JNCI Cancer Spectrum最新文献

Background: Black men in the United States bear a disproportionate share of the prostate cancer (PCa) burden, with more than 50% higher incidence and double the mortality compared with White men. Previous studies have examined racial disparities in the incidence of fatal PCa (fPCa), defined as diagnosis leading to disease-specific death within 10 years, and found that they are greater in younger vs older men. However, the extent to which these trends are driven by disparities in incidence or survival is unknown.

Methods: We conduct a retrospective analysis of data from the Surveillance, Epidemiology, and End Results program over the period 1980-2009 to decompose the incidence of fPCa into incidence and 10-year probability of death and quantify the relative disparities in these metrics by age at diagnosis.

Findings: We find that relative PCa incidence for Black vs White men significantly decreases by 0.116 units with each successive 5-year age group (95% CI = -0.183 to -0.049) but the relative probability of death within 10 years does not differ significantly by age (slope = -0.012, 95% CI = -0.060 to 0.035). Further, this deconstruction is similar before and after the introduction of prostate-specific antigen screening.

Conclusion: We conclude that higher relative incidence of fPCa in young Black men vs young White men appears to be largely driven by their significantly increased incidence of disease. This finding supports investigating targeted screening of Black men beginning at younger ages than White men.

Background: Once considered "undruggable," protein phosphatases are now recognized as potential therapeutic targets. The serine and threonine-protein phosphatase 1 regulates key cellular processes and enhances androgen receptor activity in prostate cancer, even under castration-resistant conditions, suggesting a role in disease progression.

Methods: LNCaP and PC3 cells were treated with peptides mimicking protein phosphatase 1-docking motifs in androgen receptor, alongside known bioportides (MSS1 and mitoparan). Cellular uptake was assessed by confocal microscopy and fluorescence assays. Viability was measured with PrestoBlue, and androgen receptor and Prostate-Specific Antigen expression was analyzed by quantitative reverse transcription-polymerase chain reaction and Western blot.

Results: Androgen receptor sequence contains 3 protein phosphatase 1-docking motifs: KVFF (binding site 1), HVVKW (binding site 2), and KPIYF (binding site 3). Binding site 1 and binding site 2 peptides were modified for better solubility, while binding site 3 was combined with the Tat sequence to enhance cellular uptake. Fluorophore-conjugated peptides successfully entered cells, with androgen receptor-binding site 3 showing the highest internalization in LNCaP cells (P = .0495). Treatment with the 3 androgen receptor-binding site peptides individually reduced cell viability in LNCaP and PC3 cells (P = .0352 and P = .0298, respectively). Combining androgen receptor-binding site peptides statistically reduced cell viability, particularly with all 3 peptides together (LNCaP: 68%, P = .0369; PC3: 80%, P = .0369). No statistically significant changes in androgen receptor or prostate-specific antigen expression were observed.

Conclusion: Bioportides targeting protein phosphatase 1-docking motifs, especially when combined, decrease prostate cancer cell viability, and additional protein phosphatase 1-interfering peptides such as MSS1 and mitoparan display potent cytotoxic effects. The absence of changes in androgen receptor and prostate-specific antigen expression highlights the need to further investigate their mechanisms of action.

Background: Comprehensive, multidisciplinary care is crucial for managing early-stage non-small cell lung cancer (NSCLC), typically treated via lung resection or stereotactic body radiation therapy (SBRT). We evaluated how variable access to on-site SBRT may be associated with clinical outcomes for patients with stage I NSCLC receiving surgical resection within an integrated health-care system.

Methods: We performed a retrospective cohort study of patients with stage I NSCLC treated with lung resection at Veterans Health Administration (VHA) facilities between 2006 and 2016. The VHA provides thoracic surgery at approximately 100 facilities, whereas lung SBRT is currently available at approximately 20 facilities. We compared short- and long-term outcomes for patients treated at surgery-only facilities vs those at facilities offering surgery and SBRT.

