RESUMEN
BACKGROUND: Systemic second- and third-line therapies for malignant pleural mesothelioma (MPM) result in a median progression-free survival (mPFS) of <2 months and median overall survival (mOS) of 6-9 months. Lurbinectedin binds to the DNA of the regulatory region while inhibiting tumour-associated macrophage transcription. In early trials, encouraging outcomes occurred in patients (pts) with MPM treated with lurbinectedin. We aimed to generate lurbinectedin efficacy and safety data among pts with progressive MPM. PATIENTS AND METHODS: Pts with progressing MPM treated with first-line platinum-pemetrexed chemotherapy with or without immunotherapy received lurbinectedin monotherapy. Treatment was given intravenously at 3.2 mg/m2 dose every 3 weeks until progression or unacceptable toxicity. Using Simon's two-stage design, the primary endpoint, progression-free survival (PFS) at 12 weeks (PFS12wks), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%). RESULTS: Forty-two pts from nine centres across Switzerland and Italy were recruited. Histology was epithelioid in 33 cases, sarcomatoid in 5, and biphasic in 4. Overall 10/42 (23.8%) underwent prior immunotherapy and 14/42 (33.3%) had progressed ≤6 months after first-line chemotherapy. At data cut-off PFS12wks was met by 22/42 pts (52.4%; 90% confidence interval (CI): 38.7% to 63.5%; P = 0.015) with an mPFS of 4.1 months and mOS of 11.1 months. The best response was complete and partial remission observed in one patient each and stable disease in 20 pts. The duration of disease control was 6.6 months (95% CI: 5.2-7.4). No significant difference in PFS12wks, mPFS, and mOS was recorded in epithelioid versus non-epithelioid cases and pts with prior immunotherapy versus those without. Similar mPFS but shorter mOS were observed among pts who progressed within ≤6 months after first-line chemotherapy. Lurbinectedin-related grade 3-4 toxicity was seen in 21 pts, mostly being neutropenia (23.8%) and fatigue (16.7%). CONCLUSIONS: The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS. GOV IDENTIFIER: NCT03213301.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Carbolinas , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Italia , Mesotelioma/tratamiento farmacológico , Cuidados Paliativos , Neoplasias Pleurales/tratamiento farmacológico , SuizaRESUMEN
Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.
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Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/patología , Neoplasias Pleurales/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/inmunología , Biopsia , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Masculino , Mesotelioma/tratamiento farmacológico , Mesotelioma/inmunología , Mesotelioma/mortalidad , Mesotelioma Maligno , Persona de Mediana Edad , Índice Mitótico , Pleura/citología , Pleura/inmunología , Pleura/patología , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/inmunología , Neoplasias Pleurales/mortalidad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Linfocitos T Citotóxicos/inmunología , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Androgen deprivation therapy is the mainstay of treatment for men affected by metastatic prostate cancer (PC). Unfortunately, nearly all patient will become resistant to the initial hormonal approach, developing a metastatic castration-resistant prostate cancer (mCRPC). For many years, chemotherapy with docetaxel has been the only established standard of care for men with mCRPC. Recent developments in the knowledge of the disease biology have shown that during the progression to the castrate status PC remains dependent on androgens and androgen receptor (AR) pathway. As a consequence, new agents like abiraterone acetate and enzalutamide have been rapidly developed and approved for clinical use. Other drugs with different mechanisms of action, such as sipuleucel-T, cabazitaxel, and radium-223 have shown to improve overall survival, symptom control and quality of life of mCRPC patients. However, the optimal sequencing and combination of these treatments are not defined yet. Studies on biomarkers for treatment selection, such as AR splice variants, are promising, but the initial data still need prospective validation on large patient series.
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Antineoplásicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Calidad de Vida , Animales , Antineoplásicos/uso terapéutico , Humanos , Inmunoterapia , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Análisis de SupervivenciaRESUMEN
Prostate cancer (PC) is a heterogeneous disease, whose growth is driven by androgens and androgen receptors. Androgen deprivation therapy (ADT) is the standard treatment of hormone-naïve metastatic disease. The majority of patients are treated with medical castration with GnRH agonists or antagonists, which usually determines a profound PSA decline and a radiological and clinical benefit. However, essentially all patients experience progression to castration-resistant prostate cancer (CRPC), and overall prognosis remains disappointing. Early targeting of cells that survive hormonal therapy may potentially prevent the development of CRPC. Several trials have explored the use of combination therapy with ADT and chemotherapy, targeting both the androgen dependent and independent cells simultaneously. Docetaxel was administered in combination with ADT to men with hormone-naïve metastatic prostate cancer, in the attempt to improve the duration and quality of patient survival. Three large randomized trials (the GETUG-15, CHAARTED and more recently the STAMPEDE study) have assessed these endpoints, with partially conflicting results. Overall, the results from these trials seem to support the use of early docetaxel combined with ADT in selected hormone-naïve metastatic PC patients. Full publication of the results of all studies, with longer follow-up, and the results of other ongoing trials in this setting will hopefully further define the role and the indications of this therapeutic strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hormonas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Ensayos Clínicos como Asunto , Docetaxel , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata/metabolismo , Taxoides/uso terapéuticoRESUMEN
BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management. METHODS: The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS). RESULTS: In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001). CONCLUSIONS: Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.
