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BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MutaciónRESUMEN
The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.
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ADN Tumoral Circulante , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Cetuximab , Irinotecán , Proteínas Proto-Oncogénicas B-raf/genética , ADN Tumoral Circulante/genética , Estudios Prospectivos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Colon/etiología , Neoplasias del Recto/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Irinotecán/farmacología , Irinotecán/uso terapéutico , Estudios Retrospectivos , Fluorouracilo/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
Cutaneous melanoma is the most lethal form of skin cancer and its incidence has been increasing in the past 30 years. Although this is completely resectable in most cases, thicker melanoma and those with regional lymph-node involvement are at a high risk of relapse. In recent years, the management of locoregional disease has drastically changed. In particular, in the 8th Edition of the American Joint Committee on Cancer (AJCC), subgroup classification of TNM (tumor-node-metastasis) has been modified, with the addition of the IIID stage. Furthermore, in recent randomized trials, completion lymph node dissection in case of sentinel lymph node biopsy positivity has not been shown to offer any improvement in overall survival versus observation. Consequently, radical dissection has been recommended as the standard treatment, but only in patients with palpable nodal metastases. However, the major novelty in the treatment of locally advanced melanoma has been the introduction of drugs, already used for metastatic disease, that have also shown clinical efficacy in the adjuvant setting. In fact, immunotherapies and, in the case of BRAF V600E/K-mutated melanoma, combination treatment of BRAF and MEK inhibitors have improved recurrence-free survival in these patients. In this paper, we will describe the current management of a patient with radically resectable melanoma and discuss the key points in light of the latest scientific evidence.
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Melanoma , Neoplasias Cutáneas , Humanos , Escisión del Ganglio Linfático , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Recurrencia Local de Neoplasia , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugíaRESUMEN
A few months ago, results from two randomised phase III trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were presented (RAPIDO and PRODIGE 23), consistently showing better short- and long-term outcomes with TNT as compared with standard neoadjuvant long-course chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). These results represent corroborating evidence in support of a practice that many centres had already implemented based on promising preliminary data. Also, they provide new, high-level evidence to endorse TNT as a new management option in the treatment algorithm of stage II-III rectal cancer in those centres where CRT and SCRT have long remained the only accepted standard neoadjuvant treatments. Having two consistently positive trials is certainly reassuring regarding the potential of TNT as a general treatment approach. Nevertheless, substantial differences between these trials pose important challenges in relation to the generalisability and applicability of their results, and translation of the same into practical clinical recommendations. In this article, we address a number of key questions that the RAPIDO and PRODIGE 23 trials have raised among the broad community of gastrointestinal oncologists, proposing an interpretation of the data that may help the decision making, and highlighting grey areas that warrant further investigation.
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Neoplasias del Recto/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Quimioradioterapia/métodos , Ensayos Clínicos Fase III como Asunto , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Recto/patologíaRESUMEN
OBJECTIVE: Anaplastic lymphoma kinase (ALK) gene has been demonstrated to be rearranged, mutated or amplified in several haematological and solid tumors. Moreover, the use of ALK inhibitors has recently revolutionized the treatment of ALK-rearranged patients affected by non-small cell lung carcinoma. Herein we review the genetic alterations of ALK in melanocytic neoplasms described in literature, focusing on their potential diagnostic and predictive role. MATERIALS AND METHODS: The Authors reviewed the pertinent literature through research on PubMed server was performed typing the terms "ALK", "Anaplastic lymphoma kinase", "ALKATI", "Melanoma", "Spitz", "Spitzoid". RESULTS: ALK translocations were demonstrated in melanocytic neoplasms, particularly in acral melanoma and spitzoid tumors. ALKATI was described in primary and metastatic melanoma, indicating its early occurrence in oncogenesis, with varying immunohistochemical expression of the protein. CONCLUSIONS: The identification of the specific type of ALK mutations could be interesting for planning biologic therapy of melanoma patients. Further studies are needed to evaluate the possibility to introduce an ALK-targeted therapy in patients affected by malignant melanoma.
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Quinasa de Linfoma Anaplásico/genética , Melanoma/diagnóstico , Melanoma/enzimología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/enzimología , Quinasa de Linfoma Anaplásico/análisis , Quinasa de Linfoma Anaplásico/metabolismo , Humanos , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
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Antineoplásicos , Neoplasias Colorrectales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Mutación , Panitumumab/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. METHODS: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. RESULTS: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. CONCLUSIONS: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
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Anticuerpos Monoclonales/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Difenilamina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Clorhidrato de Erlotinib/administración & dosificación , Sulfonamidas/administración & dosificación , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Difenilamina/administración & dosificación , Difenilamina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Femenino , Células HCT116 , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sulfonamidas/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. MATERIALS AND METHODS: Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership. RESULTS: The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. CONCLUSION: In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued.
