Nicola Battelli

A phase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer

BACKGROUND Docetaxel has shown some activity in advanced gastric cancer. Recent phase I studies found low hematologic toxicity and a favourable toxicity profile when docetaxel was administered on a weekly schedule. In this study, we explored the activity of weekly docetaxel in patients with advanced gastric cancer who failed first-line chemotherapy. MATERIALS AND METHODS Patients with stable or progressing disease after first-line chemotherapy received 36 mg/m2 weekly docetaxel. One cycle consisted of six administrations followed by a two-weeks rest, patients were re-evaluated at week eight. The optimal two-stage design was adopted for early stopping of the trial if responses were one or less in 21 patients (< 20% response rate with alpha and beta error probabilities 0.05 and 0.010 respectively). RESULTS Twenty-one patients have been enrolled and they are fully evaluable for response and toxicity. One patient achieved partial response, 8 patients had stable disease and 12 patients progressed. Median overall survival from the onset of salvage chemotherapy was 3.5 months. Hematologic toxicity was observed in two patients who experienced grade III leukopenia. Beginning from the third week of treatment, most of the patients (90%) showed grade II asthenia which resulted the commonest side-effect. CONCLUSIONS This schedule of weekly docetaxel did not show significant activity in pretreated patients with advanced gastric cancer.

Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

Pre-treatment neutrophil to lymphocyte ratio may be a useful tool in predicting survival in early triple negative breast cancer patients

BackgroundThere is a growing body of evidence that immune response plays a large role in cancer outcome. The neutrophil to lymphocyte ratio (NLR) has been used as a simple parameter of systemic inflammation in several tumors. The purpose was to investigate the association between pre-treatment NLR, disease-free survival and overall survival in patients with early triple negative breast cancer (TNBC).MethodsWe reviewed the records of patients with stage I-III TNBC at our Institution from 2006 to 2012. The association between pre-treatment NLR and survival was analyzed. The difference among variables was calculated by chi-square test. DFS and OS were estimated using Kaplan-Meier method. Cox analysis was performed to analyze clinical parameters for their prognostic relevance.ResultsA total of 90 patients were eligible. There was no significant correlation among pre-treatment NLR and various clinical pathological factors. Patients with NLR higher than 3 showed significantly lower DFS (p = 0.002) and OS (p = 0.009) than patients with NLR equal or lower than 3. The Cox proportional multivariate hazard model revealed that higher pre-treatment NLR was independently correlated with poor DFS and OS, with hazard ratio 5.15 (95% confidence interval [CI] 1.11-23.88, p = 0.03) and 6.16 (95% CI 1.54-24.66, p = 0.01) respectively.ConclusionOur study suggests that pre-treatment NLR may be associated with DFS and OS patients with early TNBC. Further validation and a feasibility study are required before it can be considered for clinical use.

A PHASE II STUDY OF MITOMYCIN C, VINDESINE AND CISPLATIN COMBINED WITH ALPHA INTERFERON IN ADVANCED NON-SMALL CELL LUNG CANCER

Aims and background MVP chemotherapy (mitomycin C, vindesine or vinblastine, cisplatin) is one of the most commonly used regimens for advanced non-small cell lung cancer (NSCLC). Experimental data suggest a synergistic cytotoxic activity of alpha-interferon (α-IFN) when combined with cisplatin, mitomycin C, and vinca alkaloids. In an effort to improve MVP chemotherapy activity, we have combined this regimen with α-IFN. Patients and methods Thirty-five patients with advanced NSCLC (19 stage IV) were treated with the MVP regimen (mitomycin C, 8 mg/m2; vindesine, 3 mg/m2; cisplatin, 75 mg/m2, all on day 1) plus α-2a-IFN, 3×106 U im from day 1 to 7. The cycles were repeated every 28 days. Results There were no complete responses and 18 partial responses, for an overall response rate of 51%. Median time to treatment failure was 6 months (range, 1-18), and median survival was 9.5 months (range, 1-32). WHO grade 3 toxicity was recorded in up to 8% of patients, flu-like syndrome was a common complaint; one toxic death occurred. Conclusions The combination yielded a level of response comparable to that of other cisplatin-based regimens. Larger randomized trials are needed to assess the role of α-IFN combined with chemotherapy in advanced NSCLC.

Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents

Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients.

Paclitaxel and Bevacizumab in First Line-Treatment Patients with HER-2 Negative Advanced Breast Cancer: Who could Benefit?

