17.9%) in the observation arm (p=0.001). After a median follow up time of 67.2 months, four (11%) and 15 (38%) relapses were observed in the trastuzumab and observation arm, respectively (p=0.008); subgroup analysis indicated that this effect was mainly confined to women with >3 involved axillary lymph nodes (p=0.004). The median DFS was also significantly higher for the trastuzumab-treated patients (p=0.008). CONCLUSION: Administration of trastuzumab can eliminate chemotherapy-resistant CK19 mRNA-positive CTCs, reduce the risk of disease recurrence and prolong the DFS.

Baseline nutritional evaluation in metastatic lung cancer patients: Mini Nutritional Assessment versus weight loss history.

BACKGROUND: Cancer cachexia adversely affects survival and quality of life but its timely recognition is problematic. Nutritional questionnaires, like the Mini Nutritional Assessment (MNA), could identify early those patients at risk. The aim of the study was to compare MNA with 5% weight loss, a common criterion used in oncologic evaluation. PATIENTS AND METHODS: The nutritional status of 171 chemotherapy-naive patients with metastatic lung cancer was evaluated by both methods. The results were compared and correlated with clinical and laboratory values and with clinical outcome. RESULTS: The incidence of malnourished or patients at risk was higher according to the MNA (P<0.001). Both methods correlated with the performance status (P<0.001) but MNA was further correlated with the number of metastatic sites (P=0.007) and the presence of brain metastasis (P=0.022). Of 14 laboratory values studied, 9 were correlated with MNA and 5 with the weight loss history. Both methods were correlated with response to first-line therapy, time to progression and survival but MNA had a better predictive (P<0.001) and prognostic (P < 0.001) value. CONCLUSIONS: MNA outperforms weight loss history as a baseline nutritional screening method in patients with metastatic lung cancer and could further refine prognostication.

Fifteen-year trends in metastatic breast cancer survival in Greece.

In the metastatic setting, a detected time trend to improved prognosis could be attributed to the corresponding recent advances in the therapeutic approaches. The aim of the current study was to first assess, in a large cohort of well over a thousand patients, the time trends in survival in MBC for the last 15 years and second to explore its association to prognostic factors affecting outcome including therapeutic regimen. This meta-analysis uses individual patient data collected from all the trials on MBC (6 nonrandomized, 4 randomized) conducted by HeCOG from 1991 through 2006. Four 4-year time periods (1991-1994, 1995-1998, 1999-2002, and 2003-2006) were constructed for exploration of time trends in survival according to the patient's date of metastatic diagnosis. Different first line regimens in the 10 trials include anthracycline monotherapy (epirubicin, in the early 1990s) and taxane containing regimens either as monotherapy or in different combinations with anthracyclines or other drugs. In two phase II studies and in the last randomized study, trastuzumab was administered in all the patients with HER2 overexpressing tumors. In this study, information is based on a total of 1361 patients with a median follow up of 3.7 years and median survival of 1.9 years (median survival 1.28, 1.68, 2.20, and 2.57 years for 1991-1994, 1995-1998, 1999-2002, and 2003-2006, respectively). Survival improved significantly across diagnosis time periods, by 25, 44, and 51%, respectively, in each time period (1995-1998: HR = 0.75, P = 0.004; 1999-2002: HR = 0.56, P\0.001; 2003-2006: HR = 0.49, P\0.001) as compared to the first time period (1991-1994). The effect of metastatic diagnosis time period remains almost unchanged in the presence of the following significant prognostic factors: performance status, hormonal receptor status, previous adjuvant chemotherapy, previous adjuvant hormonal treatment, visceral metastasis at entry, and number of metastatic sites. When exploring the effect of new systemic treatment introduction, taking into account the same significant prognostic factors, the effect of diagnosis time period disappears, and the survival improvement is explained directly by the introduction of new agents (hormonal treatment for metastatic disease: yes vs. no: HR = 0.72, P\0.001; taxanes at first line: yes vs. no: HR = 0.69, P = 0.002; trastuzumab at first line: yes vs. no: HR = 0.63, P\0.001). The results of this study provide significant evidence of improvement in prognosis of MBC patients within the last 15 years, taking into account all the important significant prognostic factors, and this improvement can be attributed to the use of new systemic treatment agents in the management of the disease.