Results: We identified 6289 patients undergoing lung resection, with 4673 (74.3%) treated at surgery-only sites and 1616 (25.7%) at surgery + SBRT sites. Sociodemographic factors were similar between cohorts. Surgery + SBRT sites showed higher adherence to operative quality metrics and improved patient selection. Short-term outcomes were better at surgery + SBRT sites with lower rates of 30-day major complications, 30-day mortality, and 90-day mortality. With a median follow-up of 6.3 years, 5-year overall survival was higher at surgery + SBRT sites (59.4% vs 56.9%; adjusted hazard ratio 1.12, 95% CI = 1.02 to 1.23).

Conclusion: Short- and long-term outcomes were better for patients with stage I NSCLC who underwent lung resection at facilities delivering thoracic surgery and SBRT. These findings support recommendations to increase SBRT availability at medical centers offering lung resection to ensure comprehensive multidisciplinary care is provided.

Background: Socioeconomic position (SEP) is a fundamental social determinant of health (SDoH) contributing to observed disparities in cancer and cardiovascular (CV) care among individuals with prostate cancer (PC). Understanding the influence of SEP on CV health is essential for addressing outcome inequities within this population.

Methods: We conducted a retrospective study utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare to evaluate CV outcomes in patients ≥65 years with PC from 2009 to 2017. We studied the impact of SEP on cardiovascular events (CVEs), cardiovascular mortality (CVm), PC-specific mortality (PCsm), and all-cause mortality. CVE, CVm, and PCsm were analyzed using competing risk models and all-cause mortality with Cox proportional hazards models. A subgroup analysis was performed in Non-Hispanic Black and Non-Hispanic White individuals.

Results: We included 141 242 patients of whom 76 844 were in high SEP areas (45.6%) and 64 398 in low SEP ones (54.4%). Both groups had a mean age of 72 years; patients in low SEP areas were 67.5% Non-Hispanic White, 34.4% having diabetes, 73.3% hypertension, and 67.7% dyslipidemia versus the high SEP group with 85.6% Non-Hispanic White, 30.4% diabetes, 69.9% hypertension, and 70.7% dyslipidemia. Patients in low SEP areas had higher risks of CVm (subdistribution hazard ratio [sHR] = 1.18, 95% CI = 1.12 to 1.25), PCsm (sHR = 1.12, 95% CI = 1.06 to 1.17), CVE (sHR = 1.07, 95% CI = 1.04 to 1.09), and all-cause mortality (HR 1.16, 95% CI = 1.13 to 1.20). Accentuated results were shown in the Non-Hispanic Black subgroup.

Conclusion: Adverse SEP plays a significant role in shaping outcomes among older patients with PC, contributing to elevated risks of adverse CV and survival outcomes.

Background: Granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, are associated with bone pain, potentially impacting treatment adherence. This study hypothesized that a 5-day regimen of filgrastim would result in less bone pain than single-dose pegfilgrastim in patients receiving chemotherapy for early breast cancer.

Methods: In this multicenter, open-label, randomized controlled trial, patients requiring prophylactic G-CSF during chemotherapy were randomly assigned 1:1 to receive either 5-day filgrastim or pegfilgrastim. The primary outcome was patient-reported bone pain, assessed as area under the curve of daily pain scores (0 = no pain to 10 = worst pain) over the first 5 days following G-CSF in cycle 1. Secondary outcomes included bone pain in cycles 2-4, febrile neutropenia, hospitalizations, chemotherapy delays, dose reductions, early discontinuations, chemotherapy-related deaths, health-related quality of life, and health-care resource utilization.

Results: From June 2021 to March 2023, a total of 233 patients were randomly assigned, with 219 analyzed (110 filgrastim and 109 pegfilgrastim) after excluding those who withdrew before receiving treatment. Adjusting for stratification factors and prespecified baseline covariates using repeated measures linear regression, the mean area under the curve (0-40) for cycle 1 bone pain was 10.2 (11.2) for 5-day filgrastim and 10.2 (9.81) for pegfilgrastim, with an adjusted mean difference of 0.70 (95% confidence interval = 1.62 to 3.02; P = .556). Although no clinically significant differences were observed in most secondary outcomes, the 5-day filgrastim group exhibited a numerically higher incidence of febrile neutropenia (6.4% vs 0.9%, P = .065) and hospitalization (10.0% vs 3.7%, P = .106).

