Does HIV adversely influence the outcome in advanced non-small-cell lung cancer in the era of HAART?
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ABSTRACT:
SUBMITTER: Powles T
PROVIDER: S-EPMC2394391 | biostudies-other | 2003 Aug
REPOSITORIES: biostudies-other
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Project description:Over the past decade, patients with advanced non-small-cell lung cancer (NSCLC) have witnessed substantial advances in regards to therapeutic alternatives. Among newly developed agents, angiogenesis inhibitors were extensively tested in different settings and have produced some favorable outcomes despite several shortcomings. Bevacizumab is the most examined agent in this context and has demonstrated significant survival benefits when combined with standard chemotherapy in eligible patients. Preliminary results on the addition of bevacizumab to erlotinib in patients with EGFR-mutated NSCLC seem promising. Other antiangiogenic agents were also tested, but ramucirumab and nintedanib are the only agents with a positive impact on survival. More recently, immune checkpoint inhibitors (ICIs) have had considerable success due to their prolonged durations of response, yet response rates are still deemed suboptimal, and various combination therapies are being tested in an effort to improve efficacy. Preclinical evidence suggests an immunosuppressive effect of pro-angiogenic factors, which sets up a plausible rationale for combining ICIs and antiangiogenic agents. Herein, we review the landmark data supporting the success of angiogenesis inhibitors, and we discuss the potential for combination with immunotherapy and targeted agents.
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Project description:There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.
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Project description:Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection has been widely available in industrialized countries since 1996; its widespread use determined a dramatic decline in acquired immunodeficiency syndrome (AIDS)-related mortality, and consequently, a significant decrease of AIDS-defining cancers. However the increased mean age of HIV-infected patients, prolonged exposure to environmental and lifestyle cancer risk factors, and coinfection with oncogenic viruses contributed to the emergence of other malignancies that are considered non-AIDS-defining cancers (NADCs) as a relevant fraction of morbidity and mortality among HIV-infected people twenty years after HAART introduction. The role of immunosuppression in the pathogenesis of NADCs is not well defined, and future researches should investigate the etiology of NADCs. In the last years there is a growing evidence that intensive chemotherapy regimens and radiotherapy could be safely administrated to HIV-positive patients while continuing HAART. This requires a multidisciplinary approach and a close co-operation of oncologists and HIV-physicians in order to best manage compliance of patients to treatment and to face drug-related side effects. Here we review the main epidemiological features, risk factors and clinical behavior of the more common NADCs, such as lung cancer, hepatocellular carcinoma, colorectal cancer and anal cancer, Hodgkin's lymphoma and some cutaneous malignancies, focusing also on the current therapeutic approaches and preventive screening strategies.
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Project description:BackgroundThe efficacy of preemptive therapy against cytomegalovirus (CMV) infection remains unknown in treatment-naïve patients with advanced HIV-1 infection in the HAART era.MethodsThe subjects of this single-center observation study were 126 treatment-naïve HIV-1 infected patients with positive CMV viremia between January 1, 2000 and December 31, 2006. Inclusion criteria were age more than 17 years, CD4 count less than 100/?l, plasma CMV DNA positive, never having received antiretroviral therapy (ART) and no CMV end-organ disease (EOD) at first visit. The incidence of CMV-EOD was compared in patients with and without preemptive therapy against CMV-EOD. The effects of the CMV preemptive therapy were estimated in uni- and multivariate Cox hazards models.ResultsCMV-EOD was diagnosed in 30 of the 96 patients of the non-preemptive therapy group (31%, 230.3 per 1000 person-years), compared with 3 of the 30 patients of the preemptive therapy group (10%, 60.9 per 1000 person-years). Univariate (HR?=?0.286; 95%CI, 0.087-0.939; p?=?0.039) and multivariate (adjusted HR?=?0.170; 95%CI, 0.049-0.602; p?=?0.005) analyses confirmed that CMV-EOD is significantly prevented by CMV preemptive therapy. Multivariate analysis showed that plasma CMV DNA level correlated significantly with CMV-EOD (per log10/ml, adjusted HR?=?1.941; 95%CI, 1.266-2.975; p?=?0.002). Among the 30 patients on preemptive therapy, 7 (23.3%) developed grade 3-4 leukopenia. The mortality rate was not significantly different between the two groups (p?=?0.193, Log-rank test).ConclusionsThe results indicate that preemptive therapy lowers the incidence of CMV-EOD by almost 25%. Preemptive therapy for treatment-naïve patients with CMV viremia is effective, although monitoring of potential treatment-related side effects is required.
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Project description:ObjectiveHIV-infected people have greatly elevated risk of non-Hodgkin lymphoma (NHL), particularly the AIDS-defining NHL subtypes: diffuse large B-cell lymphoma, Burkitt lymphoma and primary lymphomas arising in the central nervous system. The goals of this analysis were to comprehensively describe risks of NHL subtypes, especially those not well studied, among HIV/AIDS patients; examine risks specifically in the HAART era; and distinguish risks in HIV-infected individuals prior to diagnosis with AIDS.DesignPopulation-based registry linkage study.MethodsWe used data from the US HIV/AIDS Cancer Match Study from 1996 to 2010 (N = 273 705) to calculate standardized incidence ratios (SIRs) comparing subtype-specific NHL risks in HIV-infected people to those in the general population, and used Poisson regression to test for differences in SIRs between the HIV-only and AIDS periods.ResultsNHL risk was elevated 11-fold compared to the general population, but varied substantially by subtype. AIDS-defining NHL subtypes comprised the majority, and risks were high (SIRs ≥17), but risks were also increased for some T-cell lymphomas (SIRs = 3.6-14.2), marginal zone lymphoma (SIR = 2.4), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR = 3.6), and acute lymphoblastic leukemia/lymphoma (SIR = 2.4).ConclusionHIV-infected people in the HAART era continue to have elevated risk of AIDS-defining NHL subtypes, highlighting the contribution of moderate and severe immunosuppression to their cause. Whereas non-AIDS-defining subtypes are much less common, immunosuppression or other dysregulated immune states likely play a role in the cause of some T-cell lymphomas, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, and acute lymphoblastic leukemia/lymphoma.
