Publications by authors named "Gianluigi Ferretti"

97 Publications

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology.

Int J Mol Sci 2020 Nov 22;21(22). Epub 2020 Nov 22.

Division of Oncology, University of Verona, 37126 Verona, Italy.

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (, , , ). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.
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http://dx.doi.org/10.3390/ijms21228841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700259PMC
November 2020

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations.

Int J Mol Sci 2020 Nov 10;21(22). Epub 2020 Nov 10.

SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.
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http://dx.doi.org/10.3390/ijms21228419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696061PMC
November 2020

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy.

Cancers (Basel) 2020 Oct 6;12(10). Epub 2020 Oct 6.

Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, 37126 Verona, Italy.

Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase (MEK), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.
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http://dx.doi.org/10.3390/cancers12102870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601592PMC
October 2020

BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer.

Commun Biol 2020 Oct 1;3(1):546. Epub 2020 Oct 1.

Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Inflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.
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http://dx.doi.org/10.1038/s42003-020-01263-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530707PMC
October 2020

PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy.

Int J Mol Sci 2020 Jul 27;21(15). Epub 2020 Jul 27.

Division of Oncology, University of Verona, 37126 Verona, Italy.

Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy.
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http://dx.doi.org/10.3390/ijms21155337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432882PMC
July 2020

p53 and BLC2 Immunohistochemical Expression Across Molecular Subtypes in 1099 Early Breast Cancer Patients With Long-Term Follow-up: An Observational Study.

Clin Breast Cancer 2020 12 13;20(6):e761-e770. Epub 2020 May 13.

Biostatistics and Bioinformatic Unit, Scientific Direction, IRCCS, Regina Elena National Cancer Institute, Rome, Italy.

Introduction: p53 and antiapoptotic B-cell leukemia/lymphoma 2 (BLC2) have been proposed as prognostic markers for early breast cancer (BC), although their relationship with conventional parameters and patient prognosis, as well as their distribution within the molecular BC subtypes remains uncertain.

Patients And Methods: In this observational study, we analyzed the immunohistochemical expression of p53 and BLC2 in 1099 early BC patients surgically treated between 2000 and 2006 and followed for at least 5 years, also considering their association with pathologic factors and molecular subtypes, as well as their influence on disease-free survival.

Results: p53 and BLC2 are distributed differently across molecular subtypes (P < .0001); in particular, p53 positivity and BLC2 negativity seems to be associated with more aggressive conventional tumor phenotypes. Moreover, BLC2 negativity seems to be a significant discriminating factor for disease-free survival (P = .003) according to Kaplan-Meier analysis, while p53 seems to have no discriminating effect. Among patients with discordant p53/BLC2 phenotype, the combination p53BLC2 seems to be associated with the worst outcomes (P = .007) and significantly influenced the clinical course of node-negative patients treated only with hormone therapy (P = .004).

Conclusion: These two biomarkers, in addition to conventional pathologic factors and molecular subtype, could help define the risk and outcome of BC.
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http://dx.doi.org/10.1016/j.clbc.2020.05.005DOI Listing
December 2020

Nanoparticle albumin-bound paclitaxel/liposomal-encapsulated doxorubicin in HER2-negative metastatic breast cancer patients.

Future Oncol 2020 Aug 5;16(22):1629-1637. Epub 2020 Jun 5.

Medical Oncology 1, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.

To investigate the toxicity of nab-paclitaxel (wNP)/nonpegylated liposome-encapsulated doxorubicin (wNPLD) combination in HER2-negative metastatic breast cancer (MBC) patients as first-line treatment. Phase I, single-arm study in metastatic breast cancer patients naive to previous chemotherapy for advanced disease. A 3 + 3 dose-escalation design was used to determine the safety. Primary endpoints were the identification of dose-limiting toxicity and maximum tolerated dose. In total, 12 patients (mean age: 52 years; median metastatic sites: 2) were enrolled and 97 cycles were completed. Maximum tolerated dose was wNP + wNPLD 25 mg/m. The most common adverse events were neutropenia, nausea, diarrhea and mucositis. The objective response rate was 68% (response mean duration: 12.6 months). wNP/wNPLD combination constitutes an active regimen with mild toxicity.
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http://dx.doi.org/10.2217/fon-2019-0742DOI Listing
August 2020

From Genetic Alterations to Tumor Microenvironment: The Ariadne's String in Pancreatic Cancer.