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Neoplasias Pulmonares/mortalidad , Mesotelioma/mortalidad , Neoplasias Pleurales/mortalidad , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Humanos , Italia/epidemiología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Mesotelioma/patología , Mesotelioma/terapia , Mesotelioma Maligno , Neoplasias Pleurales/patología , Neoplasias Pleurales/terapia , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM). METHODS: Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated. RESULTS: Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred. CONCLUSION: The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Supervivencia sin Enfermedad , Femenino , Glutamatos/administración & dosificación , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Masculino , Mesotelioma/sangre , Persona de Mediana Edad , Pemetrexed , Neoplasias Pleurales/sangre , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab. MATERIALS AND METHODS: DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety. RESULTS: Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death. CONCLUSION: Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma Maligno/etiología , Pemetrexed/farmacología , Pemetrexed/uso terapéutico , Mesotelioma/patología , Platino (Metal)/uso terapéutico , Neoplasias Pleurales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Carbolinas , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Neoplasias Pulmonares/patología , Mesotelioma/tratamiento farmacológico , Mesotelioma/patología , Cuidados Paliativos , Microambiente TumoralRESUMEN
A precision medicine approach has been successfully applied in medical oncology for the treatment of non-small-cell lung cancer (NSCLC) through the identification of targetable driver molecular aberrations; activating mutations of epidermal growth factor receptor (EGFR) are the most common. Osimertinib, a third-generation, wild-type sparing, irreversible EGFR tyrosine kinase inhibitor (TKI), originally showed a striking activity after progression to first- and second-generation EGFR-TKIs when T790M resistance mutation was identified. Thereafter, upfront use of osimertinib became the standard of care based on overall survival benefit over first-generation TKIs erlotinib and gefitinib as reported in the FLAURA trial. For patients progressing on osimertinib, identification of resistance mechanisms is crucial to develop novel targeted therapeutic approaches. Moreover, innovative drugs or combination therapies are being developed for cases in which a specific resistance mechanism is not identifiable. In this review, the post-osimertinib treatment options for EGFR-mutated NSCLC are analyzed, with an outlook to ongoing clinical trials. An algorithm to guide clinicians in managing progression on osimertinib is proposed.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Progresión de la Enfermedad , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy. PATIENTS AND METHODS: This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL). RESULTS: A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms. CONCLUSIONS: Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Estudios Prospectivos , Calidad de Vida , Vinorelbina/uso terapéuticoRESUMEN
Focal pulmonary ground-glass opacities (GGOs) can be associated with bronchioloalveolar carcinoma. The present retrospective study aimed to test the validity of a multistep approach to discriminate malignant from benign localised (focal) GGOs, identifies useful diagnostic features on computed tomography (CT), and suggests appropriate management guidelines. A stepwise approach, including oral antibiotics, follow-up high-resolution CT (HRCT) 40-60 days later and CT-guided core biopsy, was used. All cases with localised GGOs detected since 2001 were reviewed. CT features were described according to a structured scheme. In total, 40 patients were evaluated. Of these, 11 patients were diagnosed with benign GGOs, 19 patients had lung cancer and 10 were undetermined. Nonpolygonal shape, apparent radial growth and clear-cut margins were associated with a malignant histology. The specificity of CT findings was low. Diagnostic accuracy increased after oral antibiotics, follow-up HRCT and percutaneous core biopsy. Overall, 18 patients underwent surgery for lung cancer. In conclusion, malignant ground-glass opacities have a fairly typical appearance, but some benign lesions closely mimic their malignant counterparts. The stepwise approach adopted in the present study increased the diagnostic specificity and reduced time to definitive diagnosis. Segmentectomy might be the ideal resection volume for such tumours.
