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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. [ABSTRACT FROM AUTHOR]

Objectives TAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer. Methods This was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35 mg/m 2 /dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled. Results Eighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9–1.8) versus 2.7 months (range 1.0–6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68–8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients. Conclusion TAS-102 showed no evidence of activity in second-line small cell lung cancer. [ABSTRACT FROM AUTHOR]

Precision medicine quite likely will be implemented at a different pace than originally hypothesized, but it is definitely the way to move forward. Even from a medical oncology perspective, a clear understanding of the changes in a molecular pathway and the timely application of a diagnostic assay are critical steps to ultimately deliver a better treatment choice to each individual patient with non–small cell lung cancer. See also pages 4800‐7. [ABSTRACT FROM AUTHOR]

Abstract: Advances in our understanding of tumour biology have encouraged reassessment of tumour classification by the site of origin in favour of molecular characteristics and/or oncogenic drivers amenable to treatment . The identification of EML4-anaplastic lymphoma kinase (ALK) as an oncogenic driver in non-small cell lung cancer (NSCLC) early in the clinical development of crizotinib and the observation of promising clinical responses in patients with NSCLC harbouring ALK translocations accelerated its clinical development in ALK-positive NSCLC. Phase I and II trials of crizotinib in patients with ALK-positive advanced NSCLC reported notably high response rates that tended to be rapid and of prolonged duration. Crizotinib was well tolerated; treatment-related adverse events were typically gastrointestinal (grade 1/2) and visual disorders (almost exclusively grade 1). Crizotinib provided NSCLC symptom relief and maintained quality of life. Based on the phase I and II trial data, the US Food and Drug Administration granted approval of crizotinib in August 2011. The consistency of the crizotinib data to date suggests accurate selection of the target population for crizotinib treatment. The ability to molecularly select patients likely to respond to an investigational agent argues that future clinical development of targeted agents should be re-evaluated. Updated trial designs incorporating molecular testing, early use of enrichment biomarkers and intermediary endpoints may accelerate and optimise clinical evaluation of targeted agents. Such trial designs should allow rapid clinical evaluation, minimise exposure of patients to therapies unlikely to be of benefit and, potentially, allow accelerated drug approval in molecularly specified populations. [Copyright &y& Elsevier]

Abstract: Introduction: In a first-line study of advanced NSCLC, pemetrexed–cisplatin was more effective among patients with adenocarcinoma and large-cell carcinoma compared with gemcitabine–cisplatin (median survival of 11.8 versus 10.4 months, P =.005), while survival with pemetrexed–cisplatin was shorter than with gemcitabine–cisplatin in patients with squamous cell carcinoma. The comparability of pemetrexed–cisplatin to other commonly used regimens within histology subgroups needs to be explored. Methods: This retrospective analysis combined the patient-level data from three phase 3 randomized controlled trials that compared the efficacy of different third generation platinum- and non-platinum based doublets. Unadjusted median survival times and Cox covariate-adjusted treatment hazard ratio (HR) estimates were calculated. Overall results and subgroups by histological type were reported. Results: This combined analysis consisted of 3467 patients. In the overall analysis, adjusted HRs favored pemetrexed (HR <1.0) to each of the other 5 regimens, though none of these HRs were statistically significant. Among patients with non-squamous histology, pemetrexed–cisplatin produced favorable HRs to each of the other regimens, achieving statistical significance when compared with vinorelbine–cisplatin (HR=0.67; 95% confidence intervals [CI]: 0.50, 0.91) and gemcitabine–cisplatin (HR=0.85; 95% CI: 0.75, 0.97). Among patients with squamous histology, 4 of the 5 comparison regimens produced favorable HRs (HR >1.0) when compared with pemetrexed–cisplatin, with only the comparison with gemcitabine–cisplatin achieving statistical significance (HR=1.23; 95% CI: 1.00, 1.51). Conclusion: In the absence of randomized clinical trial data comparing pemetrexed–cisplatin to commonly used doublets in advanced NSCLC other than gemcitabine–cisplatin, this combined analysis of multiple trials provides estimates for such comparisons. [Copyright &y& Elsevier]