Cells 2020 01 28;9(2). Epub 2020 Jan 28.

Division of Oncology, University of Verona, 37126 Verona, Italy.

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene and the tumor suppressors , and . Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies.
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http://dx.doi.org/10.3390/cells9020309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072496PMC
January 2020

Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials.

Cancers (Basel) 2019 Oct 26;11(11). Epub 2019 Oct 26.

Division of Medical Oncology1, IRCCS Regina Elena National Cancer Institute, 00128 Rome, Italy.

: We aim to understand whether all patients with hormonal receptor (HR)-positive (+)/human epidermal growth factor receptor-2 (HER2)-negative (-) metastatic breast cancer (MBC) should receive cyclin D-dependent kinase (CDK) 4/6 inhibitor-based therapy as a first-line approach.

Methods: A network meta-analysis (NMA) using the Bayesian hierarchical arm-based model, which provides the estimates for various effect sizes, were computed.

Results: First-line treatment options in HR+/HER2- MBC, including CDK 4/6 inhibitors combined with aromatase inhibitors (AIs) or fulvestrant (F), showed a significantly longer progression-free survival (PFS) in comparison with AI monotherapy, with a total of 26% progression risk reduction. In the indirect comparison across the three classes of CDK 4/6 inhibitors and F endocrine-based therapies, the first strategy resulted in longer PFS, regardless of specific CDK 4/6 inhibitor (HR: 0.68; 95% CrI: 0.53-0.87 for palbociclib + AI, HR: 0.65; 95% CrI: 0.53-0.79 for ribociclib + AI, HR: 0.63; 95% CrI: 0.47-0.86 for abemaciclib + AI) and patient's characteristics. Longer PFS was also found in patients with bone-only and soft tissues limited disease treated with CDK 4/6 inhibitors.

Conclusions: CDK 4/6 inhibitors have similar efficacy when associated with an AI in the first-line treatment of HR+ MBC, and are superior to either F or AI monotherapy, regardless of any other patients or tumor characteristics.
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http://dx.doi.org/10.3390/cancers11111661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896062PMC
October 2019

T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer.

Breast 2018 Oct 12;41:137-143. Epub 2018 Jul 12.

Oncologia Medica 1, Istituto Nazionale Tumori "Regina Elena", Roma, Italy.

Background: We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in 'field-practice' breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs).

Methods: The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement.

Results: Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1-55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4-8.6) in the BM group and 8 months (95% CI: 5.7-10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1-6.9) versus 11 (95% CI: 7.1-14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2-15.8) in the BM group and 32 months (95% CI: 24.4-39.6) in the non-BM group (p < 0.0001).

Conclusions: T-DM1 is active in breast cancer patients with BMs.
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http://dx.doi.org/10.1016/j.breast.2018.07.004DOI Listing
October 2018

Impressive Long-term Response with Pertuzumab and Trastuzumab in HER2-positive Breast Cancer with Brain Metastasis.

In Vivo 2018 Jul-Aug;32(4):839-842

Division of Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy

This is a case report of a 40-year-old woman who, after conservative breast cancer treatment, developed a HER2 positive solitary brain metastasis in the left temporal lobe, without extracranial disease. She underwent surgery resection followed by stereotactic radiotherapy and, because of early brain progression, she was submitted to the first line therapy with pertuzumab, trastuzumab and weekly paclitaxel. After six months of treatment, a brain magnetic resonance imaging revealed a complete disappearance of brain recurrence, which persisted for more than 24 months.
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http://dx.doi.org/10.21873/invivo.11317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117761PMC
October 2018

Ado-trastuzumab emtansine (T-DM1) in HER2+ advanced breast cancer patients: does pretreatment with pertuzumab matter?

Future Oncol 2017 Dec 28;13(30):2791-2797. Epub 2017 Nov 28.

Oncologia Medica 1, Istituto Nazionale Tumori 'Regina Elena', Roma, 00144, Italy.

Aim: We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen.

Patients & Methods: Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73).

Results: Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01).

Conclusion: Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.
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http://dx.doi.org/10.2217/fon-2017-0336DOI Listing
December 2017

Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer: clinical results and biological observations in taxane-pretreated patients.

