Publications by authors named "Giovanna Finocchiaro"

34 Publications

Subpopulations of Circulating Cells with Morphological Features of Malignancy Are Preoperatively Detected and Have Differential Prognostic Significance in Non-Small Cell Lung Cancer.

Cancers (Basel) 2021 Sep 6;13(17). Epub 2021 Sep 6.

Division of Thoracic Surgery, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Manzoni 56, 20089 Rozzano, MI, Italy.

Background: Non-small cell lung cancer (NSCLC) frequently presents when surgical intervention is no longer feasible. Despite local treatment with curative intent, patients might experience disease recurrence. In this context, accurate non-invasive biomarkers are urgently needed. We report the results of a pilot study on the diagnostic and prognostic role of circulating tumor cells (CTCs) in operable NSCLC.

Methods: Blood samples collected from healthy volunteers ( = 10), nodule-negative high-risk individuals enrolled in a screening program ( = 7), and NSCLC patients ( = 74) before surgery were analyzed (4 mL) for the presence of cells with morphological features of malignancy enriched through the ISET technology.

Results: CTC detection was 60% in patients, while no target cells were found in lung cancer-free donors. We identified single CTCs (sCTC, 46%) and clusters of CTCs and leukocytes (heterotypic clusters, hetCLU, 31%). The prevalence of sCTC (sCTC/4 mL ≥ 2) or the presence of hetCLU predicted the risk of disease recurrence within the cohort of early-stage (I-II, = 52) or advanced stage cases (III-IVA, = 22), respectively, while other tumor-related factors did not inform prognosis.

Conclusions: Cancer cell hematogenous dissemination occurs frequently in patients with NSCLC without clinical evidence of distant metastases, laying the foundation for the application of cell-based tests in screening programs. CTC subpopulations are fine prognostic classifiers whose clinical validity should be further investigated in larger studies.
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http://dx.doi.org/10.3390/cancers13174488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431290PMC
September 2021

Uncommon single and compound EGFR mutations: clinical outcomes of a heterogeneous subgroup of NSCLC.

Curr Probl Cancer 2022 02 19;46(1):100787. Epub 2021 Aug 19.

IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Milan, Italy.

Molecular characterization of non-small-cell lung cancer (NSCLC) is essential to define the correct therapeutic algorithm in metastatic disease. Approximately 90% of epidermal growth factor receptor (EGFR) mutations are usually associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The remaining 10% defines a small, extremely heterogeneous subgroup of mutations, with a varied profile of sensitivity and response to target therapies.This retrospective observational study includes 47 patients affected by metastatic NSCLC harboring uncommon EGFR mutations (single or compound mutation). Patients were treated with EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.Median OS resulted longer in the compound mutation group when compared to single rare mutations (33.6 vs 12 months; P = 0.473); a similar result was observed for PFS (16 vs 7.6 months; P = 0.281), although statistical significance was not reached. ORR, PFS and OS resulted similar for patients treated with first-line EGFR TKIs or chemotherapy. No difference in terms of PFS and OS was found according to the TKI administered.Compound mutations seem to be a good prognostic indicator for OS; they are also predictive of response to 1st and 2nd generation EGFR TKIs, as well as exon 19 insertions and mutations in codon 719 of exon 18. For mutations in exon 18 (not in codon 719) and exon 20 insertions, chemotherapy seems the most effective available option. The addition of immunotherapy to chemotherapy could change this approach in the next future.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100787DOI Listing
February 2022

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients Aged ≥ 75 Years With Non-small-cell Lung Cancer (NSCLC): An Italian, Multicenter, Retrospective Study.

Clin Lung Cancer 2020 11 13;21(6):e567-e571. Epub 2020 May 13.

Medical Oncology Unit, ASST Santi Paolo e Carlo, Università̀ di Milano, Milan, Italy.

Introduction: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy.

Material And Methods: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events.

Results: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years.

Conclusions: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.
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http://dx.doi.org/10.1016/j.cllc.2020.05.004DOI Listing
November 2020

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

Lancet Oncol 2020 07 12;21(7):914-922. Epub 2020 Jun 12.

Oncology Department, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland.

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.

Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.

Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.

Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292610PMC
July 2020

Neutrophil and lymphocyte blood count as potential predictive indicators of nivolumab efficacy in metastatic non-small-cell lung cancer.

Immunotherapy 2020 07 11;12(10):715-724. Epub 2020 Jun 11.

