Publications (10)40.59 Total impact
-
Article: A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors.
[show abstract] [hide abstract]
ABSTRACT: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C(min) was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. (18)F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.Clinical Cancer Research 08/2011; 17(19):6304-12. · 7.74 Impact Factor -
Article: Inflammatory breast cancer in Italy: epidemiological and clinical aspects.
[show abstract] [hide abstract]
ABSTRACT: Breast cancer represents the most common cancer among women in Italy. In the last decade, an increase in incidence and a decrease in mortality from breast cancer have been observed in Italy. These findings may be explained at least in part by the implementation of organized screening programs (SMPs). The screening programs are not diffused homogeneously throughout Italy, where approximately 60% of the population in covered, which explains in part the different outcomes observed across Italy. On the basis of the available data, the authors of this report performed a retrospective analysis on the incidence of 2 different groups of breast cancer patients: those covered or and those not covered by SMPs in Italy. The rates of incidence of T4a, T4b, and T4c breast cancer and of T4 inflammatory breast cancer (IBC) overtime appeared to be lower for the population that was covered by SMPs. On the basis of the estimated 40,000 new cases of breast cancer in Italy per year, the authors attempted to extrapolate the approximate incidence of new cases of T4 breast cancer and calculated that there were between 2800 and 3600 new cases per year taking into account the differences in incidence observed in areas covered or not covered by SMPs. Following the same extrapolations, the estimated incidence of IBC was approximately 200 to 800 new cases per year, representing from 0.6% to 2% of all breast cancers diagnosed every year in Italy.Cancer 06/2010; 116(11 Suppl):2736-40. · 4.77 Impact Factor -
Article: Inflammatory breast cancer in Italy
[show abstract] [hide abstract]
ABSTRACT: Breast cancer represents the most common cancer among women in Italy. In the last decade, an increase in incidence and a decrease in mortality from breast cancer have been observed in Italy. These findings may be explained at least in part by the implementation of organized screening programs (SMPs). The screening programs are not diffused homogeneously throughout Italy, where approximately 60% of the population in covered, which explains in part the different outcomes observed across Italy. On the basis of the available data, the authors of this report performed a retrospective analysis on the incidence of 2 different groups of breast cancer patients: those covered or and those not covered by SMPs in Italy. The rates of incidence of T4a, T4b, and T4c breast cancer and of T4 inflammatory breast cancer (IBC) overtime appeared to be lower for the population that was covered by SMPs. On the basis of the estimated 40,000 new cases of breast cancer in Italy per year, the authors attempted to extrapolate the approximate incidence of new cases of T4 breast cancer and calculated that there were between 2800 and 3600 new cases per year taking into account the differences in incidence observed in areas covered or not covered by SMPs. Following the same extrapolations, the estimated incidence of IBC was approximately 200 to 800 new cases per year, representing from 0.6% to 2% of all breast cancers diagnosed every year in Italy. Cancer 2010;116(11 suppl):2736–40. © 2010 American Cancer Society.Cancer 05/2010; 116(S11):2736 - 2740. · 4.77 Impact Factor -
Article: Long-term maintenance of prognostic value of survivin and its relationship with p53 in T4 breast cancer patients.
[show abstract] [hide abstract]
ABSTRACT: A large proportion of human tumors show deregulated expression of a variety of proteins that play a crucial role in the execution of the apoptotic program. Survivin belongs to the family of inhibitor of apoptosis proteins which were originally identified in baculoviruses. Ectopic expression of survivin conveys resistance to apoptosis to a variety of stimuli, and survivin is one of the most abundantly overexpressed genes in human tumors such as breast cancer. In this study we examined the expression of survivin protein in a series of T4 breast cancers to identify any correlation with long-term patient outcomes. Moreover, we investigated the hypothesis of a possible association between p53 and survivin as a factor further complicating the outcome. Archival specimens from 53 T4 breast cancer patients were included in the study and treated for the immunohistochemical localization of survivin and p53 using the streptavidin-biotin alkaline phosphatase method. The immunoreactivity was evaluated semiquantitatively according to the percentage of cells stained. Forty percent of tumors were positive for survivin. Statistical analysis revealed that survivin expression negatively influenced the 5- and 10-year disease-free and overall patient survival. In multivariate analysis, survivin expression was a significant independent prognostic indicator of worse outcome in overall survival [hazard ratio (HR)=2.61]. Our results showed that survivin is associated with a worse prognosis in patients with T4 breast cancer, and remarkably its prognostic relevance is maintained even long-term. Notably, p53 (HR=3.2) seems to negatively enhance the effect of survivin on survival.Experimental and therapeutic medicine 01/2010; 1(1):59-64. -
Article: Molecular alterations in key-regulator genes among patients with T4 breast carcinoma.
[show abstract] [hide abstract]
ABSTRACT: Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized cohort of T4 breast cancer patients with a long follow-up period. A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis. Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series. Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients.BMC Cancer 01/2010; 10:458. · 3.01 Impact Factor -
Article: Long-term outcomes in stage IIIB breast cancer patients who achieved less than a pathological complete response (<pCR) after primary chemotherapy.