Drug Des Devel Ther 2015 20;9:6177-83. Epub 2015 Nov 20.

Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.

Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes.

Patients And Methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m(2) on day 1 of each 3-week cycle or 125 mg/m(2) weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety.

Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1-2).

Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy.
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http://dx.doi.org/10.2147/DDDT.S89575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662373PMC
February 2016

Bilateral spontaneous pneumothorax and massive pneumomediastinum under Pazopanib therapy.

Thorac Cancer 2015 Jan 7;6(1):110-1. Epub 2015 Jan 7.

Department of Surgical Oncology, Thoracic Surgery Unit, Regina Elena National Cancer Institute - IFO Rome, Italy.

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http://dx.doi.org/10.1111/1759-7714.12165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448468PMC
January 2015

Functional and pharmacodynamic evaluation of metronomic cyclophosphamide and docetaxel regimen in castration-resistant prostate cancer.

Future Oncol 2013 Sep;9(9):1375-88

SAFU Department, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, Italy.

Aim: The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC).

Materials & Methods: CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC.

Results: Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients.

Conclusion: Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.
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http://dx.doi.org/10.2217/fon.13.99DOI Listing
September 2013

Epidermal growth factor receptor gene copy number may predict lapatinib sensitivity in HER2-positive metastatic breast cancer.

Expert Opin Pharmacother 2013 Apr 9;14(6):699-706. Epub 2013 Mar 9.

Regina Elena National Cancer Institute, Department of Oncology A, Via Elio Chianesi, 53, 00144 Rome, Italy.

Objective: Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor (TKI), associated to capecitabine represents the treatment of choice in HER2-positive metastatic breast cancer (BC) patients in progression after trastuzumab-based therapy. Though lapatinib-based therapy prolongs the time to progression, its efficacy is often limited by the development of drug resistance. It is aimed to evaluate novel biomarkers predictive of lapatinib response, we analyzed EGFR protein and gene status in a series of 50 metastatic HER2-positive BC patients.

Methods: Lapatinib was given at 1250 mg/day continuously and capecitabine at 2000 mg/m(2)/day every 3 weeks. EGFR protein expression and gene copy number (GCN) were assessed by immunohistochemistry and FISH, respectively. Receiver operating curve (ROC) analysis identified the value of > 3.36 EGFR copies/nucleus as the cut-off point able to discriminate responders versus non-responders.

Results: A statistical significant correlation between EGFR GCN value > 3.36 and response to lapatinib (p = 0.01) was found. Cox regression analysis further supported these findings evidencing that HER2 score 3+ and EGFR GCN increase are positive predictor factors of lapatinib response.

Conclusions: Though further investigations are needed to confirm these findings, EGFR GCN could be a suitable screening to identify the subset of BC patients particularly responsive to the dual TKI lapatinib.
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http://dx.doi.org/10.1517/14656566.2013.779672DOI Listing
April 2013

Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy.

BMC Cancer 2012 Oct 19;12:482. Epub 2012 Oct 19.

Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome, Italy.

Background: Data on efficacy of bevacizumab (B) beyond first-line taxane -including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT.

Methods: Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not.

Results: Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev.

Conclusion: Maintenance bevacizumab with or without anti-hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti-hormonal agents.
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http://dx.doi.org/10.1186/1471-2407-12-482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488474PMC
October 2012

Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials.

J Exp Clin Cancer Res 2011 May 12;30:54. Epub 2011 May 12.

Department of Medical Oncology, Regina Elena National Cancer Institute, Roma, Italy.

Background: Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile.

Methods: A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design.

Results: Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS.

Conclusions: Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.
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http://dx.doi.org/10.1186/1756-9966-30-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120715PMC
May 2011

HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care.

Clin Cancer Res 2011 Apr 9;17(7):2055-64. Epub 2011 Feb 9.

Medical Oncology, Regina Elena Cancer Institute, Rome, Italy.

Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.

Experimental Design: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.

Results: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04).

Conclusions: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-1920DOI Listing
April 2011

Darbepoetin alfa and history of thromboembolic events.

J Clin Oncol 2009 Nov 26;27(33):e211; author reply e212. Epub 2009 Oct 26.

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http://dx.doi.org/10.1200/JCO.2009.24.6454DOI Listing
November 2009

High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide.

Cancer Lett 2009 Sep 11;282(2):214-28. Epub 2009 Apr 11.

