JNCI Journal of the National Cancer Institute最新文献

Background: Cisplatin, gemcitabine, and durvalumab combination is a standard first-line treatment for advanced biliary tract cancer. This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced biliary tract cancer treated with cisplatin, gemcitabine, and durvalumab in real-world clinical practice.

Methods: Patients with unresectable, locally advanced, or metastatic biliary tract cancer treated with cisplatin and gemcitabine plus durvalumab across 39 centers in 11 countries in Europe, the United States, and Asia were included in this analysis.

Results: The cohort included 513 patients with advanced biliary tract cancer. The 5 most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (hazard ratio [HR] = 0.49, P = .018) and overall survival (HR = 0.11, P = .023), while TP53 mutations were linked to worse PFS (HR = 1.62, P = .0047) and TERT mutations to worse overall survival (HR = 8.92, P = .0012). No other genomic alterations were statistically associated with outcomes. Subgroup analysis showed that TP53 mutations negatively affected PFS and overall survival in intrahepatic cholangiocarcinoma, while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma. No gene alterations were linked to outcomes in gallbladder cancer.

Conclusions: This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and overall survival and highlights the negative prognostic roles of TP53 (PFS) and TERT (overall survival) mutations, providing valuable insights for personalized treatment strategies in biliary tract cancer.

Background: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction.

Methods: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates.

Results: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier.

Conclusions: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Background: Despite advances in breast cancer treatment, recurrence remains common and contributes to higher mortality risk. Among the potential mechanisms, inflammation plays a key role in recurrence by promoting tumor progression. Exercise provides a wide array of health benefits and may reduce inflammation, potentially reducing mortality risk. However, the effects of exercise, including mode (ie, resistance training [RT], aerobic training [AT], and combined RT and AT) and program duration, on inflammatory biomarkers in breast cancer survivors remain to be elucidated.

Methods: A systematic search was undertaken in PubMed, CINAHL, Embase, SPORTDiscus, and CENTRAL in August 2024. Randomized controlled trials examining the effects of exercise on interleukin-1 beta (IL-1β), interleukin 6 (IL-6), IL-8, IL-10, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) were included. A random-effects meta-analysis was undertaken to quantify the magnitude of change.

Results: Twenty-two studies were included (n = 968). Exercise induced small to large statistically significant reductions in IL-6 (standardized mean difference [SMD] = -0.85; 95% CI = -1.68 to -0.02; P = .05) and TNF-α (SMD = -0.40; 95% CI = -0.81 to 0.01; P = .05) and a trend for a decrease in CRP. When stratifying by exercise mode, trends toward reduction in IL-6 and TNF-α were observed for combined exercise, while changes were not generally affected by exercise program duration.

Conclusion: Exercise, especially combined RT and AT, can reduce pro-inflammatory biomarkers, and may be a suitable strategy to reduce inflammation in breast cancer survivors. However, further research is needed to investigate the effects of exercise mode and program duration on markers of inflammation in this survivor group.

Background: Recent advancements in cancer treatments have improved survival rates, but rising costs associated with these innovations raise concerns about their financial impact on patients. This study investigates the trade-off between improved survival and the financial toxicity over time in advanced non-small cell lung cancer (NSCLC).

Methods: We conducted a retrospective cohort study using linked data from the Western Washington SEER cancer registry and TransUnion credit records, focusing on adults diagnosed with advanced NSCLC, bladder, uterine, head and neck, and liver cancers between 2013 and 2017. Financial toxicity was assessed through major adverse financial events (AFEs), including collections, charge offs, liens, delinquent payments, foreclosures, repossessions, and bankruptcies. Multivariable multinomial logistic regression evaluated trends in a composite outcome of survival and AFEs for NSCLC patients within 2 years post-diagnosis. A falsification test evaluated a negative control group of advanced cancers lacking new therapies.

Results: Our study included 6548 patients (mean age 69; 42% female; 86% non-Hispanic White). Two-year survival for NSCLC patients increased from 15.2% to 19.2% between 2013 and 2017 (mean change 4.0%pt, 95% CI = 0.7 to 7.3). The proportion of survivors without AFEs increased by 2.2%pt (95% CI = -0.6 to 5.1), while those alive with major AFEs increased by 1.9%pt (95% CI = 0.02 to 3.6). This trend was absent in the negative control group.

Conclusions: The trade-off between survival gains and increased economic hardships linked to treatment innovations underscores the need to expand our focus beyond clinical outcomes and implement protective measures that ensure healthcare advancements promote population health without inducing financial distress.

Li Fraumeni syndrome (LFS) arising from germline TP53 mutation results in defective DNA repair and increased risk of multiple primary cancers beginning in childhood. Curative intent radiotherapy is often used to treat childhood cancer, but its impact on children with LFS has not been reviewed. We undertook a retrospective case-series review of 47 children with a solid cancer diagnosed age less than 16 years to assess time and survival after second cancer diagnosis. After radiotherapy for the first cancer diagnosis, median time to second primary cancer diagnosis was 13.3 years and median survival 9.7 years. Where no radiotherapy was received, median time to second primary cancer diagnosis was 25.1 years (χ2 = 14.8, P < .0001; Hazard Ratio = 7.9 [95% CI = 2.8 to 22.6]), and median survival of 29.2 years (χ2 = 12.5, P = .004, Hazard Ratio = 3.2 [95% CI = 1.5 to 6.6]). Radiotherapy for first cancer in children with LFS is associated with adverse outcomes and ought to be considered only in the absence of other potentially curative options. Where unavoidable, second cancer risks must be minimized.

Background: HIV prevalence in Harare reached a maximum of around 33% of adults in 1995, before falling to 12% in 2019. We examine trends in the incidence of Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and squamous cell conjunctival cancers (SCCCs) in the population of Harare in relation to changes in HIV prevalence, and the increasing availability and use of antiretroviral therapy (ART).

Methods: Data from the population-based cancer registry of Harare are used to calculate incidence rates for the Black (African) population for the years 1990-2019.

Results: Incidence of KS increased to a peak in the late 1990s, after which rates declined, especially at younger ages. Mean age at diagnosis increased by about 8 years in men and 6 years in women. SCCC shows a similar trend to that of KS, with a dramatic 10-fold increase in incidence, followed by an equivalent fall. Although Hodgkin lymphoma showed no change in incidence over the 30-year period, rates of NHL progressively increased. Incidence in younger adults (aged younger than 44) stabilized after about 2001 but continued to increase in older individuals.

Conclusions: The availability of high-quality cancer registry data over a long period has provided a unique opportunity to study the effects of the epidemic of HIV-AIDs and of ART availability on the risk of cancer in an African population. As HIV prevalence fell and ART coverage expanded, incidence of KS and SCCC declined, whereas for NHL the trends suggest that long-term infection with HIV may pose an increased risk, despite ART.