Abstract: Background: This is a phase II randomized study to evaluate the efficacy and safety of bortezomib and pemetrexed alone or in combination, in patients with previously treated advanced non-small-cell lung cancer (NSCLC). The primary end point was assessment of response rate. Methods: A total of 155 patients were randomized (1:1:1) to pemetrexed (500mg/m2) on day 1 plus bortezomib (1.6mg/m2) on days 1 and 8 (Arm A) or pemetrexed (500mg/m2) on day 1 (Arm B) or bortezomib (1.6mg/m2) on days 1 and 8 (Arm C) of a 21 day cycle. Response rate was assessed by investigators using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and toxicity assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system. Results: Response rate was 7% in Arm A, 4% in Arm B, and 0% in Arm C; disease control rates were 73%, 62%, and 43%, respectively. Median overall survival was 8.6 months in Arm A, 12.7 months in Arm B, and 7.8 months in Arm C; time to progression was 4.0 months, 2.9 months, and 1.4 months, respectively. Most common reported adverse events ≥grade 3 were neutropenia (19%), thrombocytopenia (15%), and dyspnea (13%) in Arm A, neutropenia (10%) in Arm B, and dyspnea (13%) and fatigue (10%) in Arm C. Conclusion: In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity. [Copyright &y& Elsevier]

Abstract: Background: In a large phase III study, cisplatin and pemetrexed had non-inferior efficacy and better tolerability compared with cisplatin and gemcitabine in chemonaïve patients with non-small cell lung cancer (NSCLC). The current analysis characterised the clinical benefit (i.e. survival) relative to clinical risk (i.e. drug-related toxicity) of the doublets. Patients and methods: A total of 1669 patients (of 1725 randomised) received 500mg/m2 pemetrexed IV followed by 75mg/m2 cisplatin IV on day 1 or gemcitabine 1250mg/m2 on days 1 and 8 and 75mg/m2 cisplatin on day 1, administered every 3weeks for up to 6 cycles. Survival without toxicity (i.e. clinical benefit to risk) was defined as the time from randomisation to the first occurrence of any grade 3 or 4 drug-related toxicity or death, and was analysed using Kaplan–Meier and Cox methods. Results: In the overall patient population, survival without grade 3 or 4 drug-related toxicity was significantly longer for patients treated with cisplatin and pemetrexed versus cisplatin and gemcitabine (HR=0.70; P <0.001), as was survival without grade 4 drug-related toxicity (HR=0.83; P <0.001). For patients with non-squamous NSCLC, survival without toxicity with cisplatin and pemetrexed was superior to cisplatin and gemcitabine for grade 3 or 4 drug-related toxicity (HR=0.64; P <0.001) and for grade 4 drug-related toxicity (HR=0.77; P <0.001), whereas no treatment-arm difference was observed in the squamous subgroup. Conclusions: Patients with non-squamous NSCLC treated with front-line cisplatin and pemetrexed have superior survival without toxicity (i.e. clinical benefit-to-risk profile) compared with patients treated with cisplatin and gemcitabine. [Copyright &y& Elsevier]

Abstract: Proteasome inhibition is a novel therapeutic approach that is being investigated in non-small cell and small cell lung cancer (NSCLC and SCLC). Proteasome inhibition affects a range of intracellular signals and disrupts the levels of numerous proteins, causing apoptosis via multiple pathways. Importantly, malignant cells are more sensitive to proteasome inhibition than normal cells. A number of proteasome inhibitors have demonstrated activity in preclinical studies, both as single agents and in combination with conventional and novel antineoplastic agents. However, only bortezomib, a dipeptide boronic acid analog, has been investigated in lung cancer clinical trials, in which it has shown activity as a single agent and in combination regimens. Numerous preclinical and clinical studies are ongoing in both NSCLC and SCLC. Proteasome inhibition could potentially play a significant role in the future management of these conditions. [Copyright &y& Elsevier]

Abstract: The presence of bone metastases is indicative of disseminated disease and typically indicates a short-term prognosis in cancer patients. Palliation of symptoms is the primary goal of therapy, with multidisciplinary efforts yielding the best results. New classes of drugs, such as bisphosphonates that significantly increase the time to first skeletal-related event (SRE), represent useful tools for the treatment of bone metastases. While the optimal duration of therapy needs to be defined, there is clinical benefit derived from the use of this class of agents. A potential role for bisphosphonates in the prevention of bone metastases is under current evaluation in clinical trials encompassing different solid tumor types. In combination with ongoing clinical trials, basic research to identify potential novel targets in the tumor cells-bone microenvironment will further define future strategies in the treatment of bone metastases. [Copyright &y& Elsevier]

