JNCI Journal of the National Cancer Institute最新文献

Background: The cornerstone of the treatment of malignant peripheral nerve sheath tumors (MPNST) is surgical resection. Radiation and chemotherapy are variably employed. The optimal treatment remains uncertain, particularly for unresectable or metastatic disease and patients with neurofibromatosis type-1 (NF-1).

Methods: We present data for fifty-eight patients with newly diagnosed MPNST enrolled on the Children's Oncology Group study ARST0332. Patients were treated with risk-adapted therapy including surgery with or without radiotherapy and ifosfamide and doxorubicin chemotherapy.

Results: Most patients had primary tumors that were greater than 5 cm (86%), deep (95%), and invasive (74%), and 10% had distant metastases. Thirty-two (55%) patients had germline NF-1 and 26 (45%) did not. Thirty-one patients received neoadjuvant therapy and 22 were evaluable for response with 5 (23%) attaining an objective response, 10 (45%) stable disease, and 7 (32%) progressive disease. Estimated 5-year event-free survival (EFS) was 87%, 52% and 0% for the low- (n = 8), intermediate- (n = 44) and high-risk (n = 6) patients, respectively. In univariate analysis, EFS and overall survival (OS) differed by sex, presence or absence of metastatic disease, risk group, and achievement of upfront or delayed R0/R1. There was no difference in EFS or OS based on germline NF-1 status.

Conclusion: The treatment strategy in ARST0332 achieved excellent outcomes for low-risk MPNST. Patients with high risk (metastatic) MPNST have poor outcomes and novel treatments are needed. (NCT00346164).

Background: Drinking water can be an important source of exposure to nitrate and disinfection by-products, including trihalomethanes (THMs) and haloacetic acids (HAAs). N-nitroso compounds formed endogenously after nitrate ingestion are animal carcinogens, and THM and HAA exposures increase the risk of some cancers. Our objectives were to evaluate associations of drinking water nitrate and disinfection byproducts with total and aggressive (distant stage, poorly differentiated grade, fatal, or Gleason score ≥7) prostate cancer in the Agricultural Health Study cohort.

Methods: Male participants who were cancer free and used private wells or public water supplies (PWS) for drinking water at enrollment (1993-1997, n = 40 403) were followed through 2021 (mean = 21.9 years). Average nitrate-nitrogen (nitrate-N) concentrations were estimated for private well users based on state-specific geologic and meteorologic factors. We used monitoring data to compute average nitrate-N, THMs, and HAAs for PWS users. We estimated hazard ratios (HRs, 95% CIs) per doubling and categories of exposure for total (n = 3625) and aggressive (n = 2200) prostate cancer using Cox proportional hazards regression.

Results: Median (interquartile range) average water nitrate-N was 1.49 (0.76-3.01) mg L-1; 6% >10 mg L-1 (PWS maximum contaminant level). Compared to nitrate-N ≤ 1 mg L-1, exposures >10 mg L-1 were significantly positively associated with total (1.16, 1.01-1.35; P = .10 for trend) and aggressive disease (1.22, 1.02-1.47; P = .03 for trend). We observed weak associations between higher nitrate-N (Q4 vs Q1) and total (1.05, 0.95-1.16) and aggressive (1.13, 0.99-1.27) disease. We did not observe associations with total THMs or HAAs.

Conclusions: These findings suggest that drinking water nitrate-N exposure, at average levels > 10 mg L-1, is a risk factor for prostate cancer, particularly aggressive disease.

Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment paradigm for HER2-expressing breast cancer, including HER2-low disease. However, biomarkers associated with T-DXd activity remain poorly defined. We conducted a comprehensive analysis of clinical, genomic, and immune correlates of T-DXd outcomes to identify molecular determinants of therapeutic benefit and resistance.

Methods: We retrospectively analyzed 2 independent cohorts of patients with advanced breast cancer treated with T-DXd at Dana-Farber Cancer Institute and Yale Cancer Center between 2018 and 2024. We included patients with ≥2 tumor blocks with HER2 immunohistochemistry (IHC) assessments prior to T-DXd. Clinical data on 524 patients were manually reviewed, and genomic profiling and immune microenvironment assessments were performed on a subset of patients. Multivariable Cox proportional hazards models evaluated associations between molecular features and overall survival (OS) and time to next treatment (TTNT).