Humanitas Clinical and Research Center - IRCCS -, via Manzoni 56, 20089 Rozzano (Mi), Italy.

We retrospectively evaluated the role of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) as prognostic factors in metastatic non-small-cell lung cancer patients treated with nivolumab. Medical records of 65 patients were reviewed. NLR and LMR were calculated at baseline (t0) and at first radiological tumor assessment (t1). At univariate analysis, low NLR or high LMR values at t0 were associated with longer overall survival (p = 0.0001). At multivariate analysis including NLR and LMR at t0 and t1 and their trend, only NLR at t1 (p < 0.0001) and NLR trend (p < 0.0001) were significantly associated with overall survival outcomes. Our study suggests that NLR value at first tumor assessment or NLR trend could be used as prognostic indicators during nivolumab treatment in metastatic non-small-cell lung cancer.
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http://dx.doi.org/10.2217/imt-2019-0154DOI Listing
July 2020

Be-TeaM: An Italian real-world observational study on second-line therapy for EGFR-mutated NSCLC patients.

Lung Cancer 2020 02 16;140:71-79. Epub 2019 Dec 16.

Oncology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 1, 71013, San Giovanni Rotondo, FG, Italy. Electronic address:

Objectives: Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice.

Patients And Methods: Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting.

Results: Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3 % received gefitinib, 32.5 % afatinib and 14.2 % erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7 %, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5 % underwent only 1 liquid biopsy, 10.7 % only 1 tissue biopsy and 18.3 % >1 biopsy, both liquid and solid in 85.4 %. The T790M positivity rate was 45.3 %; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8 % were T790M+ and 60.2 % T790M-/undetermined. By the observation end, 87.9 % patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+.

Conclusion: Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790M status is not always feasible.
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http://dx.doi.org/10.1016/j.lungcan.2019.12.006DOI Listing
February 2020

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Future Oncol 2019 Nov 11;15(33):3775-3782. Epub 2019 Nov 11.

Department of Oncology & Hematology, Humanitas Clinical & Research Center, Rozzano, Milan, Italy.

The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in -mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Median overall survival resulted longer in group A versus B and C (p < 0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p = 0.06). TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.
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http://dx.doi.org/10.2217/fon-2019-0349DOI Listing
November 2019

Liquid Biopsy Testing Can Improve Selection of Advanced Non-Small-Cell Lung Cancer Patients to Rechallenge with Gefitinib.

Cancers (Basel) 2019 Sep 25;11(10). Epub 2019 Sep 25.

Cell Biology and Biotherapy Unit, Istiuto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, 80131 Naples, Italy.

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4-3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6-5.3 months), resulting in a statistically significant difference (Long rank test = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing.
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http://dx.doi.org/10.3390/cancers11101431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826724PMC
September 2019

Predictive and Prognostic Role of Metabolic Response in Patients With Stage III NSCLC Treated With Neoadjuvant Chemotherapy.

Clin Lung Cancer 2020 01 22;21(1):28-36. Epub 2019 Jul 22.

Department of Nuclear Medicine, Humanitas Clinical and Research Center-IRCCS, Rozzano (Mi), Italy. Electronic address:

Introduction: The purpose of this study was to assess the predictive and prognostic role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in candidates with stage III non-small-cell lung cancer (NSCLC) to neoadjuvant chemotherapy.

Patients And Methods: Sixty-six patients with stage III NSCLC treated with induction chemotherapy from March 2013 to December 2017 were retrospectively identified. Response assessment were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. 18F-FDG PET/CT metabolic parameters were analyzed as absolute values as well as percentage changes (Δ) between 2 consecutive scans, for primary tumor (T) and for regional lymph nodes (N). All clinical variables and metabolic parameters were compared with treatment response and correlated with progression-free survival (PFS) and overall survival (OS), based on a median follow-up of 9.4 months.

Results: Post-induction therapy standardized uptake value (SUV)max_T, SUVmean_T, metabolic tumor volume (MTV_T), and total lesion glycolysis of the tumor (TLG_T) varied significantly between responders and non-responders (6.6 vs. 13.8; P = .001; 4.2 vs. 8.1; P < .001; 6 vs. 17.9; P = .002; and 24.1 vs. 136.3; P < .001, respectively). Likewise, percentage changes (Δ_T) were significantly different between the 2 groups (P < .001). Along with primary tumor, also post-SUVmax_N, post-SUVmean_N, and post-TLG_N (P = .024, P = .015, and P = .024, respectively), as well as all percentage changes (Δ_N) were different between responders and non-responders. RECIST 1.1 and EORTC response classifications were discordant in 27 patients (40.9%; κ = 0.265; P = .003). On multivariate analysis, post-TLG_N was an independent predictor for both PFS and OS, whereas RECIST 1.1 was a predictor only for OS.