Summary: Purpose:: The incidence of bronchioloalveolar carcinoma (BAC) has risen steadily over the last decades along with the increasing frequency of adenocarcinomas. BAC is relatively resistant to commonly used chemotherapy regimens. A phase II study with single agent paclitaxel in patients with stages IIIB, IV or recurrent BAC was performed. Experimental design:: Patients with BAC with at least one target bidimensionally measurable lesion staged as unresectable stages IIIB, IV or recurrent disease, not previously irradiated; ECOG performance status 0–2; life expectancy greater than 3 months; age range between 18 and 75, received paclitaxel at a dose of 200mg/m2 i.v. as 3h continuous infusion on day 1 every 21 days. Treatment was continued until progression or up to a maximum of six cycles. Results:: Nineteen patients were eligible. Median number of cycles was 3 (range 0–6); 35% of patients received the planned six cycles of chemotherapy. One patient died of unrelated cause before the start of treatment. Both hematological and non-hematological toxicities were generally mild. Only one partial response (PR) was observed among the 18 eligible patients who started protocol treatment, with a response rate of 5.6% (95% CI: 0.1–27.3%). After an independent review, two PR were confirmed, for a response rate of 11.1% (95% CI: 1.4–34.7%); nine patients had stable disease (50.0%), three patients had progressive disease (11.1%) and four patients were not assessable (22.2%). Median survival was 8.6 months (95% CI: 5.8–14.5) and 1-year survival was 35.0% (95% CI: 14.1–55.8). Median progression free survival for all patients was 2.2 months (95% CI: 1.5–6.0). The study was terminated due to the low response rate. Conclusions:: Paclitaxel as single agent in stages IIIB–IV BAC was well tolerated and manageable but of limited efficacy. BAC should not be excluded from trials of new forms of chemotherapy. [Copyright &y& Elsevier]

Background: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established.Methods: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m2 on day 1), vindesine (3 mg/m2 on days 1 and 8), and cisplatin (100 mg/m2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided.Results: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P =.589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P =.128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival.Conclusion: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of ?-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low ?-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by ?-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between ?-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of ?-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.Oncogene (2003) 22, 3548-3553. doi:10.1038/sj.onc.1206419 [ABSTRACT FROM AUTHOR]

Surgery remains the mainstay of treatment for early non-small cell lung cancer (NSCLC) but more than 80% of recurrences occur within 2 years from radical surgery. The pattern of recurrence may differ by histology with more local recurrences seen for patients with squamous cell carcinoma and more distant metastases seen in patients with adenocarcinoma. A number of studies demonstrate that dissemination of cancer cells at levels much below those detected by any current available imaging techniques, including PET scanning also, affect prognosis of patients with clinical early-stage NSCLC. The current clinical evidence does not recommend adjuvant chemotherapy and/or radiotherapy in completely resected stage I–II–IIIA for N1. There are few randomised trials available for analysis of neo-adjuvant chemotherapy involving patients with resectable stage III disease; overall these trials suggest that induction chemotherapy (with or without radiation) improves survival, particularly in those patients who undergo significant downstaging. Heterogeneous study populations limit the ability to define the optimal patient population who would most benefit from this approach. There is no conclusive evidence that neo-adjuvant chemotherapy in early NSCLC is associated with an increased post surgical morbility and mortality. Additional trials are needed. More recently neo-adjuvant chemotherapy has been tested in resectable stage I–II NSCLC and proved to be feasible and better tolerated than adjuvant chemotherapy. Several randomised trials are currently ongoing. In the next future the role of targeted biological therapies as agents acting on minimal residual disease should be explored. [Copyright &y& Elsevier]

The gemcitabine/cisplatin combination is a key regimen in unresectable locally advanced and metastatic non-small-cell lung cancer (NSCLC), and, consequently, it is a logical step forward to investigate the activity of this new combination in less advanced stages of NSCLC. Efficacy data of several phase II studies performed in a mixed study population of stage IIIA and IIIB disease investigating gemcitabine/cisplatin as induction treatment indicate an average response rate >60%. The treatment is rather well tolerated and toxicity is especially mild when a 3-week schedule is used. More recently, five randomized studies, one already completed, have been designed to investigate the role of induction chemotherapy in early stage (I and II) NSCLC. In Italy, an ongoing randomized clinical trial called Chemotherapy for Early Stages Trial (ChEST) compares the efficacy of surgery alone or surgery plus induction gemcitabine/cisplatin in operable patients (T2-3N0, T1-2N1, T3N1) having progression-free survival as a primary end point. [Copyright &y& Elsevier]