Results: Among 524 patients, HER2 IHC discordance between sequential tumor biopsies was observed in 20% of patients and was independently associated with significantly worse OS (hazard ratio [HR] = 0.67; P = .012) and TTNT (HR = 0.65; P = .002), resembling outcomes seen in HER2 0 tumors. Genomic analysis revealed that PTEN mutations correlated with inferior TTNT (HR = 2.2; q = 0.068), whereas ERBB2 amplifications predicted improved OS and TTNT. An inflamed tumor microenvironment determined by digital pathology was associated with significantly poorer TTNT outcomes (median TTNT = 5.5 months) compared with immune-desert phenotypes (median OS = 9.6 months, P = .03).

Conclusions: This study identifies HER2 IHC discordance and specific genomic and immune features as prognostic biomarkers of T-DXd efficacy. These findings warrant prospective validation and may inform biomarker-driven strategies to optimize T-DXd therapy in HER2-expressing malignancies.

Background: Tattooing can deliver carcinogens directly into the skin and cause immunological responses, and yet the relationship between tattooing and melanoma risk is unknown.

Methods: In a population-based case-control study with 1167 melanoma cases (566 in situ; 601 invasive) and 5835 frequency-matched controls, we examined tattooing and melanoma risk using multivariable logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Although ever receiving a tattoo was not strongly associated with melanoma risk, heavier tattooing exposure was associated with decreased risk. Overall melanoma risk was decreased among individuals who had received 4 or more tattoo sessions (OR = 0.44, 95% CI = 0.27 to 0.67) and individuals who had 3 or more large tattoos (OR = 0.26, 95% CI = 0.10 to 0.54) compared with those who were never tattooed. Invasive melanoma risk was also decreased among individuals who received their first tattoo before age 20 (OR = 0.48, 95% CI = 0.29 to 0.82) compared with never tattooed individuals.

Conclusions: Our findings suggest that more tattoo exposure is associated with reduced melanoma risk, which does not support previously hypothesized associations between tattooing and increased melanoma risk. Unmeasured confounding is likely to contribute to our findings because we were not able to control for important melanoma risk factors. Potential causes of these associations could include sun exposure-related behaviors or immune responses to tattooing. Further investigation is warranted to clarify these relationships.

Background: Interim 10-year results from the Nordic-European Initiative on Colorectal Cancer (NordICC), a randomized controlled trial (RCT) of screening colonoscopy, demonstrated a statistically significant reduction in colorectal cancer (CRC) incidence but not mortality, contrary to results from 4 flexible sigmoidoscopy RCTs.

Methods: We constructed CRC incidence and mortality Kaplan-Meier curves through 10 years to standardize comparisons across RCTs and examined CRC screen detection and stage. Novel analyses of 1 flexible sigmoidoscopy RCT (Prostate, Lung, Colorectal, and Ovarian cancer screening trial [PLCO]) assessed year-by-year mortality in screen-detected CRCs.

Results: At 10 years, all RCTs demonstrated statistically significant CRC incidence reductions with screening (ratio = 0.77, 95% confidence interval [CI] = 0.70 to 0.84, to ratio = 0.82, 95% CI = 0.69 to 0.97, vs control arm; P ≤ .011). Two flexible sigmoidoscopy RCTs and NordICC showed no statistically significant CRC mortality reduction (ratio = 0.84, 95% CI = 0.64 to 1.10, to ratio = 0.90, 95% CI = 0.69 to 1.18; P = .10-0.23). In 3 flexible sigmoidoscopy RCTs and NordICC, relative reductions were greater in CRC incidence than CRC mortality, but only NordICC reported higher CRC mortality with screening vs the control arm for the first 7 years. In contrast, PLCO observed fewer CRC deaths with screening by year 2 (ratio = 0.59; P = .03), and screen-detected CRCs were less often advanced (odds ratio = 0.26; P < .001) or fatal (ratio = 0.50; P < .001).