Conclusions: Several metabolic parameters may differentiate responders from non-responders following neoadjuvant chemotherapy in stage III NSCLC. As compared with RECIST 1.1, EORTC seems to be more appropriate for evaluation therapeutic response. Finally, post-TLG_N has significant prognostic information.
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http://dx.doi.org/10.1016/j.cllc.2019.07.004DOI Listing
January 2020

Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.

Immunotherapy 2019 08 14;11(11):945-952. Epub 2019 Jun 14.

Department of Oncology & Hematology, Humanitas Clinical & Research Center, Rozzano (MI), Italy.

Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
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http://dx.doi.org/10.2217/imt-2019-0029DOI Listing
August 2019

Impact of Exon 19 Deletion Subtypes in EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer Treated With First-Line Tyrosine Kinase Inhibitors.

Clin Lung Cancer 2019 03 2;20(2):82-87. Epub 2018 Nov 2.

Department of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Italy.

Background: Common epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs.

Patients And Methods: In this retrospective analysis, 106 patients with metastatic NSCLC harboring EGFR exon 19 deletions and treated with first-line TKIs were included. The primary end point was overall survival (OS), the secondary end point progression-free survival (PFS). Analyses were performed by grouping exon 19 deletions according to 2 models: we compared different type of deletion (delE746_A750 vs. deletions other than delE746-A750, defined as "uncommon") or different starting codon of deletion (E746 vs. L747).

Results: The frequency of uncommon deletions of exon 19 was 36%. When delE746_A750 (n = 68) was compared to the other deletions in exon 19 (n = 38), no differences were found, either in terms of OS (P = .65) or PFS (P = .65). Similarly, no difference in OS (P = .74) or PFS (P = .99) emerged when comparing the E746 group (n = 81) to the L747 group (n = 25). On multivariate analysis including clinical characteristics and type of deletions (delE746_A750 vs. uncommon deletions or E746 vs. L747), only the presence of brain metastases at diagnosis or during TKI treatment was associated with shorter PFS but not with worse OS.

Conclusion: Different exon 19 deletions are equally sensitive to first-line EGFR-TKIs in EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2018.10.009DOI Listing
March 2019

Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations.

Br J Cancer 2019 01 31;120(1):57-62. Epub 2018 Oct 31.

Istituto Tumouri "Giovanni Paolo II", Bari, Italy.

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.

Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.

Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.

Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
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http://dx.doi.org/10.1038/s41416-018-0234-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325128PMC
January 2019

Tumor heterogeneity, hypoxia, and immune markers in surgically resected non-small-cell lung cancer.

Nucl Med Commun 2018 Jul;39(7):636-644

Departments of Nuclear Medicine.

Objectives: This study aimed to determine the prognostic role of textural features and their association with metabolic parameters, hypoxia, and cancer-related immune markers in non-small-cell lung cancer (NSCLC) patients.

Patients And Methods: The trial was registered at http://www.clinicaltrials.gov (NCT02519062). From January 2010 to May 2014, 44 patients (male : female=33 : 11; median age: 69.5 years), referred to our Institution for NSCLC resection, were enrolled. Tumor specimens were assessed for HIF-1α, CD68-TAMs, CD8-TILs, PD-1-TILs, and PD-L1 expressions. All patients underwent fluorine-18-fluorodeoxyglucose (F-FDG) PET before surgery. Semiquantitative parameters included maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume, and total lesion glycolysis, whereas for heterogeneity, we considered tumor sphericity, skewness, kurtosis, entropy, and energy. Parameters were correlated with disease-free survival (DFS) considering a median follow-up of 22.7 months.