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

In the present study we have explored the sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide (CDDO-Im). For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/ADR and A2780/CISP, OVCAR3, SKOV3 and HEY cancer cell lines and primary ovarian cancer cells, providing evidence that: (i) the majority of these cell lines are highly sensitive to the pro-apoptotic effects induced by CDDO-Im; (ii) TRAIL, added alone exerted only a weak proapoptotic, but clearly potentiated the cytotoxic effect elicited by CDDO-Im; (iii) the apoptotic effect induced by CDDO-Im involves GSH depletion, c-FLIP downmodulation and caspase-8 activation; (iv) CDDO-Im inhibits STAT3 activation and CDDO-Im sensitivity is inversely related to the level of constitutive STAT3 activation. Importantly, studies on primary ovarian cancer cells have shown that these cells are sensitive to the pro-apoptotic effects of CDDO-Im. These observations support the experimental use of synthetic triterpenoids in the treatment of ovarian cancer.
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http://dx.doi.org/10.1016/j.canlet.2009.03.018DOI Listing
September 2009

Factor v leiden mutation in patients with breast cancer with a central venous catheter: risk of deep vein thrombosis.

Support Cancer Ther 2006 Jan;3(2):98-102

Division of Medical Oncology, Clinical Pharmacology and New Drugs Development Unit, European Institute of Oncology, Milan, Italy.

Background: The objective of this study was to analyze the influence of the prothrombotic factor V Leiden (FVL) and G20210A prothrombin mutations on the frequency of the first episode of catheter-related deep vein thrombosis (DVT) in a cohort of patients with locally advanced or metastatic breast cancer during continuous venous insult (infusion of 5-fluorouracil-based chemotherapy).

Patients And Methods: Between January 1999 and February 2001, we retrospectively analyzed the incidence of first DVT in 300 consecutive patients with locally advanced or metastatic breast cancer treated at a single institution with a combination of chemotherapy administered continuously through a totally implanted access port. We identified 25 women (study group) with catheter-related DVT. For each of the 25 patients, we selected 2 women eligible for identical chemotherapy who had similar age, stage of disease, and prognostic features as a control group. The prothrombotic FVL and prothrombin mutation G20210A genotype analyses were performed in all patients. Analyses were performed on blinded samples, and all patients signed a specific informed consent form. A total of 25 cases (with thrombosis) and 50 frequency-matched controls were evaluated for FVL.

Results: Five cases and 2 controls were found with the mutation in the FVL, for incidences of 20% (95% CI, 9%-39%) and 4% (95% CI, 1%-14%), respectively. Thus, the frequency of the mutation was significantly higher in the cases than in controls (P = 0.04), and a logistic regression analysis, adjusted by age, yielded an odds ratio of 6.1 (95% CI, 1.1%-34.3%; P = 0.04). Time from start of infusion chemotherapy to thrombosis was not significantly different between those with the mutation (median, 31 days) and without the mutation (median, 43 days; P = 0.6). Only 1 subject (in the case group) was found with the G20210A mutation in the prothrombin gene.

Conclusion: Factor V Leiden carriers with locally advanced or metastatic breast cancer are at high risk of catheter-related DVT during chemotherapy. Clinicians should be aware of this increased risk, and alternative cytotoxic treatments not requiring continuous infusions should be considered for these patients.
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http://dx.doi.org/10.3816/SCT.2006.n.005DOI Listing
January 2006

Taxanes and gemcitabine doublets in the management of HER-2 negative metastatic breast cancer: towards optimization of association and schedule.

Anticancer Res 2008 Mar-Apr;28(2B):1245-58

Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.