The gemcitabine/cisplatin combination is a key regimen in unresectable locally advanced and metastatic non-small-cell lung cancer (NSCLC), and, consequently, it is a logical step forward to investigate the activity of this new combination in less advanced stages of NSCLC. Efficacy data of several phase II studies performed in a mixed study population of stage IIIA and IIIB disease investigating gemcitabine/cisplatin as induction treatment indicate an average response rate >60%. The treatment is rather well tolerated and toxicity is especially mild when a 3-week schedule is used. More recently, five randomized studies, one already completed, have been designed to investigate the role of induction chemotherapy in early stage (I and II) NSCLC. In Italy, an ongoing randomized clinical trial called Chemotherapy for Early Stages Trial (ChEST) compares the efficacy of surgery alone or surgery plus induction gemcitabine/cisplatin in operable patients (T2-3N0, T1-2N1, T3N1) having progression-free survival as a primary end point. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. Despite the introduction of immunotherapy, KRAS‐positive, advanced non–small cell lung cancer is still characterized by a poor prognosis. In this study, KRAS mutation subtypes did not influence survival. [ABSTRACT FROM AUTHOR]

Summary: The results of large randomised studies have clearly demonstrated that adjuvant chemotherapy prolongs overall survival by approximately 5% at 5 years in patients with early-stage non-small cell lung cancer (NSCLC). The benefit appears to be largely confined to patients with stage II/III disease, although approximately 25% of patients with stage I disease are at high risk of relapse within 5 years of surgery and therefore could benefit from adjuvant chemotherapy. There is an urgent need to predict more accurately which patients are likely to relapse after surgery and who, therefore, might benefit from further therapy. Preliminary studies indicate that molecular tumour markers may be able to identify tumours that are more likely to respond to chemotherapy and patients who are more likely to achieve improved survival from those who do not benefit at all from adjuvant chemotherapy. A pivotal study has shown that analysis of tumour gene expression can be used to predict the risk of relapse with greater accuracy than that which is achievable using clinical factors. In the future, pharmacogenomics may be used in this approach to identify patients for adjuvant chemotherapy, thus increasing the efficacy of treatment and reducing the burden of therapy in patients who are unlikely to benefit from further therapy. [Copyright &y& Elsevier]

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50–90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20–30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5–10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed. [Copyright &y& Elsevier]

Treatment with talazoparib resulted in an improvement or no change from baseline in patient-reported pain and health-related quality of life in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair alterations in the TALAPRO-1 trial. Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory—Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. In the 97 men in the PRO population treated with talazoparib (BRCA1/2 , n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (–1.08 [–1.52, –0.65]) and the BRCA1/2 subset (–1.15 [–1.67, –0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy (has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives. [ABSTRACT FROM AUTHOR]

Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [−0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients <50, 50–59, 60–69 and ≥ 70 years old, respectively; trend test: p = 0.02) and in patients who started AA within 9 months after starting the first-line therapy (0.88 [0.82; 0.99]) than in patients who started AA later (0.99 [0.91; 1.08]) (interaction: p = 0.03). Results were similar for PFS. AA increased the risk of hypertension (p < 0.0001), but not the risk of pulmonary thromboembolic events (p = 0.21). In the 2LT of advanced NSCLC, adding AA significantly prolongs OS and PFS, but the benefit is clinically limited, mainly observed in younger patients and after shorter time since the start of first-line therapy. • The addition of antiangiogenics (AA) in second line reduces 20% the risk of progression. • The addition of AA in second line reduces 7% the risk of death. • The benefit is higher in younger patients and in those with platinum-refractory tumours. • However, addition of AA significantly increased the risk of grade ≥3 toxicities. [ABSTRACT FROM AUTHOR]

Abstract: Background: EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy. Methods: Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1months (HR=0.78) and planned to randomise 598 patients to observe 514 deaths. Results: After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n =86) and placebo (n =87) arms were well balanced. After a median follow up of 41months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p =0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9months, HR=0.61, [95% CI 0.45, 0.83]), p =0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo). Conclusions: Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156). [ABSTRACT FROM AUTHOR]