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Project description:ObjectivePolymorphisms in XPG were considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We investigated the impact of several potential SNPs of XPG on the efficacy of platinum-based chemotherapy in NSCLC patients.MethodsA total of 433 patients were consecutively selected between Nov. 2006 and Dec. 2007, and were followed-up up to Nov. 2011. The genotyping of six SNPs (rs2296147, rs751402, rs873601, rs4150375, rs17655 and rs2094258) were genotyped using the Taqman real-time PCR method with a 7900 HT sequence detector system.ResultsPatients carrying CT+TT genotype of rs2296147 had a significantly longer median PFS (17.5 months) and OS (26.8 months) than CC genotype. Hazard ratio (HR) for PFS and OS in patients with CT+TT genotype of rs2296147 was respectively 0.73(0.51-0.97) and 0.66(0.48-0.99) when compare CC genotype, respectively. Similarly, patients with rs2094258 AG+GG genotype had a longer median progression time (18.4 months) and overall survival time (27.3 months) when compared with those with AA genotype, and HRs(95% CI) for PFS and OS were 0.44(0.34-0.78) and 0.51(0.39-0.82), respectively.ConclusionsOur study suggests rs2296147 CT+TT and rs2094258 AG+GG genotypes contribute to the better survival of NSCLC. Our study provides significant information on role of prognostic value of XPG SNPs, and detecting of XPG could be used as predictive markers toward individualizing NSCLC treatment strategies.
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Project description:Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 ug/mL, 22.3 ug/mL and 27.1 ug/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7ug/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment.
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Project description:BACKGROUND:BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. METHODS:We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. RESULTS:The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p?=?0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p?=?0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p?=?0.03) and of death (p?=?0.004). CONCLUSIONS:These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.
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Project description:AIM:To evaluate the potential prognostic value of GNAS1 T393C polymorphism in advanced non-small cell lung cancer. METHODS:We extracted genomic DNA from the peripheral blood leucocytes of 94 patients with advanced non-small cell lung cancer. Quantitative real-time polymerase chain reaction was used to determine the allelic discrimination. The correlation between genotype and overall survival was evaluated using the multivariate analysis and Kaplan-Meier approach. RESULTS:Thirty-eight out of 94 (40%) patients displayed a TT genotype, 29 out of 94 (31%) a CT genotype and 27 out of 94 (29%) a CC genotype. The median survival of TT (25 mo) genotype carriers was longer than CT (12 mo) or CC (8 mo) genotype carriers. The favorable TT genotype predicted better overall survival (OS) (2-year OS: 48%; P =0.01) compared with CT (2-year OS: 18%) or CC (2-year OS: 15%) genotype. However, dichotomization between C-genotypes (CC + CT) and T-genotypes (TT) revealed signi?cantly lower survival rates (2-year OS: 16%; P = 0.01) for C allele carriers. CONCLUSION:Our data provided strong evidence that the GNAS1 T393C genetic polymorphism in?uenced the prognosis in advanced non-small lung cancer with a worse outcome for C allele carriers.
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Project description:BackgroundHER2 mutation is found in 1%-2% of lung cancer patients. Studies comparing chemotherapy to HER2-TKIs are limited. This study aimed to investigate the molecular and clinical patterns of HER2 mutations in advanced non-small cell lung cancer (NSCLC), and compare the different outcomes between chemotherapy and HER2-TKIs.MethodsAdvanced or recurrent non-small cell lung cancer patients with de novo HER2 mutations (N = 75) were included in this study. Molecular information, clinical features, and treatment outcomes were retrospectively collected from a web-based patient registry and hospital chart review.ResultsBetween October 2012 and December 2018, 65 patients with in-frame insertion mutations, eight with point mutations and two with gene amplification were found. The most common subtypes of insertion mutations were A775_G776insYVMA, G776delinsVC, and V777_G778insGSP. HER2 mutated patients were mostly young-aged, females, never or light smokers, with adenocarcinoma. Chemotherapy achieved better outcomes than HER2-TKIs (median PFS: 5.5 vs. 3.7 months in the first-line setting and 4.2 vs. 2.0 months in the second-line setting, P = 0.001 and 0.031, respectively). In particular for the most common subtype, YVMA insertions, PFS was significantly longer in chemotherapy than HER2-TKIs both in the first-line (6.0 vs. 2.6 months, P = 0.008) and the second-line (4.2 vs. 2.6 months P < 0.001).ConclusionsHER2 mutated lung cancer patients were younger, mostly females, never or light smokers, with histologically diagnosed adenocarcinomas. Compared with afatinib, chemotherapy might bring more benefit to HER2 mutated advanced lung cancer patients, especially the most common type of HER2 exon 20 insertions, A775_G776insYVMA subtype.Key pointsChemotherapy achieved better outcomes than afatinib for Chinese HER2 mutated advanced NSCLC patients, especially for the most common subtype, YVMA insertions.
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