Publications (16)107.79 Total impact
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Article: EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients: how do we interpret the clinical and biomarker data?
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ABSTRACT: The clinical development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for treatment of non-small cell lung cancer (NSCLC) is a major breakthrough in the field. Erlotinib is the first of this class of drug demonstrated in a placebo-controlled trial to prolong survival of patients with previously treated NSCLC. The challenge now is how best to select patients for this treatment. Clinical factors including female gender, East Asian ethnic origin, adenocarcinoma histology, and a history of never-smoking are associated with better response rates, but response to erlotinib is not exclusive to these populations or essential for a survival benefit. Molecular factors such as EGFR mutation and increased EGFR gene copy number provide objective tests that may be superior to clinical factors for patient selection, but assay for these factors is crucially dependent on available tumor tissue and to date, there are no published data from randomized trials where tumor tissue is available from all patients. Here we review the clinical and biological factors that may be applied to select patients for treatment with EGFR-TKIs and conclude that the available data are premature for definitive guidelines to select against an EGFR-TKI.Targeted Oncology 04/2012; 3(3):173-186. · 0.46 Impact Factor -
Article: Impact of biomarkers on non-small cell lung cancer treatment.
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ABSTRACT: Chemotherapy represents the mainstay of non-small cell lung cancer (NSCLC) treatment, but response is usually observed in only one out of three patients. Massive efforts have been carried out to identify biomarkers that might help clinicians to choose appropriate drugs, by identifying potentially sensitive subjects and spare toxicities in patients who are unlikely to benefit from treatment. Low excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) levels have been associated with increased sensitivity to cisplatin and gemcitabine, respectively, while reduced class III beta-tubulin expression has been associated with taxane activity. Initial prospective studies showed the feasibility of a customized approach based on biomarker assessment, and phase III trials will hopefully provide further validation of this approach. The impact of biomarkers for patient selection has now been well established for tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), with EGFR mutations emerging as the most reliable predictor for improved outcome. Relevant clinical issues are represented by the identification of patients who can be reasonably excluded from treatment and by the development of therapeutic approaches able to overcome acquired resistance to anti-EGFR strategies.Targeted Oncology 03/2010; 5(1):5-17. · 3.61 Impact Factor -
Article: Clinical implications of MET gene copy number in lung cancer.
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ABSTRACT: MET, the receptor for HGF, has recently been identified as a novel promising target in several human malignancies, including non-small-cell lung cancer (NSCLC). Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of the EGF receptor (EGFR) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET TKIs could be an effective strategy in this setting and led to the clinical investigation of multiple MET TKIs in combination with erlotinib. Results from ongoing and future trials will clarify the role of MET TKIs for the treatment of NSCLC and will provide insights into the most appropriate timing for their use.Future Oncology 02/2010; 6(2):239-47. · 3.16 Impact Factor -
Article: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
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ABSTRACT: MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.Cancer cell 01/2010; 17(1):77-88. · 25.29 Impact Factor -
Article: Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients.
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ABSTRACT: To investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non-small-cell lung cancer (NSCLC). This retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections. EGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P = .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean > or = 5 copies/cell) was observed in 48 cases (MET+, 11.1%), including 18 cases with true gene amplification (4.1%). MET+ status was associated with advanced stage (P = .01), with grade 3 (P = .016) and with EGFR FISH+ result (P < .0001). No patient with activating EGFR mutation resulted MET+. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P = .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P = .04). MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.Journal of Clinical Oncology 05/2009; 27(10):1667-74. · 18.37 Impact Factor -
Article: Gemcitabine for the treatment of advanced nonsmall cell lung cancer.