Abstract: Background: EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy. Methods: Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1months (HR=0.78) and planned to randomise 598 patients to observe 514 deaths. Results: After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n =86) and placebo (n =87) arms were well balanced. After a median follow up of 41months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p =0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9months, HR=0.61, [95% CI 0.45, 0.83]), p =0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo). Conclusions: Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156). [Copyright &y& Elsevier]

Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions. This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments. NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair. We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat). Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality. • Germline pathogenic variants (PVs) are found in 7% of unselected patients with malignant pleural mesothelioma (MPM). • Carriers of these PVs are more sensitive to asbestos than non-mutated patients. • Most of these PVs occur in DNA repair genes that may be druggable. • Tazemetostat targets MPM spheroids defective for DNA repair master gene ataxia telangiectasia mutated (ATM). [ABSTRACT FROM AUTHOR]

It is partially unknown whether the immune response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection persists with time. To address this issue, we detected the presence of SARS-CoV-2 antibodies in different groups of individuals previously diagnosed with COVID-19 disease (group 1 and 2), or potentially exposed to SARS-CoV-2 infection (group 3 and 4), and in a representative group of individuals with limited environmental exposure to the virus due to lockdown restrictions (group 5). The primary outcome was specific anti-SARS-CoV-2 antibodies in the different groups assessed by qualitative and quantitative analysis at baseline, 3 and 6 months follow-up. The seroconversion rate at baseline test was 95% in group 1, 61% in group 2, 40% in group 3, 17% in group 4 and 3% in group 5. Multivariate logistic regression analysis revealed male gender, close COVID-19 contact and presence of COVID-19 related symptoms strongly associated with serological positivity. The percentage of positive individuals as assessed by the qualitative and quantitative tests was superimposable. At the quantitative test, the median level of SARS-CoV-2 antibody levels measured in positive cases retested at 6-months increased significantly from baseline. The study indicates that assessing antibody response to SARS-CoV-2 through qualitative and quantitative testing is a reliable disease surveillance tool. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity represents a well-known risk factor for renal cell carcinoma development. Several studies evaluated the relationship between obesity and outcome in patients with nonmetastatic and metastatic renal cell carcinoma using different parameters such as BMI, visceral fat area and s.c. fat area. These studies suggest that obesity is associated with a better prognosis in renal cell carcinoma patients. This phenomenon is called obesity paradox and it was found in other diseases in which obesity rep resents an established risk factor such as heart failure, diabetes, atrial fibrillation, hypertension and coronary heart disease. The purpose of this review is to analyze the mec hanisms by which obesity increases the risk of renal cell carcinoma development, to describe the evidence available to date about the link obesity-outcome and to evaluate the mech anisms to explain this apparently paradoxical relationship. [ABSTRACT FROM AUTHOR]

• In NSCLC, immunotherapy with checkpoint inhibitors has proven successful. • To extend clinical benefit, many immunotherapy-based combinations were developed. • Blockade of CTLA-4 and PD-1 targets complementary pathways in T cell activation. • Checkmate 227 trial reported OS benefit with front-line nivolumab and ipilimumab. • Many issues related to patient selection and sequencing remain unaddressed. Immunotherapy-based options for patients with advanced non-small cell lung cancer (NSCLC) are increasing at an unprecedented pace, carrying the promise to prolong survival of this deadly disease. To maximize responses and extend benefit to a larger portion of patients, immunotherapy combination strategies are currently under investigation, with chemo-immunotherapy already in use. Combinations of programmed death-1/ligand-1 (PD-1/L1) and cytotoxic T lymphocytes antigen-4 (CTLA-4) were developed with the rationale of targeting complementary pathways involved in T cell activation, and already showed to be highly active in other malignancies. Recently, the phase III Checkmate 227 trial showed that combination of nivolumab and ipilimumab provided survival benefit in untreated advanced NSCLC patients. However, accurate patients' selection and appropriate sequencing of different immunotherapy-based approaches remain unsolved. In this review, we provide an overview of the currently available evidence on double immune checkpoint inhibition (ICI) for NSCLC treatment and discuss current issues and future perspectives. [ABSTRACT FROM AUTHOR]

The article present a case study of a 63-year-old White female with chronic diarrhea, hematochezia, and abdominal pain. It mentions a total-body computed tomography (CT) scan revealed bilateral pleural effusion, enlarged mediastinal lymph nodes, ascites, lytic lesion of the lumbar vertebra, multiple liver metastases, and a lesion of the duodenum/pancreas uncinate process; and also mentions a chest CT scan revealed abundant bilateral pleural/pericardial effusion and slightly enlarged heart.

