Real-world retrospective study of KRAS mutations in advanced non-small cell lung cancer in the era of immunotherapy.

BACKGROUND: KRAS mutation-positive (KRAS-positive), advanced nonsmall-cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real-world data by mutation subtype in the era of immunotherapy are still incomplete. METHODS: The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS-positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first-line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co-mutations. RESULTS: From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS-positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5-12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first-line treatment, the median OS was 12.2 months (95% CI, 8.3-16.1 months), and the median progression-free survival was 5.6 months (95% CI, 4.5-6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression-free survival and OS. CONCLUSIONS: KRAS-positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype. PLAIN LANGUAGE SUMMARY: This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses.

BACKGROUND: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib. PATIENTS AND METHODS: Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs. RESULTS: In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]). CONCLUSION: Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC. CLINICALTRIALS.GOV IDENTIFIER: NCT03148795.

Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. METHODS: In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. FINDINGS: Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. INTERPRETATION: Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. FUNDING: Pfizer/Medivation.

Telomerase-based GX301 cancer vaccine in patients with metastatic castration-resistant prostate cancer: a randomized phase II trial.

Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccination schedules may exhaust reactive lymphocytes. GX301 is a telomerase-based cancer vaccine whose safety and immunological effects were tested in a phase I trial applying an eight administrations schedule. Main objective of this study was to comparatively analyse safety and immunological response to three GX301 regimens in metastatic castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. This was a multicentre, randomized, parallel-group, open-label trial registered with EudraCT (2014-000095-26) and ClinicalTrials.gov (NCT02293707, 2014). Ninety-eight patients were randomized to receive either eight (regimen 1), four (regimen 2) or two (regimen 3) vaccine administrations. Sixty-three patients were assessable for the primary immunological end-point. Vaccine-specific immune responses were evaluated by intracellular staining for IFN, elispot and cytotoxic assay at 90 and 180 days from baseline. No major side effects were recorded. A 54% overall immune responder rate was observed with 95% of patients showing at least one vaccine-specific immune response. Rate of immunological responders and number of immunizations were proportionally related, suggesting superiority of regimens 1 and 2 over regimen 3. Overall survival did not differ among regimens in both immunological responders and non-responders and was inversely associated (P = 0.002) with increase in the number of circulating CD8 + T regulatory cells at 180 days. These data indicate that GX301 cancer vaccine is safe and immunogenic in metastatic castration-resistant prostate cancer patients. Schedules with high number of administrations should be preferred in future studies due to their better immunological outcome.

The evolving paradigm of precision medicine in lung cancer.

PURPOSE OF REVIEW: In this review, we report a complete and updated summary of the most recent treatment advances in the fields of oncogene-addicted disease and provide expert perspectives on the evolving paradigm of precision medicine in lung cancer patients. RECENT FINDINGS: The advent of innovative genome sequencing technologies is rapidly increasing the number of targetable molecular alterations in advanced nonsmall cell lung cancer (NSCLC), leading to the introduction of novel selective inhibitors into the clinical arena, showing unprecedent tumor responses against rare and elusive NSCLC targets. The results of the ADAURA trial suggested that targeting EGFR pathway in the adjuvant setting is a feasible and effective strategy. The routine use of next-generation sequencing (NGS) is currently recommended as new standard approach to profile advanced NSCLC samples while recent findings suggest the potential application of a plasma-based first approach for tumor genotyping. Innovative umbrella trials provide the right infrastructure to investigate the role of precision medicine in advanced NSCLC, but failed to show clinical benefit. SUMMARY: Implementing NGS-based molecular screening, increasing patients' access to biomarker driven-clinical trials, ensuring equal access to molecular testing and innovative treatments, overcoming disparities and preserve health systems' financial sustainability represents the main challenges of precision medicine worldwide.

Wnt/IL-1ß/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3ß/ß-catenin/c-myc axis that also increased IL-8 and IL-1ß production. IL-8 and IL-1ß-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1ß secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3ß/ß-catenin and IL-8/IL-1ß signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.

Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features.

BACKGROUND: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. OBJECTIVE: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. METHODS: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. RESULTS: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. CONCLUSIONS: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.

What does the future hold for the Lung Cancer Ambition Alliance project: an interview with Giorgio Scagliotti.

Bio Dr Scagliotti is currently Professor of Oncology at the University of Torino, Italy. Dr Scagliotti earned his medical degree and completed the postgraduate training in respiratory medicine, internal medicine and medical oncology at the University of Torino. He is currently chief of the Medical Oncology Division at the S. Luigi Hospital, Orbassano (Torino), former Head of the Department of Oncology at University of Torino. Dr. Scagliotti is a member of several scientific societies, including the Italian Society of Respiratory Medicine, the European Respiratory Society, the American Society of Clinical Oncology and the International Association for the Study of Lung Cancer (IASLC). From 2003-07 Executive Board Member of the IASLC. He has been Associate Editor for Journal of Thoracic Oncology and currently International Editor for Clinical Lung Cancer. He is the author or co-author of more than 360 publications in peer-reviewed journals and he is the International Editor of the 4th Edition of "Lung Cancer : Principles and practice" and co-editor of the IASLC textbook of multidisciplinary approach to thoracic Oncology.

Long-term disease control in a metastatic squamous cell carcinoma of the oral cavity treated with maintenance metronomic capecitabine.

Recurrent or metastatic disease occurs in two-thirds of head and neck squamous cell carcinomas and it is associated with poor prognosis. Systemic treatment with platinum-based chemotherapy in combination with the epidermal growth factor receptor-targeting monoclonal antibody cetuximab represents a preferred option for these patients. Upon the achievement of tumor response by combined treatment, maintenance with single-agent cetuximab is usually administered with the aim of prolonging disease control at the price of reasonable toxicity. Although rarely, however, cetuximab needs to be discontinued in the absence of disease progression because of intolerable side effects. Here we describe the case of a 66-year-old man with a metastatic cancer of oral cavity, who had to discontinue maintenance cetuximab and who achieved prolonged disease control with metronomic capecitabine. We suggest that capecitabine could be an effective and safe maintenance option in case of cetuximab intolerance.

Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS: Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P). RESULTS: Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm (p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION: In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE: This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial.

BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

Long-term disease control and high clinical benefit in a patient with advanced thyroid cancer treated with lenvatinib.

We report a case of a 37-year-old man with metastatic differentiated thyroid carcinoma, previously submitted to total thyroidectomy, radio-iodine therapy and lung metastasectomy, who underwent systemic treatment with lenvatinib for tumor recurrence in the lung, mediastinal lymph nodes, left gluteus and left orbit. Lenvatinib induced rapid and durable disease regression; the drug effect has continued after >1 year, as well as a very considerable clinical benefit. The results achieved by lenvatinib in treatment of metastatic differentiated thyroid carcinoma are clear and irrefutable. Real-life data, obtained by case reports and retrospective studies, are equally important to increase the knowledge about this drug and improve the clinical management.

Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes.

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

Lung cancer: current therapies and new targeted treatments.

Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the disease. 5-year survival rates vary from 4-17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg-patients with poor performance status and elderly patients-are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.

Detailed genomic characterization identifies high heterogeneity and histotype-specific genomic profiles in adrenocortical carcinomas.