Conclusions: After 10 years, NordICC is similar to 2 flexible sigmoidoscopy RCTs in observing statistically significant reductions in CRC incidence but not CRC mortality. However, only NordICC observed greater CRC mortality with screening vs the control arm for 7 years. Granular analyses of CRC cases and deaths in NordICC, paralleling our PLCO analyses, could provide insight into why CRC mortality results differ in NordICC vs flexible sigmoidoscopy RCTs.

Background: Breast cancer (BC) survivors receiving adjuvant treatments often report clinically relevant cancer-related cognitive complaints (CRCC), which have a significant impact on quality of life. We aimed to develop a comprehensive model of prediction of CRCC, including clinical and serum inflammatory protein data.

Methods: We included 9575 stage I-III BC patients from the CANTO cohort (NCT01993498). Data were collected at diagnosis, 2 (year-2), and 4 (year-4) years post-diagnosis. Outcome of interest was CRCC (cognitive dimension of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 questionnaire, score < 75/100) at year-2 and year-4. Serum inflammatory markers (IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IFNg, IL-1, IL1Ra, TNF-a, and CRP) were available in a subset of patients with hormone-receptor-positive BC. Multivariable logistic regression models assessed associations of baseline clinical and inflammatory variables with CRCC.

Results: Rates of CRCC were 31% (diagnosis), 39% (year-2), and 37% (year-4). Baseline validated predictors of CRCC reported at year-2 were chemotherapy, pretreatment CRCC, pain, and fatigue; predictors of CRCC reported at year-4 were pretreatment CRCC, pain, and anxiety. Other clinically relevant factors associated with CRCC at both time points during model development were pretreatment insomnia, receipt of endocrine therapy, and younger age/premenopausal status. No significant associations were observed between inflammatory markers and CRCC.

Conclusions: Approximately 1 in 3 BC survivors in this cohort reported CRCC at diagnosis, with this rate being stable until year-4 after diagnosis. Pretreatment symptom burden and chemotherapy were validated as risk factors for long-term CRCC. No associations between inflammatory markers and self-reported CRCC emerged from this study.

Background: Substantial cancer underdiagnosis, especially early-stage cancers, occurred during the COVID-19 pandemic in the United States. Medicaid expansion under the Affordable Care Act could facilitate access to timely detection of cancer during pandemic-related financial and employment instability. This study examines the association of Medicaid expansion and changes in cancer stage at diagnosis during the COVID-19 pandemic.

Methods: We compared changes in proportions of early-stage (stage I/II) cancer diagnosis in Medicaid expansion states versus non-expansion states among 1 844 515 individuals aged 18-64 years newly diagnosed with cancer in 2018-2022 from the National Cancer Database using a difference-in-differences (DD) approach. Adjusted DD estimates were calculated with linear probability models and stratified by key sociodemographic factors and cancer type.

Results: We found that Medicaid expansion was statistically significantly associated with smaller decreases in proportions of early-stage cancer diagnosis among individuals aged 18-44 years (DD = 1.26; 95% CI = 0.54 to 1.98), men (DD = 0.61; 95% CI = 0.08 to 1.14), and those with high comorbidity burden (Charlson-Deyo comorbidity score ≥ 2; DD = 1.51; 95% CI = 0.24 to 2.78), treated in academic facilities (DD = 0.55; 95% CI = 0.03 to 1.06), or diagnosed with prostate cancer (DD = 1.52; 95% CI = 0.56 to 2.47).

Conclusions: Our findings suggest a protective effect of Medicaid expansion on early-stage cancer diagnoses during the COVID-19 pandemic and public health emergency in the United States, informing policy makers and the public in the 10 states that have yet to expand Medicaid eligibility. Findings can also inform policy makers and the public in all states about the public health implications of upcoming large federal cuts to Medicaid programs and coverage.

Background: Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying.

Methods: This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard.

Results: In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients.

Conclusion: The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.