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ABSTRACT: Gemcitabine is a pyrimidine nucleoside antimetabolite agent which is active in several human malignancies, including nonsmall cell lung cancer (NSCLC). Because of its acceptable toxicity profile, with myelosuppression being the most common adverse event, gemcitabine can be safely combined with a number of cytotoxic agents, including platinum derivatives and new-generation anticancer compounds. In fact, the combination of gemcitabine and cisplatin is a first-line treatment for patients with advanced NSCLC, pharmacoeconomic data indicating that it represents the most cost-effective regimen among platinum-based combinations with third-generation cytotoxic drugs. The drug has been investigated in the context of nonplatinum-based regimens in a number of prospective clinical trials, and might provide a suitable alternative for patients with contraindications to platinum. Recently, gemcitabine-based doublets have been successfully tested in association with novel targeted agents with encouraging results, providing further evidence for the role of the drug in the treatment of NSCLC. In the last few years several attempts have been pursued in order to identify molecular predictors of gemcitabine activity, and recent data support the feasibility of genomic-based approaches to customize treatment with the ultimate goal of improving patient outcome.OncoTargets and Therapy 01/2009; 2:209-17. · 1.26 Impact Factor -
Article: EGFR mutations and HER2/3 protein expression and clinical outcome in Chinese advanced non-small cell lung cancer patients treated with gefitinib.
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ABSTRACT: To assess the role of various epidermal growth factor receptor (EGFR) mutations and HER2/3 protein expression as predictive markers of responsiveness to gefitinib therapy in Chinese patients with advanced non-small cell lung cancer (NSCLC). A total of 106 Chinese NSCLC patients who had failed at least one chemotherapy regimen received gefitinib 250 mg once daily. All the 106 tumors from these patients were screened for mutations in the EGFR exons 18-24, and 84 tumors were studied by immunohistochemistry for HER2/3 expression and correlated with clinical treatment outcome. Patients with EGFR mutations had a significantly higher overall response rate (ORR), longer time to progression (TTP) and overall survival (OS) compared with those with wild-type receptor. No difference in ORR was observed between patients with exon 19 deletion and patients with other EGFR mutations. ORR in HER2-positive patients was significantly higher than in the HER2-negative group, irrespective of EGFR mutational status, and a trend for better ORR was observed for HER3-positive patients. HER2 and HER3 expression levels were not associated with any difference in terms of TTP and OS. Nevertheless, when considering the subgroups of non-responders to gefitinib, median TTP in patients with mutated EGFR was significantly longer than in those with no mutations (8.0 vs. 3.0 months, P = 0.0065). EGFR-mutated patients had no significant difference in ORR, TTP and OS according to HER2 and/or HER3 expression. EGFR mutations are effective predictors for gefitinib efficacy in Chinese patients with advanced NSCLC. HER2 and HER3 expression does not provide any additional information for selecting patients most likely to benefit from gefitinib treatment.Journal of Cancer Research and Clinical Oncology 12/2008; 135(6):771-82. · 2.56 Impact Factor -
Article: Single-agent and combination therapeutic strategies to inhibit hepatocyte growth factor/MET signaling in cancer.
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ABSTRACT: Receptor tyrosine kinases are often aberrantly activated in human malignancies and contribute to cancer development and progression. Specific receptor tyrosine kinase inhibitors have been shown to be clinically effective therapies in subsets of cancer patients with either hematologic or solid tumors. Activation of the hepatocyte growth factor (HGF)/MET signaling pathway has been found to play a critical role in oncogenesis, cancer metastasis, and drug resistance. These observations have led to the development of agents that can effectively inhibit HGF/MET signaling through direct inhibition of the receptor (anti-MET antibodies), through inactivation of its ligand HGF (AMG102, L2G7), by interfering with HGF binding to MET (NK4), or by inhibiting MET kinase activity (PHA-665752 and SU11274). Moreover, the combination of anti-MET therapeutic agents with either signal transduction inhibitors (ERBB family or mTOR inhibitors) or with cytotoxic chemotherapy has been evaluated in preclinical models. These studies provide insight into the rational development of combination therapeutic strategies that can be evaluated in clinical trials. This review will discuss different strategies of MET inhibition with a specific focus on combination therapeutic approaches.Clinical Cancer Research 11/2008; 14(19):5941-6. · 7.74 Impact Factor -
Article: EGFR tyrosine kinase inhibitors: a therapy for a few, for the majority or for all non-small cell lung cancer patients?