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. [ABSTRACT FROM AUTHOR]

• QoL assessment is crucial for a complete evaluation of anticancer treatments. • We described QoL adoption and reporting in randomized phase III lung cancer trials. • QoL is not assessed in a high proportion of trials, even in metastatic setting. • Timely inclusion of QoL results in primary publications is worsening in last years. • QoL is a tool for the selection of the most tailored therapy for every patient. We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012–2015 vs. 30.6% in 2016–2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012–2015 vs. 61.8% 2016–2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012–2015 vs. 2016–2018. QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Neoantigens, which are expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. Cancer immunotherapies to target neoantigens are of growing interest and are in early human trials, but methods to identify neoantigens either require invasive or difficult-to-obtain clinical specimens, require the screening of hundreds to thousands of synthetic peptides or tandem minigenes, or are only relevant to specific human leukocyte antigen (HLA) alleles. We apply deep learning to a large (N = 74 patients) HLA peptide and genomic dataset from various human tumors to create a computational model of antigen presentation for neoantigen prediction. We show that our model, named EDGE, increases the positive predictive value of HLA antigen prediction by up to ninefold. We apply EDGE to enable identification of neoantigens and neoantigen-reactive T cells using routine clinical specimens and small numbers of synthetic peptides for most common HLA alleles. EDGE could enable an improved ability to develop neoantigen-targeted immunotherapies for cancer patients. [ABSTRACT FROM AUTHOR]

The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post- and predocetaxel setting, due to the significant improvement in overall survival. More recently, enzalutamide also showed impressive results in the treatment of men with nonmetastatic CRPC. Unfortunately, not all patients with CRPC are responsive to enzalutamide, and even in responders, benefits are limited by the development of drug resistance. Adaptive resistance of metastatic prostate cancer to enzalutamide treatment can be due to the activation of both androgen receptor (AR)-dependent pathways (expression of constitutively active AR splice variants, AR point mutations, gene amplification and overexpression) and mechanisms independent of AR signaling pathway (altered steroidogenesis, upregulation of the glucocorticoid receptor, epithelial–mesenchymal transition, neuroendocrine transformation, autophagy and activation of the immune system). In this review, we focus on resistance mechanisms to enzalutamide, exploring how we could overcome them through novel therapeutic options. [ABSTRACT FROM AUTHOR]

Objectives Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress. Materials and methods We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test. Results We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients’ survival after chemotherapy. Overexpression of LIP restored cisplatin’s pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8 + CD107 + T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients’ samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models. Conclusion The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8C T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8C and CD4C T-lymphocytes co-cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8C T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune-environment. [ABSTRACT FROM AUTHOR]

The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities. The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of “any-grade” and “severe” toxicity for haematological and non-haematological adverse events of each group. We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy. This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity. [ABSTRACT FROM AUTHOR]

Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castrationresistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on newgeneration hormonal therapies. Several in vitro studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined. [ABSTRACT FROM AUTHOR]

Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of TOP2A and TS mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II-III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). TOP2A and TS expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors (P = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively (P = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials. Simultaneously other therapeutic strategies which recruit an adaptive immune response against tumoral antigens or employ externally manipulated tumor infiltrating lymphocytes might change the natural history of bladder cancer in the near future. This review describes the rationale for the use of immunotherapy in bladder cancer and discusses recent and ongoing clinical trials with checkpoint inhibitors and other novel immunotherapy agents. [ABSTRACT FROM AUTHOR]

