ABSTRACT
BACKGROUND: Adjuvant chemotherapy for Luminal B-like breast cancers usually includes anthracycline-based regimens. However, some patients are reluctant to receive chemotherapy because of side-effects, especially alopecia, and ask for a "less intensive" or personalized approach. PATIENTS AND METHODS: We conducted a phase II feasibility trial to evaluate pegylated liposomal doxorubicin (PLD, Caelyx®) as adjuvant chemotherapy. Patients who received surgery for pT1-3, any N, and luminal B-like early-stage breast cancer (EBC) candidates for adjuvant chemotherapy were included. PLD was administered intravenously at 20 mg/m2 biweekly for eight courses. Endocrine therapy was given according to menopausal status. Trastuzumab was administered in HER2-positive disease. The primary endpoint was to evaluate the feasibility of this regimen, defined as the ability of a patient to achieve a relative dose intensity (RDI) of at least 85% of the eight cycles of treatment. Secondary endpoints included adverse events (AEs), tolerability, breast cancer-free survival, disease-free survival, and overall survival. RESULTS: From March 2016 to July 2018, 63 patients were included in the trial. Median age was 49 years (range: 33-76), with mostly pre- and peri-menopausal (65%) and stage I-II (94%). Only 5% of patients had HER2-positive EBC. Median RDI was 100% (range: 12.5-100%; interquartile range, IQR: 87.5-100%). The proportion of patients meeting the primary endpoint was 84% (95% confidence interval, CI: 73-92%). Overall, 55 out of 63 enrolled patients completed treatment (87%, 95% CI: 77-94%). Most common AEs were palmar-plantar erythrodysesthesia (12.2%), fatigue (10.4%), and mucositis (8.5%). Only 13% of patients had G3 AEs. None had alopecia. After a median follow-up of 3.9 years (range: 0.3-4.7) two distant events were observed, and all patients were alive at the date of last visit. CONCLUSIONS: The trial successfully met its primary endpoint: the regimen was feasible and well tolerated and could be considered for further evaluation as a treatment option for patients with contraindications to standard anthracyclines or requiring a personalized, less intensive approach.
Subject(s)
Breast Neoplasms , Breast Neoplasms/drug therapy , Doxorubicin/analogs & derivatives , Feasibility Studies , Female , Humans , Middle Aged , Polyethylene GlycolsABSTRACT
PURPOSE: Incomplete response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) patients is correlated to high risk of relapse. This study aimed to evaluate the role of adjuvant chemotherapy in TNBC with residual tumor after NACT. METHODS: We retrospectively reviewed the outcome of patients with TNBC with residual tumor at surgery after a neoadjuvant treatment, followed by either adjuvant chemotherapy or observation. Primary endpoints were Disease Free Survival (DFS) and Overall Survival (OS). RESULTS: Between January 2000 and December 2016, 223 patients with early TNBC operated at the European Institute of Oncology were eligible. A total of 83.4 % of patients received adjuvant chemotherapy after surgery. 90 patients received standard dose infusional regimens, while 96 patients (51.6 %) received oral metronomic chemotherapy. Adjusting the analysis by surgical stage and Ki67 value there was a benefit for DFS and OS in favor of the group that received postoperative chemotherapy (DFS-HR 0.58 p = 0.04; OS-HR 0.54, p = 0.02). At a subgroup analysis according to the different adjuvant treatments received, a benefit for metronomic chemotherapy versus no chemotherapy both for DFS (HR 0.46, p = 0.008) and OS (HR 0.45, p = 0.009) was reported. CONCLUSION: Our retrospective analysis in a large cohort of TNBC patients with residual disease after NACT confirms the benefit of adding a postoperative treatment to reduce risk of relapse and death. Based on these results, we suggest that the adjuvant therapy based on metronomic cyclophosphamide and methotrexate deserves further investigation in this patients population.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Neoadjuvant Therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasm, Residual , Retrospective Studies , Triple Negative Breast Neoplasms/drug therapyABSTRACT
Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test.Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005).FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers.
Subject(s)
Drug Resistance, Neoplasm , Everolimus/pharmacology , Gene Expression Regulation, Neoplastic , Receptor Protein-Tyrosine Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , Allosteric Site , Animals , Cell Line, Tumor , Female , HCT116 Cells , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Phosphorylation , RNA InterferenceABSTRACT
BACKGROUND: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). PATIENTS & METHODS: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). RESULTS: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). CONCLUSION: Capecitabine and gemcitabine is highly active in TETs.