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ABSTRACT: The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.Expert Opinion on Medical Diagnostics 10/2007; 1(2):183-191. -
Article: Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial.
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ABSTRACT: In non-small-cell lung cancer (NSCLC), clinical and biologic predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies, and there is urgent need to validate these results in prospective trials. The ONCOBELL trial is a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt. EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and presence of phospho-Akt was evaluated using immunohistochemistry. Additional tests included immunohistochemistry analysis of EGFR, FISH analysis of HER2, and mutation analysis of EGFR, HER2, and K-ras. From November 2004 to February 2006, 183 patients were screened, and 42 patients were enrolled onto the trial. We observed one complete and 19 partial responses, for an overall response rate (RR) of 47.6% (95% CI, 32.5% to 62.7%). Median duration of response was 6.1 months, median time to progression (TTP) was 6.4 months, 1-year survival rate was 64.3%, and median survival time was not reached. EGFR FISH-positive patients, compared with negative patients, had higher RR (68.0% v 9.1%, respectively; P < .001), longer TTP (7.6 v 2.7 months, respectively; P = .02), and a trend for longer survival (median survival not reached v 7.4 months, respectively; P = .3). Therapy was well tolerated, and there were no drug-related deaths. Median follow-up time was too short for significance tests of differences in survival outcomes. Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.Journal of Clinical Oncology 06/2007; 25(16):2248-55. · 18.37 Impact Factor -
Article: Is gemcitabine cost effective in cancer treatment?
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ABSTRACT: Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monotherapy or in association with other cytotoxic compounds, in pancreatic, ovarian, breast, bladder and non-small-cell lung cancer. The drug has an acceptable toxicity profile with myelosuppression being the most common adverse event. Pharmacoeconomic assessments have been performed in order to determine whether gemcitabine is a cost effective cancer treatment. Several cost analyses have investigated gemcitabine in association with cisplatin in the treatment of non-small-cell lung cancer, indicating that the combination is cost effective when compared with either old- or new-generation platinum-based treatments. Results in other malignancies are not corroborated by the same quality of evidence, therefore more extensive analyses are warranted. Overall, available data indicate that accurate selection of patients and careful cost analyses should be included in the development of new anticancer drugs for an appropriate use of limited healthcare resources.Expert Review of Pharmacoeconomics & Outcomes Research 06/2007; 7(3):239-49. -
Article: EGFR and HER2 Gene Copy Number and Response to First-Line Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer (NSCLC)
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ABSTRACT: Background: A critical point in designing clinical trials comparing chemotherapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC) is the expected benefit with standard chemotherapy in presence of biological features indicative of TKI sensitivity. The aim of this study was to assess whether EGFR and HER2 gene copy number and Akt activation are associated with response to first-line chemotherapy. Methods: Tumor samples from 190 patients with NSCLC were analyzed. EGFR and HER2 gene copy number were evaluated by fluorescence in situ hybridization in 185 and 184 cases, respectively. Akt activation was assessed by immunohistochemistry (n = 176). Additional biomarkers included EGFR DNA sequencing (n = 65), and EGFR immunohistochemistry (n = 185). Results: Response rate was not associated with EGFR, HER2, and P-Akt status, irrespective of the method used for biomarker assessment. Among patients with EGFR gene mutations, response to chemotherapy was observed only in individuals with exon 19 deletion (response rate: 46.6% versus 0%, p = 0.02). Among the 190 patients analyzed, 123 received a treatment with a TKI as second- or third-line therapy. When assessed by fluorescence in situ hybridization or DNA sequencing, EGFR-positive patients seemed to be more sensitive to TKIs than to chemotherapy in terms of response rate and time to progression, whereas in EGFR-negative patients, response rate and time to progression favored chemotherapy. Conclusion: This study suggested that EGFR expression and gene copy number, HER2 gene copy number, and P-Akt expression are not associated with response to first-line chemotherapy in NSCLC. Prospective phase III trials should compare standard chemotherapy with a TKI in selected NSCLC.Journal of Thoracic Oncology 04/2007; 2(5):423-429. · 3.66 Impact Factor -
Article: Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors.