Results: SUVmax (cutoff: 7.9; P=0.015), SUVpeak (cutoff: 6.7; P=0.013), SUVmean (cutoff: 5.5; P=0.028), metabolic tumor volume (cutoff: 3.6 cm; P=0.027), and entropy (cutoff: 1.89; P=0.045) showed a statistically significant association with DFS. Also, a high expression of cytoplasmic HIF-1α (score 3) was associated with DFS (hazard ratio: 0.09; P=0.003). All F-FDG PET variables differed significantly in tumors with high or low entropy (≤1.89). Also, a significantly higher level of mean CD8-TILs was observed in tumors with higher entropy (P=0.041).Using identified prognostic factors, we developed a scoring system, which was confirmed to be associated with DFS (P<0.004). On receiver operating characteristics analysis, a score above 3 was defined as the optimal cutoff point.

Conclusion: Tumor heterogeneity, metabolic parameters, and high expression of hypoxia were found to be prognostic factors in NSCLC patients who were candidates for surgery. Higher levels of entropy appear to be associated with increased density of CD8-TILs. The combination of investigated prognostic factors enabled the development of a potential scoring system associated with DFS.
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http://dx.doi.org/10.1097/MNM.0000000000000832DOI Listing
July 2018

Checkpoint inhibitors: 'raising the bar' also in brain metastases from non-small-cell lung cancer?

Immunotherapy 2018 04;10(5):403-410

Department of Oncology & Hematology, Humanitas Clinical & Research Center, Rozzano (MI), Italy.

Despite efforts, brain metastases (BM) remain a critical issue in the management of patients affected by non-small-cell lung cancer (NSCLC). To date, radiotherapy is still considered the gold standard treatment; on the other hand, systemic chemotherapeutical agents are not so often an effective therapy for BM, whereas targeted agents in oncogene-addicted disease have shown a good activity also on BM. Anti-programmed death-1/programmed death ligand-1 agents represent a new valid therapeutic strategy for NSCLC as well as for several tumor types, but their efficacy on patients with BM is still unclear mainly due to the strict selection criteria adopted in clinical trials. The aim of the present article is to discuss the potential activity of checkpoint inhibitors in patients with BM from NSCLC.
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http://dx.doi.org/10.2217/imt-2017-0151DOI Listing
April 2018

Non-small cell lung cancer treatment (r)evolution: ten years of advances and more to come.

Ecancermedicalscience 2017 30;11:787. Epub 2017 Nov 30.

Humanitas Research Hospital, Medical Oncology, Via Manzoni 56, 20089 Rozzano, Italy.

Diagnostic and treatment algorithms in non-small cell lung cancer (NSCLC) are evolving at a never-before-seen pace. Histological subtyping to maximise treatment efficacy and avoid toxicity has marked the beginning of the revolution, opening the way to molecular characterisation to guide genomically driven treatments with targeted agents, led by Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) inhibitors. More recently, agents against the Program Death 1 receptor (PD-1) and ligand 1 (PD-L1) have entered the clinical arena, offering new hope to NSCLC patients, although several uncertainties remain to be elucidated. Here, we review the most clinically relevant advances in the diagnosis and treatment of NSCLC in the past decade.
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http://dx.doi.org/10.3332/ecancer.2017.787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718252PMC
November 2017

Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer.

Lung Cancer 2016 09 14;99:31-7. Epub 2016 Jun 14.

Thoracic Oncology Division, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141 Milan, Italy, Italy; Formerly Department of Thoracic Oncology, 1st Pulmonary Oncological Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy. Electronic address:

Objectives: Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies.

Materials And Methods: A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy.

Results: Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progression-free survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent.

Conclusion: Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists.
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http://dx.doi.org/10.1016/j.lungcan.2016.06.008DOI Listing
September 2016

Outcome Evaluation of Oligometastatic Patients Treated with Surgical Resection Followed by Hypofractionated Stereotactic Radiosurgery (HSRS) on the Tumor Bed, for Single, Large Brain Metastases.

PLoS One 2016 27;11(6):e0157869. Epub 2016 Jun 27.

Radiotherapy and Radiosurgery Department, Humanitas Cancer Center and Research Hospital, Milan, Italy.

Purpose: The aim of this study was to evaluate the benefit of a combined treatment, surgery followed by adjuvant hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large brain metastasis (BM).

Methods And Materials: Fom January 2011 to March 2015, 69 patients underwent complete surgical resection followed by HSRS with a total dose of 30Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after radiotherapy and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the irradiated volume, and brain distant progression as the presence of new brain metastases or leptomeningeal enhancement outside the irradiated volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated.