Objectives Non-small-cell-lung-cancer (NSCLC) in young adults (≤45 years-old) accounts for a very small proportion, as this disease usually occurs in people at older age. The youthful NSCLC may constitute an entity with different clinical-pathologic characteristics, having predominance of adenocarcinoma histology and affecting mostly non-smoker subjects. However, without specific guidelines, it is currently considered, both clinically and biologically, as the same disease of the older counterpart, although differences have been documented. Materials and methods Using formalin-fixed paraffin embedded diagnostic tissues (FFPE), targeted next-generation sequencing (NGS) technology allowed to provide insight the mutational pattern of 46 oncogenes and tumor-suppressor genes in 26 young patients (Y). Two additional populations, including a FFPE series of aged counterpart (A: 29 patients) and a group of healthy young controls (C: 21, blood provided), were also investigated to compare NGS profiles. Results Clinical features of enrolled young patients harmonized with literature data, being most of patients women (58%), never-smokers (38%) and with adenocarcinoma histology (96%). C group was adopted to filter all the non-synonymous genetic variations (NS-GVs) not-associated with malignant overt disease. This skimmed selection mostly highlighted three genes: TP53, EGFR and KRAS. TP53 NS-GVs were numerically more numerous in younger, many involving specific annotated hotspot (R248, R273, G245, R249 and R282); the majority of EGFR NS-GVs was detected in young patients, with higher allelic frequency and mostly represented by exon 19 deletions. On the contrary, KRAS NS-GVs were mainly detected in aged population, with a prevalent compact pattern involving p.G12 position and associated with adenocarcinoma histology. Conclusion This retrospective study confirmed the feasibility of NGS approach for genetic characterization of NSCLC young adult patients, supporting the involvement of TP53, EGFR, and KRAS alterations in the early onset of NSCLC. Some of these GVs, or their pattern, may potentially contribute to customized targeted therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings. Methods Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed phase III studies were included in a meta-analysis using a random-effects model. Studies included were: JMEI (second-line pemetrexed, N = 399); JMDB (first-line pemetrexed/cisplatin, N = 1252); JMEN (pemetrexed maintenance after non-pemetrexed/platinum doublet, N = 481); and PARAMOUNT (pemetrexed maintenance after first-line pemetrexed/cisplatin, N = 539). Patients were predominantly Eastern Cooperative Oncology Group performance status (PS) 0/1. The ratio of OS hazard ratio (HR) (pemetrexed versus control) for younger patients over that for older patients within each study was used as the measure of the differential effect of pemetrexed. Data were examined using age cutoffs of 65 and 70 years. Results Among the four studies, 32% of patients were aged ≥65 years and 14% were aged ≥70 years. The test of heterogeneity among studies was non-significant for subgroups defined by age 65 ( P = 0.083) and age 70 ( P = 0.848). The pooled ratio of the OS HR (pemetrexed versus control) in patients <65 years to that in patients ≥65 years was 0.92 (95% confidence intervals [CI] 0.67–1.25). Similar results were seen for the analysis using the age 70 years cut-off (0.80 [95% CI 0.62–1.04]). Conclusions In patients with non-squamous NSCLC with good PS, the effect of pemetrexed on OS was not found to be different in younger and older patients undergoing treatment in the first-line, second-line, or maintenance settings. [ABSTRACT FROM AUTHOR]

The identification of actionable targets in oncogene-addicted non-small cell lung cancer (NSCLC) has fueled biomarker-directed strategies, especially in advanced stage disease. Despite the undeniable success of molecular targeted therapies, duration of clinical response is relatively short-lived. While extraordinary efforts have defined the complexity of tumor architecture and clonal evolution at the genetic level, not equal interest has been given to the dynamic mechanisms of phenotypic adaptation engaged by cancer during treatment. At the clinical level, molecular targeted therapy of EGFR -mutant and ALK -rearranged tumors often results in epithelial-to-mesenchymal transition (EMT) and histological transformation of the original adenocarcinoma without the acquisition of additional genetic lesions, thus limiting subsequent therapeutic options and patient outcome. Here we provide an overview of the current understanding of the genetic and non-genetic molecular circuits governing this phenomenon, presenting current strategies and potentially innovative therapeutic approaches to interfere with lung cancer cell plasticity. [Display omitted] • Cancer cell plasticity poses a formidable challenge to tumor eradication in oncogene-addicted NSCLC. • EMT, NE and SCC transformation are common non-genetic mechanisms of drug resistance observed in patients. • Preclinical and translational studies are necessary to identify vulnerabilities linked to phenotypic plasticity. • Innovative strategies targeting phenotypic adaptation are required to improve patient outcome. [ABSTRACT FROM AUTHOR]