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ABSTRACT: The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy.The Oncologist 03/2007; 12(2):211-20. · 3.91 Impact Factor -
Article: Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC).
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ABSTRACT: The Epidermal Growth Factor Receptor (EGFR) family, including EGFR, HER2, HER3, and HER4, is implicated in the development and progression of cancer, and is expressed in many human epithelial malignancies, including Non-Small Cell Lung Cancer (NSCLC). Several molecules were synthesized to inhibit the extracellular domain of EGFR, such as cetuximab (Erbitux), the extracellular domain of HER2, such as trastuzumab (Herceptin) or the EGFR tyrosine kinase domain, such as gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib and erlotinib are orally active, selective EGFR tyrosine-kinase inhibitors (EGFR-TKI) that produce objective response rates in about 10% of advanced NSCLC. More recently, erlotinib produced a significant improvement in survival when compared to placebo in pretreated NSCLCs. Among clinical characteristics, although female gender, and adenocarcinoma histology, showed to be significantly associated to TKI sensitivity, never smoking history is probably the most relevant factor. Presence of specific EGFR gene mutations or EGFR gene amplification confer a particularly sensitive phenotype, and patients with activation of the anti-apoptotic protein Akt are more sensitive, when Akt activation is sustained by a EGFR dependent mechanism. Cetuximab is a human-murine chimeric anti-EGFR IgG monoclonal antibody that has demonstrated both in vitro and in vivo antitumor activity in tumor cell lines expressing EGFR. It has shown impressive activity when combined with radiation by increasing the antitumor effect of radiation therapy. Cetuximab has a synergistic effect with cisplatin and may play a role in reversing resistance to chemotherapy. Cetuximab demonstrated to be active in pretreated NSCLCs, and its activity as first-line therapy in combination with chemotherapy is currently under evaluation. Efforts should be made for the identification of biological mechanism underlying cetuximab sensitivity and emerging data suggest that the drugs is more active in patients with EGFR gene amplification. In NSCLC, trastuzumab produced disappointing results when combined with chemotherapy, but probably patients were not properly selected. Recent findings in gefitinib treated patients support HER2 analysis by fluorescence in situ hybridization as a complementary test for selection of patient candidate for EGFR targeted therapies. Combination of EGFR targeting agents with other biological drugs is under investigation.Reviews on Recent Clinical Trials 02/2006; 1(1):1-13. -
Article: Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.
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ABSTRACT: In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity. HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations. Patients with HER2 high copy number (high polysomy and gene amplification [HER2 FISH positive]) represented 22.8% of patients, and compared with patients with no or low gain (HER2 FISH negative), had significantly better objective response (OR, 34.8% v 6.4%; P = .001), disease control rate (DCR, 56.5% v 33.3%; P = .04), time to progression (TTP, 9.05 v 2.7 months; P = .02), and a trend toward longer overall survival (OS, 20.8 v 8.4 months; P = .056). HER2 protein expression investigated by immunohistochemistry was positive in only five of 72 (7%) patients analyzed and all 89 patients tested by DNA sequencing were negative for mutations in HER2 exon 20. Patients with HER2 FISH-positive tumors displaying increased expression of EGFR protein, gene gain, or mutations (EGFR positive) had a significantly better OR, DCR, TTP, and OS than patients negative for both receptors. Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.Journal of Clinical Oncology 09/2005; 23(22):5007-18. · 18.37 Impact Factor -
Article: Perspectives on salvage therapy for non-small-cell lung cancer.
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ABSTRACT: Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.Oncology (Williston Park, N.Y.) 08/2005; 19(8):989-95; discussion 995-6, 999, 1003-4, passim. · 1.03 Impact Factor
Top co-authors
Top Journals
Institutions
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2008–2012
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Dana-Farber Cancer Institute
- • Department of Medical Oncology
- • Carole M. and Philip L. Lowe Center for Thoracic Oncology
Boston, MA, USA
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2007–2009
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Istituto Clinico Humanitas IRCCS
- Department of Oncology and Hematology
Rozzano, Lombardy, Italy
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