Results: The median preoperative volume and maximum diameter of BM was 18.5cm3 (range 4.1-64.2cm3) and 3.6cm (range 2.1-5-4cm); the median CTV was 29.0cm3 (range 4.1-203.1cm3) and median PTV was 55.2cm3 (range 17.2-282.9cm3). The median follow-up time was 24 months (range 4-33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33.0%; the median, 1-and 2-year OS was 24 months (range 4-33 months), 91.3% and 73.0%. No severe postoperative morbidity or radiation therapy toxicity occurred in our series.

Conclusions: Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157869PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922580PMC
July 2017

When is surgery indicated for small-cell lung cancer?

Lung Cancer 2015 Dec 17;90(3):582-9. Epub 2015 Oct 17.

Division of Thoracic and General Surgery, Istituto Clinico Humanitas IRCCS, Rozzano, Italy.

Small-cell lung cancer (SCLC) comprises 13-20% of all lung cancers but is the fifth leading cause of cancer death worldwide. SCLC prognosis remains poor despite improvements in diagnosis and therapy over the last 30 years. Current treatment is systemic chemotherapy, flanked by thoracic irradiation for limited stage disease; however, about two-thirds of patients are diagnosed with extensive stage disease when thoracic irradiation is not worthwhile. Randomized trials on surgical resection in patients with limited stage disease conducted in the pre-PET era, when both staging and treatment were inadequate, did not support a role for surgery in disease management. However recent retrospective and population-based studies indicate that outcomes after surgery in patients with very early SCLC are comparable to those in patients with non-SCLC, and that survival is better than in SCLC patients not given surgery. CT screening identifies SCLC at an earlier stage - with better survival - than usual care, and offers the hope that more SCLC patients may become long-term survivors. However, cases must be exhaustively staged to identify those likely to benefit from surgery. Finding a specific SCLC marker to facilitate early diagnosis remains a priority.
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http://dx.doi.org/10.1016/j.lungcan.2015.10.019DOI Listing
December 2015

Prognostic and predictive value of MET deregulation in non-small cell lung cancer.

Ann Transl Med 2015 Apr;3(6):83

Department of Medical Oncology, Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy.

Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients.
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http://dx.doi.org/10.3978/j.issn.2305-5839.2015.03.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416957PMC
April 2015

Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography.

Am J Respir Crit Care Med 2015 May;191(10):1166-75

1 Department of Thoracic Surgery.

Rationale: Screening for lung cancer with low-dose spiral computed tomography (LDCT) has been shown to reduce lung cancer mortality by 20% compared with screening with chest X-ray (CXR) in the National Lung Screening Trial, but uncertainty remains concerning the efficacy of LDCT screening in a community setting.

Objectives: To explore the effect of LDCT screening on lung cancer mortality compared with no screening. Secondary endpoints included incidence, stage, and resectability rates.

Methods: Male smokers of 20+ pack-years, aged 60 to 74 years, underwent a baseline CXR and sputum cytology examination and received five screening rounds with LDCT or a yearly clinical review only in a randomized fashion.

Measurements And Main Results: A total of 1,264 subjects were enrolled in the LDCT arm and 1,186 in the control arm. Their median age was 64.0 years (interquartile range, 5), and median smoking exposure was 45.0 pack-years. The median follow-up was 8.35 years. One hundred four patients (8.23%) were diagnosed with lung cancer in the screening arm (66 by CT), 47 of whom (3.71%) had stage I disease; 72 control patients (6.07%) were diagnosed with lung cancer, with 16 (1.35%) being stage I cases. Lung cancer mortality was 543 per 100,000 person-years (95% confidence interval, 413-700) in the LDCT arm versus 544 per 100,000 person-years (95% CI, 410-709) in the control arm (hazard ratio, 0.993; 95% confidence interval, 0.688-1.433).

Conclusions: Because of its limited statistical power, the results of the DANTE (Detection And screening of early lung cancer with Novel imaging TEchnology) trial do not allow us to make a definitive statement about the efficacy of LDCT screening. However, they underline the importance of obtaining additional data from randomized trials with intervention-free reference arms before the implementation of population screening.
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http://dx.doi.org/10.1164/rccm.201408-1475OCDOI Listing
May 2015

Phase II study of afatinib, an irreversible ErbB family blocker, in EGFR FISH-positive non-small-cell lung cancer.