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Adenocarcinoma Bronquioloalveolar/diagnóstico por imagen , Adenocarcinoma Bronquioloalveolar/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Adenocarcinoma Bronquioloalveolar/patología , Anciano , Antibacterianos/uso terapéutico , Biopsia , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Tomografía Computarizada por Rayos XRESUMEN
The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Glutamatos/administración & dosificación , Guanina/análogos & derivados , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Factores de Edad , Anciano , Ensayos Clínicos Fase II como Asunto , Femenino , Guanina/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Pemetrexed , Estudios RetrospectivosRESUMEN
BACKGROUND: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. MATERIALS AND METHODS: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. RESULTS: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. CONCLUSIONS: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas/genética , Quinazolinas/administración & dosificación , Anciano , Biopsia con Aguja , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Cohortes , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Femenino , Gefitinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación/efectos de los fármacos , Estadificación de Neoplasias , Probabilidad , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/efectos de los fármacos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate serum changes of matrix metalloproteinases (MMPs) 2 and 9, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) levels in patients with advanced non-small cell lung cancer (NSCLC) and their association with main clinicopathological parameters during chemotherapy with cisplatin and gemcitabine. PATIENTS AND METHODS: In this prospective study, consecutive patients with stage III and IV NSCLC were enrolled. Serum MMP2 and 9, VEGF and EGFR levels were monitored in blood samples taken on day 1 of starting chemotherapy (baseline 1st), and after 3 cycles of chemotherapy (2nd) using commercial sandwich ELISA method. RESULTS: 116 patients were evaluated. Males / females 100 / 6, ECOG performance status (PS) 0/1/2: 47/65/4, stage III / IV: 49/67, squamous /adeno/large cell carcinoma 41/31/19. Forty-two (36%) patients achieved partial response (PR), 32 (28%) stable disease (SD) and 42 (36%) showed progressive disease (PD). Mean serum values -/+ standard deviation (SD) of the analyzed markers at baseline/at response evaluation were: EGFR 86 -/+ 87/96 -/+ 47 fmol/ml; MMP9 236 -/+ 156/162 -/+ 133 ng/ml ; MMP2 525 -/+ 189/569 -/+ 201 ng/ml; VEGF 555 -/+ 476/599 -/+ 611 pg/ml; VEGF adjusted for platelets (PLT) 1.9 -/+ 1.45/2.4 -/+ 2.78 pg/10(6). In logistic regression model for response rate adjusted for stage, the increase in MMP9 levels during chemotherapy (mean = 74 ng/ml -/+ SD 140) was predictive for progression (p=0.041) with 5% increase in the odds of progression for an increase of 10 ng. CONCLUSION: MMP9 level increase was found to be predictive of disease progression. EGFR levels could refl ect extracellular domain (ECD) loss from resistant cells and its shedding into the circulation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/sangre , Receptores de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, against which some antitumoral drugs have been developed. There is a lack of information as to EGFR expression in malignant pleural mesothelioma (MPM), an aggressive and fatal cancer poorly responsive to current oncological treatments. Our aim was to: (a) compare EGFR immunohistochemical expression with mRNA levels measured by real time PCR; (b) assess the relationships between EGFR expression and clinico-pathological data including survival; (c) analyze the EGFR mutations. We developed an immunohistochemical method of EGFR evaluation based on the number of immunoreactive cells and staining intensity in 61 MPMs. EGFR immunoreactivity was documented in 34/61 (55.7%) cases. A significant correlation between EGFR protein and mRNA levels (p = 0.0077) was found, demonstrating the reliability of our quantification method of EGFR membrane expression. Radically resected patients (p = 0.005) and those with epithelial histotype (p = 0.048) showed an increased survival. No statistical correlation between EGFR immunoreactivity and patients survival was observed. No EGFR mutation was documented. This study documents EGFR overexpression in MPM at the protein and the transcriptional levels; it proposes a reliable method for EGFR expression evaluation in MPM. EGFR levels are not associated with clinico-pathological features of patients, including survival.
Asunto(s)
Receptores ErbB/análisis , Mesotelioma/química , Neoplasias Pleurales/química , Adulto , Anciano , Cromatografía Líquida de Alta Presión , Receptores ErbB/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Mesotelioma/patología , Persona de Mediana Edad , Mutación , Neoplasias Pleurales/patología , ARN Mensajero/análisisRESUMEN
Malignant Pleural Mesothelioma (MPM) remains a relevant public health issue, and asbestos exposure is the most relevant risk factor. The incidence has considerably and constantly increased over the past two decades in the industrialized countries and is expected to peak in 2020-2025. In Italy, a standardized-rate incidence in 2011 among men was 3.5 and 1.25 per 100,000 in men and women, respectively, and wide differences are noted among different geographic areas. The disease remains challenging in terms of diagnosis, staging and treatment and an optimal strategy has not yet been clearly defined. The Third Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Bari (Italy) in January 30-31, 2015. This Consensus has provided updated recommendations on the MPM management for health institutions, clinicians and patients.