Conclusion: There was no significant difference in bone pain between 5-day filgrastim and pegfilgrastim.

Background: Human papillomavirus infection contributes to the development of almost all cervical malignancies, aside from gastric-type adenocarcinoma of the cervix, a rare aggressive subtype without human papillomavirus infection.

Methods: To address the carcinogenic mechanism of this disease, we performed a comparative multi-omics analysis of gastric-type adenocarcinoma of the cervix and usual-type endocervical adenocarcinoma in 3 independent cohorts of patients with gastric-type adenocarcinoma of the cervix and usual-type endocervical adenocarcinoma. The first cohort comprised 8 gastric-type adenocarcinoma of the cervix and 22 patients with usual-type endocervical adenocarcinoma treated at the National Cancer Center Hospital between 2002 and 2020, who were examined by targeted and whole transcriptome sequencing. The other 2 cohorts comprised 52 patients with gastric-type adenocarcinoma of the cervix and 109 patients with usual-type endocervical adenocarcinoma and 39 patients with gastric-type adenocarcinoma of the cervix and 232 patients with usual-type endocervical adenocarcinoma, whose mutational data were obtained from the Center for Cancer Genomics and Advanced Therapeutics (Japanese patients) and Genomics Evidence Neoplasia Information Exchange (US patients) public databases, respectively. Metabolomic analysis was performed in 8 patients, including 5 with gastric-type adenocarcinoma of the cervix.

Results: TP53 mutations were more prevalent in gastric-type adenocarcinoma of the cervix than in usual-type endocervical adenocarcinoma in all 3 cohorts. Transcriptome analysis consistently revealed frequent suppression of TP53-related pathways in gastric-type adenocarcinoma of the cervix. Metabolites preferentially detected in gastric-type adenocarcinoma of the cervix tissues suggest TP53 alterations are implicated in intratumoral metabolic properties.

Conclusion: The development of gastric-type adenocarcinoma of the cervix is likely driven by TP53 mutations, which play a large role in shaping intracellular signaling and metabolic profiles within tumor cells.

Background: Cancer survivors may be more likely to experience accelerated declines in physical function compared to cancer-free controls, but objective data and knowledge of preventive interventions are limited.

Methods: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, single-blinded, randomized trial conducted at 8 centers across the United States that enrolled 1635 sedentary adults aged 70-89 years and with physical limitations but who could walk 400 m at baseline, of which 371 (22.7%) reported a history of cancer. Participants were randomized in a 1:1 ratio to a health education or physical activity program. The primary endpoint was time to major mobility disability, defined objectively by the inability to walk 400 m in less than 15 minutes.

Results: Cancer history modified the effect of randomized group on major mobility disability (P = .006). Among those randomized to the health education program, participants with a history of cancer were 53% more likely to develop major mobility disability compared with participants who did not have a history of cancer (Hazard Ratio (HR) = 1.53; 95% CI = 1.18 to 1.99; P = .001). Among participants with a history of cancer, those randomized to the physical activity program were 43% less likely to develop major mobility disability compared with the health education program (HR = 0.57; 95% CI = 0.40 to 0.82; P = .003).

Conclusion: In this analysis of a randomized clinical trial, cancer survivors had an increased risk of mobility disability compared with non-cancer controls, and physical activity attenuated this risk.

Background: Gene expression assays help personalize adjuvant chemotherapy decisions for hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC). The 70-gene risk of distant-recurrence signature, MammaPrint, demonstrated clinical utility in guiding chemotherapy de-escalation in genomically low risk patients in the MINDACT trial. This study evaluates MammaPrint as a continuous predictor of chemotherapy benefit in HR+HER2- EBC using real-world data (RWD) from the FLEX Registry.

Methods: The study evaluated 1002 patients treated with endocrine therapy (ET) only or ET with chemotherapy (ET+CT) enrolled in FLEX (NCT03053193) with 5-year median follow-up. Propensity-score matching balanced treatment groups by menopausal status, T-stage, and nodal status. The primary endpoint was distant recurrence-free interval (DRFI). Regression and Cox proportional hazards models assessed chemotherapy benefit across MammaPrint Index (MPI) risk.