J Thorac Oncol 2015 Apr;10(4):665-72

*Istituto Toscano Tumori, Ospedale Civile di Livorno, Livorno, Italy; †Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano, Italy; ‡IRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul Cancro, Lung Cancer Unit, Genova, Italy; §San Gerardo Hospital, Monza, Italy; ‖Istituto Oncologico Veneto IRCSS, Padova, Italy; ¶Clinical Research Center, Center of Excellence on Aging, University Foundation, Chieti, Italy; #IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy; **Boehringer Ingelheim Pharma GmbH & Co. KG, Vienna, Austria; ††Boehringer Ingelheim Italia SpA, Milan, Italy; and ‡‡Boehringer Ingelheim Ltd., Bracknell, UK.

Introduction: Afatinib, an oral irreversible ErbB Family Blocker, has demonstrated efficacy and safety in epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. It is unknown whether such activity also occurs in patients with EGFR gene overexpression, regardless of mutation status. This phase II study investigated the activity and safety of afatinib in advanced non-small-cell lung cancer with increased EGFR gene copy number and/or gene amplification by fluorescence in situ hybridization (FISH), with or without EGFR mutation.

Methods: EGFR gene overexpression was assessed by FISH analysis; patients with high polysomy or gene amplification were considered FISH positive. Patients received daily afatinib less than or equal to 50 mg (monotherapy). Endpoints included objective response rate (ORR; primary), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Of 223 patients screened, 69 patients were FISH-positive and met eligibility criteria for treatment. The ORR was 13.0% overall (n =9 of 69). Higher ORRs were observed in patients with gene amplification (20.0%; n =5 of 25) and EGFR mutation-positive tumors (25.0%; n =3 of 12). The DCR was 50.7% overall (n = 35 of 69; median duration: 24.9 weeks) with higher DCRs observed in patients with gene amplification 64.0%; (n = 16 of 25), and in patients with EGFR mutation-positive tumors 66.7% (n = 8 of 12). In the overall population, median PFS was 8.4 weeks and median OS was 50.4 weeks. The most common afatinib-related adverse events were rash/acne (83%) and diarrhea (78%).

Conclusions: First- or second-line afatinib demonstrated preliminary activity and manageable safety in EGFR FISH-positive patients with advanced non-small-cell lung cancer.
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http://dx.doi.org/10.1097/JTO.0000000000000442DOI Listing
April 2015

Increased SOX2 gene copy number is associated with FGFR1 and PIK3CA gene gain in non-small cell lung cancer and predicts improved survival in early stage disease.

PLoS One 2014 15;9(4):e95303. Epub 2014 Apr 15.

University of Colorado School of Medicine, Aurora, Colorado, United States of America.

Background: We aimed to investigate prevalence and prognostic role of SOX2, PIK3CA, FGFR1 and BRF2 gene gain in patients with surgically resected non-small cell lung cancer (NSCLC).

Methods: SOX2, PIK3CA, FGFR1 and BRF2 gene copy number was assessed by fluorescence in situ hybridization (FISH) in arrayed tissue cores from 447 resected NSCLCs.

Results: Increased gene copy number (FISH+) for SOX2, PIK3CA, FGFR1 and BRF2 was observed in 23.6%, 29.2%, 16.6% and 14.9% of cases, respectively. FISH+ status for each gene was significantly associated with smoking history, squamous cell carcinoma (SCC) histology, and increased copy number of the other studied genes. Multivariate analysis of overall survival indicated increased SOX2 gene copy number (P = 0.008), stage I-II (P<0.001), and adenocarcinoma or SCC histology (P = 0.016) as independent, favorable prognostic factors. A statistically significant interaction was observed between stage and SOX2 gene status (P = 0.021), indicating that the prognostic impact of SOX2 gene gain differs across stages and is limited to patients with stage I-II disease (HR 0.44, 95% CI: 0.25-0.77; P = 0.004, adjusted for histology).

Conclusions: Increased SOX2 gene copy number is an independent and favorable prognostic factor in surgically resected, early stage NSCLC, regardless of histology. SOX2, PIK3CA, FGFR1 and BRF2 gene gains are likely to occur concurrently, with potentially relevant implications for the development of new therapeutic strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095303PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988173PMC
May 2015

Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy.

Eur J Cancer 2010 Oct 12;46(15):2746-52. Epub 2010 Aug 12.

Department of Oncology, Istituto Clinico Humanitas, Rozzano, Italy.

Background: NGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies.

Patients And Methods: Thirty-three patients with progressive disease at study entry received NGR-hTNF 0.8 μg/m(2) given intravenously every 3 weeks. The median number of prior treatment regimens was three (range, 2-5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective.