[show abstract] [hide abstract]
ABSTRACT: Pathological complete response (pCR) to primary chemotherapy is the main determinant for improved disease-free survival (DFS) and overall survival (OS). The primary endpoints of our study were the long-term DFS and OS rates in homogeneously treated stage IIIB breast cancer patients who failed to achieve a pCR (<pCR), in relation to residual tumor burden. The secondary endpoint was the prognostic relevance of hormone receptor (HR) and human epidermal growth factor receptor (HER)-2 status. We analyzed 58 of 74 consecutive stage IIIB patients treated between 1996 and 2001 who achieved <pCR following a primary cisplatin, epirubicin, and vinorelbine regimen for up to six cycles. At the time of patient accrual, trastuzumab was not available. After definitive surgery, pathological residual disease remained in 40 (69%) patients in both the breast and axilla, in 14 (24%) patients in only the breast, and in four (7%) patients in only the axilla. Fifty-eight (78%) of 74 patients achieved <pCR and 16 (22%) had pCR both in the breast and axilla. After a median follow-up of 99 months (range, 72-134 months), in patients with <pCR the estimated 10-year DFS and OS rates were 37.6% and 50.3%, respectively, significantly worse than in the pCR group (p = .003 and p = .008, respectively). Patients with four or more axillary nodes involved had a significantly worse 10-year DFS rate (28.9% versus 62.7%; p = .036). Patients with HR(-) tumors had significantly lower 10-year DFS (17.3% versus 46.4%; p = .018) and OS (17.3% versus 70.2%; p = .002) rates. Overall, the triple-negative (TN) group showed only a marginally significantly worse OS rate (p = .048). HER-2 status alone, in the absence of trastuzumab, did not appear to significantly affect outcomes. Our data suggest that, in stage IIIB patients who achieve <pCR, the number of residual nodes and HR(-) status are strong predictors of poor outcomes. After a long follow-up time, HER-2 expression does not appear to significantly affect DFS and OS. TN patients showed a trend toward early recurrence and death.The Oncologist 11/2009; 14(11):1051-60. · 3.91 Impact Factor -
Article: Targeting insulin-like growth factor type 1 receptor in cancer therapy.
[show abstract] [hide abstract]
ABSTRACT: It is believed that the insulin-like growth factor receptor type 1 (IGF-1R) signaling pathway plays a pivotal role in cancer growth, progression, and resistance to anticancer therapies. Strategies are being developed to block IGF-1R as an anticancer treatment. We reviewed several potential strategies for disrupting the IGF axis. We also reviewed the effects of two drugs that target the IGF-1R: monoclonal antibodies and tyrosine kinase inhibitors. Preliminary results of studies involving these agents provided a foundation for ongoing clinical trials, whose results in the near future will help us understand how to incorporate anti IGF-1R strategies into the current anticancer armamentarium.Targeted Oncology 10/2009; 4(4):255-66. · 3.61 Impact Factor -
Article: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.
[show abstract] [hide abstract]
ABSTRACT: Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha.Cancer Research 11/2008; 68(19):8022-30. · 7.86 Impact Factor -
Article: Epothilones in breast cancer: current status and future directions.
[show abstract] [hide abstract]
ABSTRACT: Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.Expert Review of Anti-infective Therapy 09/2008; 8(8):1299-311. · 2.65 Impact Factor -
Article: Dose-dense primary chemotherapy, as part of multidisciplinary treatment, for inoperable stage III B breast cancer--long-term results of a phase II trial.
[show abstract] [hide abstract]
ABSTRACT: Primary chemotherapy as part of multidisciplinary approach is the established treatment for inoperable stage III B breast cancer. The primary endpoints were conversion to operable disease and feasibility of conservative surgery (breast-conserving therapy: BCT); secondary were clinical and pathological complete response rate, local and distant control and safety of the primary regimen. Between 1998 and 2001, 40 inoperable breast cancer patients < or =60 years, 72% T4abc and 28% T4d, received 6 cycles of primary PEV dose-dense regimen: cisplatin 50 mg/m2, epirubicin 100 mg/m2 and vinorelbine 25 mg/m2, i.v. (q 14). Modified radical mastectomy (MRM) or BCT was performed, followed by adjuvant chemotherapy, radiotherapy and hormone therapy. All patients were converted to operable disease, and BCT was feasible in 24% of T4abc patients. After a median follow-up of 84 months (range 58-96), local and distant relapses were 7.5% (0% in BCT ) and 25% (25% in BCT), respectively. Clinical response was 80% (clinical complete response [cCR]: 20%); pathological complete response (pCR) was 40% in breast, 50% in axilla (pLN0); 32% both in breast and axilla. Neutropenia (G4, 30%), leukopenia (G4, 25%), alopecia (G2, 100%), nausea and vomiting (G4, 20%) were the most common toxicities. The PEV dose-dense regimen seems to be highly effective in terms of resectability and pCR. Toxicity, mainly hematological, was acceptable. Successful BCT is feasible, in selected patients, without compromising local and distant control.Oncology 01/2007; 72(1-2):17-26. · 2.27 Impact Factor
Top co-authors
Top Journals
- Cancer (1)
- Clinical Cancer Research (1)
- Cancer (1)
- Oncology (1)
- BMC Cancer (1)
Institutions
-
2011
-
Hospital Universitari Vall d'Hebron
Barcelona, Catalonia, Spain
-
-
2009–2010
-
Università degli studi di Cagliari
Cagliari, Sardinia, Italy -
Azienda Ospedaliera Universitaria Cagliari
Cagliari, Sardinia, Italy
-