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Glicoproteínas de Membrana/aislamiento & purificación , Neoplasias/diagnóstico , Proteínas de Fusión Oncogénica/aislamiento & purificación , Receptor trkA/aislamiento & purificación , Receptor trkB/aislamiento & purificación , Receptor trkC/aislamiento & purificación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica/normas , Hibridación Fluorescente in Situ/normas , Oncología Médica/normas , Glicoproteínas de Membrana/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Medicina de Precisión/normas , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Investigación Biomédica Traslacional/normasRESUMEN
BACKGROUND: High neutrophil to lymphocyte ratio (NLR) has shown to be a predictor of poor outcomes in various malignancies, including pancreatic cancer. METHODS: We assessed 70 consecutive pts with histologically confirmed mPC who received chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic centers between January 2012 and November 2015. Variables assessed for prognostic correlations included age ≥ 66, sex, Karnofsky PS score, primary tumor site, baseline CA19.9 level ≥ 59xULN, 12-week decrease of the CA19.9 level ≥ 50% from baseline, basal bilirubin level, baseline NLR, biliary stent implantation, and liver metastasis. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by a Cox proportional hazard model. RESULTS: According to NLR values, the patients were divided into two groups: high and low. Low group patients showed a better median PFS (7 months versus 5 months) and median OS (13 months versus 7 months) in respect to high group patients. At multivariate analysis, Karnofsky PS < 80% (HR = 0.4; CI 0.2-1.2), liver metastases (HR = 0.4; CI 0.18-0.82), and NLR ≥ 5 (HR = 2.7; 95% CI 1.4-5.2) were predictors of poorer OS. Based on the presence of one or more independent prognostic factors, three risk categories were identified: good-risk, intermediate-risk and poor-risk. The median OS was 22, 10, and 7 months, respectively. CONCLUSIONS: Baseline NLR is an independent predictor of survival of patients with mPC receiving palliative chemotherapy and could be useful to develop a simple clinical score to identify a subgroup of patients with a low chance to benefit from chemotherapy.
RESUMEN
Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10â¯mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitorâ¯+â¯MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients' selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Terapia Neoadyuvante , Quimioterapia Adyuvante , HumanosRESUMEN
OBJECTIVE: The approval of the anti-PD1 antibody nivolumab has provided a significant therapeutic opportunity in the landscape of metastatic melanoma. In pivotal clinical trials, nivolumab improved clinical outcomes with a great safety profile. However, in real-world practice, the majority of the population with metastatic melanoma does meet one or more eligibility criteria of pivotal trials, since they have an ECOG-PS ≥ 2 or active/untreated known brain metastases. Waiting for larger real-wold studies that are currently lacking, but would be crucial to confirm the efficacy of nivolumab in challenging patients and to detect rare adverse events that could not be noticed in pivotal trials, this review collects both literature and unpublished case reports on nivolumab treatment in metastatic melanoma. PATIENTS AND METHODS: Case reports, published from 2016 to February 2018, and five, unpublished case reports, representative of Italian clinical practice, were reported and potential issues that physicians could face with the use of nivolumab in the real world were discussed. RESULTS: Among Italian cases, one patient had a huge retro-nuchal mass, which significantly decreased with few cycles of nivolumab; two patients were affected by cardiovascular comorbidities and one had brain metastasis; the last had a long history of disease, firstly diagnosed in 1997. A literature review was mainly focused on the experience in the management of rare immune adverse events related to treatment. CONCLUSIONS: Nivolumab confirmed its efficacy and safety in real-world; the decision-making process on starting and scheduling the treatment, even in the management of adverse events, should consider multiple factors related to both patient (i.e., BRAF status, ECOG PS, comorbidities) and disease (burden, metastasis).
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Background: Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. Patients and methods: In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. Results: A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. Conclusion: This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Biopsia Líquida/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab/administración & dosificación , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Mutación , Metástasis de la Neoplasia , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
BACKGROUND: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. PATIENTS AND METHODS: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. RESULTS: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. CONCLUSIONS: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Italia , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Resultado del TratamientoRESUMEN
BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75â years). RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65â years, 86 >70â years and 35 >75â years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65â years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65â years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75â years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75â years. CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75â years and grade ≥3 fatigue in patients <75â years. TRIAL REGISTRATION NUMBER: 2009-014041-81.
RESUMEN
BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib. METHODS: Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI. RESULTS: Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated. CONCLUSIONS: Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Genes ras , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Resultado del Tratamiento , Proteínas ras/genéticaRESUMEN
BACKGROUND: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. PATIENTS AND METHODS: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. RESULTS: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). CONCLUSIONS: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.