Results: NGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion-time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9-57.8%). Median PFS and overall survival were 2.5 months (95% CI, 2.1-2.8) and 13.1 months (95% CI, 8.9-17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4 months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10 months.

Conclusion: Based on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2010.07.012DOI Listing
October 2010

Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones.

Neoplasia 2009 Oct;11(10):1084-92

Clinical Research Center, Center of Excellence on Aging, University-Foundation, 66013 Chiety, Italy.

Mutations inducing resistance to anti-epidermal growth factor receptor (EGFR) therapy may have a clinical impact even if present in minor cell clones which could expand during treatment. We tested this hypothesis in lung cancer patients treated with tyrosine kinase inhibitors (TKIs). Eighty-three patients with lung adenocarcinoma treated with erlotinib or gefitinib were included in this study. The mutational status of KRAS and EGFR was investigated by direct sequencing (DS). KRAS mutations were also assessed by mutant-enriched sequencing (ME-sequencing). DS detected KRAS mutations in 16 (19%) of 83 tumors; ME-sequencing identified all the mutations detected by DS but also mutations in minor clones of 14 additional tumors, for a total of 30 (36%) of 83. KRAS mutations assessed by DS and ME-sequencing significantly correlated with resistance to TKIs (P = .04 and P = .004, respectively) and significantly affected progression-free survival (PFS) and overall survival (OS). However, the predictive power of mutations assessed by ME-sequencing was higher than that obtained by DS (hazard ratio [HR] = 2.82, P = .0001 vs HR = 1.98, P = .04, respectively, for OS; HR = 2.52, P = .0005 vs HR = 2.21, P = .007, respectively, for PFS). Survival outcome of patients harboring KRAS mutations in minor clones, detected only by ME-sequencing, did not differ from that of patients with KRAS mutations detected by DS. Only KRAS mutations assessed by ME-sequencing remained an independent predictive factor at multivariate analysis. KRAS mutations in minor clones have an important impact on response and survival of patients with lung adenocarcinoma treated with EGFR-TKI. The use of sensitive detection methods could allow to more effectively identify treatment-resistant patients.
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http://dx.doi.org/10.1593/neo.09814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745674PMC
October 2009

Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients.

J Clin Oncol 2009 Apr 2;27(10):1667-74. Epub 2009 Mar 2.

Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Department of Oncology-Hematology, University of Milan School of Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.

Purpose: 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).

Patients And Methods: 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.

Results: 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).

Conclusion: MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.
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http://dx.doi.org/10.1200/JCO.2008.19.1635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341799PMC
April 2009

Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC).

Rev Recent Clin Trials 2006 Jan;1(1):1-13

Bellaria Hospital-Department of Medical Oncology, Via Altura 3, 40139-Bologna-Italy.

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.
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http://dx.doi.org/10.2174/157488706775246157DOI Listing
January 2006

EGFR tyrosine kinase inhibitors: a therapy for a few, for the majority or for all non-small cell lung cancer patients?

Expert Opin Med Diagn 2007 Oct;1(2):183-91

Istituto Clinico Humanitas IRCCS, Division of Oncology-Hematology, via Manzoni 56, 20089-Rozzano, Italy +39 02 8224 4097 ; +39 02 8224 4590 ;

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.
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http://dx.doi.org/10.1517/17530059.1.2.183DOI Listing
October 2007

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.

J Clin Oncol 2007 Jun;25(16):2248-55

Department of Hematology-Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy.

Purpose: 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.

Patients And Methods: 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.

Results: 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.

Conclusion: Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.
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http://dx.doi.org/10.1200/JCO.2006.09.4300DOI Listing
June 2007

Is gemcitabine cost effective in cancer treatment?

Expert Rev Pharmacoecon Outcomes Res 2007 Jun;7(3):239-49

Istituto Clinico Humanitas IRCCS, Department of Onco-Hematology, Via Manzoni 56, 20089 Rozzano, Italy.

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.
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http://dx.doi.org/10.1586/14737167.7.3.239DOI Listing
June 2007

EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).

J Thorac Oncol 2007 May;2(5):423-9

Department of Hematology-Oncology, Istituto Clinico Humanitas, Rozzano, Italy.

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.
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http://dx.doi.org/10.1097/01.JTO.0000268676.79872.9bDOI Listing
May 2007
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