The management of human epidermal receptor-2 (HER-2) negative metastatic breast cancer (MBC) is usually problematic, since no standard therapy exists in this setting. For some patients, combination chemotherapy represents a valuable approach, although its use is often limited by the risks of increased toxicity as well as impairments in quality of life (QoL) that often outweigh the marginal efficacy benefit. Against this background, the use of taxanes, either paclitaxel or docetaxel, in combination with gemcitabine as first-line treatment of HER-2 negative MBC is supported by the evidence of the single-agent activity of these drugs, beneficial pharmacological interactions, different mechanisms of action and largely non superimposable toxicity profiles. A number of phase II studies have explored the activity of a taxane plus gemcitabine in both chemonaïve and pretreated MBC patients, all showing remarkably high response rates and exceptional tolerability. In randomized phase III trials, the paclitaxel and gemcitabine combination showed significant improvements in objective responses, time to progression and overall survival, as compared to paclitaxel monotherapy, whereas the docetaxel and gemcitabine doublet demonstrated equal efficacy and better tolerability, as compared to docetaxel plus capecitabine. In addition to standard threeweekly dosing regimens, alternative schedules of administration of taxanes and gemcitabine doublets (weekly, twoweekly) might deserve further investigation due to their potential usefulness in reducing pharmacological toxicity while maintaining or increasing dose-intensity and clinical efficacy. Furthermore, uncertainty exists on which taxane should be preferred in combination with gemcitabine, since no head-to-head comparison between paclitaxel-gemcitabine and docetaxel-gemcitabine has been performed so far. Ongoing trials will address these issues and future investigations will also include the evaluation of bevacizumab, the monoclonal antibody targeted against vascular endothelial growth factor (VEGF), in combination with taxanes and gemcitabine doublets.
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June 2008

Do HER-2 positive metastatic breast cancer patients benefit from the use of trastuzumab beyond disease progression? A mono-institutional experience and systematic review of observational studies.

Breast 2008 Oct 1;17(5):499-505. Epub 2008 May 1.

Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.

Though preclinical evidence supports the protracted use of trastuzumab to reach sustained anti-tumor activity, the activity of trastuzumab beyond disease progression remains controversial in HER-2 over-expressing (HER-2+) metastatic breast cancer (MBC) patients. We retrospectively evaluated a total of 59 patients with HER-2 + MBC treated at our institution with trastuzumab-based therapies. Our results were added to those obtained in similar observational studies and summary estimates for overall response (OR) and clinical benefit (CB) to first and second trastuzumab-based lines were calculated. In our series of patients we observed an OR of 59.3% and 27% for first and second trastuzumab-based lines, respectively, with a corresponding CB of 83% and 62.2%, respectively. Time to first and second progression were 9.5 months and 6.7 months, respectively. The combined analysis showed an OR of 50% for first trastuzumab-based regimen and 21.2% for second trastuzumab-based line. The corresponding values for CB were 77.6% and 42.6%, respectively. A second trastuzumab-containing regimen beyond progression yields a considerable rate of OR and CB in HER-2 + MBC patients. Randomized trials are warranted.
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http://dx.doi.org/10.1016/j.breast.2008.03.006DOI Listing
October 2008

Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation.

Cancer Chemother Pharmacol 2008 Sep 6;62(4):717-25. Epub 2007 Dec 6.

Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Preclinical evidence suggests that the cyclo-oxygenase-2 (COX-2) enzyme plays an important role in breast cancer progression. The aim of the present phase II study was to determine the activity and safety of the combination of the COX-2 inhibitor celecoxib with capecitabine in metastatic breast cancer (MBC) patients pretreated with anthracyclines and/or taxanes.

Methods: Eligible patients received capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 21 days and celecoxib 200 mg twice daily, continuously, until disease progression or unacceptable toxicity.

Results: About 42 pretreated MBC patients were enrolled into the study. Median number of previous chemotherapy lines for metastatic disease was 2 (0-3). Seven patients (19%) responded to treatment while disease stabilization occurred in 17 patients (40.5%). Overall, 20 patients (47.5%) achieved clinical benefit [objective responses (CR) plus stable disease (SD) >/=6 months]. Median time to progression (TTP) and median overall survival (OS) were 5.2 and 17.8 months, respectively. Treatment was very well tolerated: grade 3 toxicities were observed in only five patients, respectively, and no grade 4 adverse events were reported. Celecoxib was never discontinued for toxicity. Analysis of COX-2 expression in the 22 patients with available tissue revealed a significantly longer TTP and OS for patients whose tumors over-expressed COX-2.

Conclusions: The combination of capecitabine and celecoxib is active and safe in far advanced MBC patients. Interestingly, this association resulted in a lower-than-expected toxicity, as compared to single-agent capecitabine. The clinical relevance of COX-2 as determinant of sensitivity to treatment with celecoxib should be further evaluated in larger series of patients.
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http://dx.doi.org/10.1007/s00280-007-0650-1DOI Listing
September 2008