Background: Angiogenesis is essential for tumor growth and development of metastases in human breast cancer. Randomized studies have shown that bevacizumab (inhibitor of VEGF) combined with taxane-based regimens increases response rates and prolongs Progression-Free Survival (PFS) of patients with Metastatic Breast Cancer (MBC). However predictive or prognostic markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed. In this retrospective analysis, we investigated the impact of traditional clinical and pathological features in order to identify the subgroups of patients who derive the greatest benefit from antiangiogenic-agents. Patients and methods: Retrospectively, we included consecutive patients treated with bevacizumab (10 mg/Kg on days 1 and 15) and paclitaxel (90 mg/m2, on days 1, 8 and 15) as first-line treatment for HER2-negative MBC at our Institution between June 2007 and December 2012. Results: 33 patients were included. Median age was 50 years (31-68). 78. 8%, 12.1% and 9.1% of patients had luminal B, triple negative and luminal A breast cancer, respectively. 66. 6% of patients had visceral disease. The overall response rate was 31.2%. Median PFS and overall survival (OS) were 7.7 months (range 1. 9-14.0 months) and 95.2 months (range 11.6-205.8 months), respectively. Univariate analysis highlighted a statistically significant relationship between PFS to the first line and the following factors: relapse-free survival (RFS 12 months; p<0,001), disease control rate (p=0,001), Ca15. 3 reduction of more than 50% from baseline (p=0,03), reduction of LDH from baseline (p=0,02). No significant relationship resulted between PFS and the biological characterization of neoplasia, age, receptor status, Ki-67, nodal status at diagnosis, having carried out a previous (neo) adjuvant chemotherapy (with or without taxane), having visceral disease at time of relapse, the histological evidence of lymph-vascular invasion. At multivariate analysis, RFS was the only confirmed independent prognostic factor (p=0.01; HR=0. 18; 95% CI 0. 04-0.73). Conclusion: Our results confirmed the efficacy and the acceptable toxicity profile of bevacizumab plus paclitaxel as first-line regimen for MBC. RFS may be a useful tool in the clinical practice to select HER-2 negative MBC which may obtain a better prognosis administering this particular regimen.

Tivozanib for the treatment of renal cell carcinoma

ABSTRACT Introduction: Renal cell carcinoma (RCC) represents a heterogeneous group of cancers with distinct histological features, molecular alterations, prognosis, and response to therapy. Target agents directed against vascular endothelial growth factor and its receptor and mammalian target of rapamycin (mTOR) inhibitors have completely changed the landscape of RCC. However, the rate of complete response is still low, thus supporting the research of novel therapeutic agents. Area covered: The authors describe the chemical features of tivozanib, its pharmacodynamic and pharmacokinetic properties, and the results obtained in human phase I–III clinical trials. Tivozanib received its first global approval in EU, Iceland, and Norway on 28 August 2017 for the first-line treatment of adult patients with advanced RCC and for adult patients who are VEGFR and mTOR inhibitor-naive following disease progression after one prior treatment with cytokines. Expert opinion: The US Food and Drug Administration did not approve tivozanib due to the lack of a significant advantage in terms of survival compared to sorafenib. To date, the role of tivozanib in the pharmaceutical landscape of mRCC appears to be very limited. However, ongoing trials on the association between tivozanib and immunotherapy may represent a promising strategy to be assessed in future clinical trials.

Re: Gut Microbiome Influences Efficacy of PD-1-based Immunotherapy Against Epithelial Tumors

Experts’ summary: We read with interest the paper by Routy et al [1]. They found that primary resistance to immune checkpoint inhibitors “can be attributed to abnormal gut microbiome composition”. They observed the efficacy of “fecal microbiota transplantation” or oral supplementation with Akkermansia muciniphila in restoring response to anti-PD-1 agents in mouse models of epithelial tumors. The authors suggested that this is dependent on IL-12 because of the increase in the recruitment of CCR9CXCR3CD4 T lymphocytes.

Safety and efficacy of bevacizumab in combination with first-line chemotherapy in advanced breast cancer: Data from the Italian cohort of the ATHENA trial

Aims and Background The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study. Methods A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers. Results A total of 278 patients were included. Median age was 57 years (range, 26–85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease. Conclusions Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.

Using of Androgen Receptor Expression as a Novel Potential Biomarker in Predicting Survival of Women with Metastatic Triple Negative Breast Cancer

Background and objective: The androgen receptor (AR) is a member of the steroid receptor subfamily with well-known biological and therapeutic importance in prostate cancer. There is evidence that the androgen signalling pathway may play a critical role also in normal and malignant breast tissue. They are highly expressed in triple negative breast cancer (TNBC) but it is not clear if AR expression is correlated with survival in advanced TNBC. Therefore, in the present study we investigated the prognostic value of AR expression in metastatic TNBC. Patients and methods: Stage IV TNBC was included in the analysis. Patients with poor performance status (ECOG>2) were excluded. Tumors with >10% nuclear-stained cells were considered to be positive for AR. Univariate and multivariate analyses were performed. Results: From a database of 208 TNBC patients, 24 cases of advanced TNBC were identified; out of 24 patients, 33% were AR positive. The median age at diagnosis was 61 years (range 30-78 years). All patients included in the study received first-line chemotherapy for their disease. Median progression free-survival (mPFS) and overall survival (OS) were 3.5 months (range 0.3-27.3 months) and 25.9 months (range 2.52-122.2 months), respectively. Univariate analysis showed that AR negative advanced TNBC had a significantly worse PFS (3.2 vs 7.9 months; p=0.02; HR=2.57, 95% CI 1.15-10.53) and OS (20.5 vs 47.4 months; p=0.01; HR=2.88, 95% CI 1.32- 9.43). Multivariate analysis confirms that AR expression was an independent prognostic factor of PFS (p=0.04; HR=2.19, 95% CI 1.52-5.91), as well as for OS (p=0.05; HR=2.21, 95% CI 0.98-2.55). Conclusions: Our preliminary results suggested that the assessment of AR expression may be a useful tool to identify patients with a good or a poor prognosis. Furthermore, since that about one third of metastatic TNBC expressed ARs, they may represent a target for novel potential treatment options in advanced TNBC.