Results: Most patients were postmenopausal (70.1%), node-negative (70.0%), and had grade 2 tumors (51.2%). The regression models showed that MPI strongly predicted 5-year DRFI in ET only (R2 = 0.99, P < .001) and ET + CT (R2 = 0.90, P < .001) groups, corresponding to an average absolute chemotherapy benefit of 5.6% in High 1 and 10.9% in High 2. Minimal improvement in DRFI with chemotherapy was observed for Low (1.7%) and UltraLow (<1.0%) risk groups. A multivariate Cox model with an MPI-by-treatment interaction term demonstrated that increasing MPI risk was associated with greater chemotherapy benefit on DRFI (HR = 0.15, P = .047). Chemotherapy benefit was significantly associated with premenopausal status, but not age, T-stage, nodal status, or grade.

Conclusions: These RWD from the FLEX Registry demonstrate that MPI is predictive of both DRFI prognosis and chemotherapy benefit in HR+HER2- EBC. (NCT03053193).

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard-of-care for hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib, the first approved CDK4/6i, significantly improved progression-free survival (PFS) in randomized controlled trials (RCTs). However, real-world (RW) outcomes may differ due to broader patient populations. This meta-analysis evaluates the applicability of pivotal RCT findings to RW settings.

Methods: We conducted a systematic review and meta-analysis of RW studies on HR+/HER2- MBC treated with palbociclib+aromatase inhibitors (AI) or fulvestrant, reporting median PFS (mPFS) and/or overall survival (mOS). Pooled mPFS/OS was estimated using the median of medians (MM) and weighted MM (WM). RW estimates were deemed comparable to RCTs if MMPFS/OS or WMPFS/OS fell within RCTs' 95% confidence intervals (CIs). Similar criteria applied to pooled hazard ratios (HRs) of PFS/OS for palbociclib+AI vs AI in visceral/nonvisceral subgroups.

Results: Twelve RW studies were analyzed. First-line palbociclib+AI MMPFS (22.5 months, 95% CI = 19.5 to 31.8) aligned with PALOMA-1/2 pooled mPFS (23.9, 95% CI = 20.2 to 27.6). First-line palbociclib+fulvestrant MMPFS (13.5, 95% CI = 11.6 to 28.5) exceeded PALOMA-3 (11.2, 95% CI = 9.5 to 12.9). Second-line palbociclib+fulvestrant MMPFS (11.5 months, 95% CI = 6.3 to 15.3) was consistent with PALOMA-3. RW first-line mOS (51.2 months, 95% CI = 49.1 to 53.3) surpassed PALOMA-1/2 pooled mOS (45.7, 95% CI = 37.5 to 53.8). WMOS (49.1 months, 95% CI = 49.1 to 53.3) was slightly lower than RCTs (53.7, 95% CI = 37.5 to 53.8). Palbociclib+AI outperformed AI in RW visceral disease, aligning with RCTs, and showed heterogeneous but favorable benefit in nonvisceral disease.

Conclusions: RW data confirm palbociclib+endocrine therapy effectiveness, reinforcing its applicability to broader patient populations.

Solid organ transplant recipients (SOTRs) in the United States have lower risks for breast and prostate cancers than the general population. To explore whether pretransplant screening explains this observation, we conducted a case-control study of US adults aged 65 years or older using the SEER-Medicare database (2000-2019). We included 252 279 breast cancer cases, 3 855 275 female controls, 316 981 prostate cancer cases, and 2 361 846 male controls. We used Medicare claims to identify solid organ transplant procedures and screening with mammography or prostate-specific antigen testing before case/control selection. SOTRs exhibited reduced risks for breast cancer (adjusted odds ratio = 0.60, 95% CI = 0.45 to 0.80) and prostate cancer (0.84, 95% CI = 0.71 to 1.00). These inverse associations were significant among screened individuals, although a borderline association for breast cancer was suggested in unscreened women. Pretransplant cancer screening probably largely explains the reduced risks of breast and prostate cancer among US SOTRs, but there may also be other protective factors.