Molecular characterization of adrenocortical carcinoma has been recently established, but the correlation between molecular profiles and clinical and pathological characteristics is still poorly defined with no data available about genetic heterogeneity along disease progression. In this scenario, a detailed molecular profile was correlated with clinical and pathological characteristics in adrenocortical carcinoma patients to identify potentially novel biomarkers. Targeted next-generation sequencing and copy number variation analyses for 18 most frequently altered genes in adrenocortical carcinoma were assessed on 62 adult cases (including 10 with matched primary and metastatic/recurrence samples) and results correlated with major clinical and pathological characteristics of tumors. A total of 433 somatic deleterious genetic alterations (328 gene mutations and 105 copy number variations) were identified in 57/62 cases, five resulted wild type for all genes tested. TERT, CDK4, ZNRF3,and RB1 were altered in more than 30% of cases. Among histological variants genotypes were significantly different. Lowest mutation burden was found in the oncocytic type (p = 0.006), whereas the highest with a prevalence of RB1 (p = 0.001) and CDK4 (p = 0.002) was found in the conventional and myxoid ones, respectively. None of the 10 cases with matched samples showed a stable genotype along tumor progression, although allelic frequencies or percentages of altered nuclei at fluorescence in situ hybridization were in most cases similar among different tumor samples for genes that were stable along tumor progression. Among individual genes, an altered p53/Rb1 pathway was the strongest adverse molecular signature, being associated with high Ki-67 index, high tumor stage, aggressive disease status, and shorter disease-free survival. The genomic signature in adrenocortical carcinoma is changing along tumor progression and is associated with specific clinical and pathological features, including histological variant and prognosis.

FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report.

BACKGROUND: Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient. CASE PRESENTATION: We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases. CONCLUSIONS: This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

Thymidine phosphorylase: the unforeseen driver in colorectal cancer treatment?

5-Fluorouracil- and leucovorin-based chemotherapy regimens are the backbone of colorectal cancer treatment. The addition of oxaliplatin, irinotecan and monoclonal antibodies to this backbone has largely improved clinical outcomes, but has also led to new questions, with conflicting data frequently reported in studies. Thymidine phosphorylase (TP) is a nucleoside-metabolizing enzyme involved in 5-fluorouracil pharmacokinetics, as well as inflammatory responses, neoangiogenesis and apoptosis. TP expression is regulated by hypoxia, inflammatory cytokines and antitumoral agents. We hypothesize that TP could be the unforeseen driver in the conflicting data observed with different regimens commonly used in colorectal cancer treatment. Greater comprehension of the role of this enzyme in tumor progression and pyrimidine metabolism may lead to more accurate, patient-tailored therapy.

MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression.

BACKGROUND: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. PATIENTS AND METHODS: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. RESULTS: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. CONCLUSION: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. FINDINGS: Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. INTERPRETATION: These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. FUNDING: Novartis Pharmaceuticals Corporation.

Prognostic impact of pretreatment neutrophil-to-lymphocyte ratio in castration-resistant prostate cancer patients treated with first-line docetaxel.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, has been associated with poor outcome in several solid tumors, including prostate cancer. We retrospectively investigated the prognostic role of pretreatment NLR in metastatic castration-resistant prostate cancer (mCRPC) patients treated with first-line docetaxel. METHODS: All CRPC patients treated with first-line docetaxel at two Italian institutions, with available data about baseline neutrophil and lymphocyte values, were included in this retrospective analysis. Patients were divided in two groups according to NLR ratio (low NLR: ≤3; high NLR: >3). Outcome measures were progression-free (PFS) and overall survival (OS), measured from the start of docetaxel treatment. Univariate and multivariate analysis (adjusting for baseline prostate-specific antigen, alkaline phosphatase, lactate dehydrogenase, hemoglobin, albumin, performance status, use of opioids and presence of visceral disease) were performed. RESULTS: One hundred and seventy-nine patients treated between 2004 and 2016 were analyzed and 110 had information about pretreatment NLR. Forty-six patients (42%) had low NLR and 64 (58%) had high NLR. Median PFS was 8.8 months in patients with low NLR versus 7.3 months in those with high NLR [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.75-1.69, p = .58]. Median OS was 34.9 months in patients with low NLR versus 20.2 months in those with high NLR (HR 1.85, 95% CI 1.07-3.19, p = .02). At multivariate analysis, NLR confirmed an independent impact on OS (HR 3.16, 95% CI 1.50-6.65, p = .002). CONCLUSION: In this retrospective series, metastatic CRPC patients who started first-line docetaxel with a low pretreatment NLR had a significantly better survival. In addition to known prognostic factors, NLR can be useful to improve prognostic evaluation of patients in this setting.