International Journal of Cancer最新文献

Germline pathogenic variants in BRCA1/2 substantially increase lifetime risks of both breast and ovarian cancers. However, whether specific mutation characteristics predispose carriers to breast-ovarian double primary cancers (DPC) and whether DPC affects ovarian cancer outcomes-particularly in the PARP inhibitor (PARPi) era-remain unclear. We conducted a retrospective analysis of patients with germline BRCA1/2-mutated high-grade serous ovarian cancer in China from 2015 to 2025, including 114 DPC patients and 296 ovarian cancer (OC)-only patients as controls. Clinical characteristics, mutation profiles, and survival outcomes were compared between the two groups. Among 114 DPC patients, 92 were diagnosed with breast cancer first, 12 with ovarian cancer first, 9 had synchronous diagnoses, and 1 was unknown. Compared with the OC-only group, BRCA1/2 mutations in the DPC group were predominantly located outside the Ovarian Cancer Cluster Region (BRCA1: 63.1% vs. 48.9%, p = 0.019; BRCA2: 80.0% vs. 56.2%, p = 0.008). Among BRCA2-mutated patients, DNA-binding domain mutations were enriched in the DPC group (33.3% vs. 17.8%, p = 0.018). Both groups benefited from first-line PARPi maintenance. No significant differences in progression-free or overall survival were observed between DPC and OC-only patients on either univariable or multivariable analysis. A subgroup analysis restricted to the 92 patients whose breast cancer preceded ovarian cancer yielded consistent results. In conclusion, the location of BRCA1/2 mutations influences susceptibility to breast-ovarian DPC. DPC status was not significantly associated with inferior survival in this cohort; however, long-term outcomes warrant validation in larger, prospectively followed populations.

Short-term exposure to fine particulate matter (PM2.5) is an established risk factor for cardiopulmonary mortality, but its acute association with cancer mortality remains poorly characterized. We examined associations between short-term PM2.5 fluctuations and daily all-cancer and site-specific mortality across all 47 Japanese prefectures from January 1, 2013, to December 31, 2022. Using a nationwide time-stratified case-crossover design, we fitted prefecture-specific conditional quasi-Poisson regression models and pooled the estimates by random-effects meta-analysis, expressing associations as the excess relative risk (ERR) per 10 μg/m³ increase in PM2.5 (lag 0-2 days). Sensitivity analyses varied lag structures, meteorological spline specifications, and co-pollutant adjustment. A 10 μg/m³ increase in short-term PM2.5 was associated with a 0.88% increase in all-cancer mortality (95% CI: 0.57-1.18; p < 0.001). The association was consistent across sex, age, and primary site (all interaction p > 0.40), with significant estimates for breast (ERR 2.06%), colorectal (1.06%), stomach (0.81%), and lung (0.77%) cancers. Associations attenuated with longer moving-average windows and were no longer statistically significant from lag 0-5 onward. A measurable fraction of cancer deaths was attributable to PM2.5 above the WHO 24-h guideline (15 μg/m³), with the largest fractions tracking prefecture-specific coefficients rather than ambient concentration. These findings indicate that short-term PM2.5 exposure is associated with higher daily mortality across diverse cancer types in Japan, even at relatively low ambient levels. Because the individual-level effect size is small and attenuated to non-significance after adjustment for either NO₂ or SO₂, these findings are best interpreted as supporting population-level air-quality measures rather than individual clinical intervention.

Cholangiocarcinoma (CCA) has poor outcomes despite curative-intent surgery. Neoadjuvant chemotherapy may improve tumor response and resectability. This study evaluated the efficacy and safety of neoadjuvant modified FOLFOXIRI (mFOLFOXIRI) in patients with potentially resectable CCA. In this prospective, single-arm, phase II study, 25 patients with potentially resectable cholangiocarcinoma received six cycles of neoadjuvant mFOLFOXIRI every 2 weeks. Surgical resection was performed when feasible. The primary endpoint was objective response according to RECIST version 1.1. Secondary endpoints included resectability, R0 resection, recurrence-free survival (RFS), overall survival (OS), safety, and health-related quality of life assessed using EQ-5D-5L. The objective response rate was 44.0%, with partial response in 11 patients, stable disease in 10 patients, and progressive disease in four patients. After neoadjuvant therapy, 20 patients (80.0%) were considered resectable, and 16 (64.0%) underwent curative-intent resection, with an R0 resection rate of 75.0%. Major pathological response occurred in two patients (12.5%). Among resected patients, seven (43.8%) had recurrence, with a median RFS of 18.93 months. The median OS in the overall cohort was 26.70 months. In unadjusted Kaplan-Meier analyses, radiologic response and surgical resection were significantly associated with longer overall survival. Grade 3-4 neutropenia occurred in 36.0% of patients, and no treatment-related deaths occurred. Health-related quality of life remained generally stable during treatment. Neoadjuvant mFOLFOXIRI showed promising antitumor activity, enabled a high rate of curative-intent resection, and demonstrated manageable toxicity in patients with potentially resectable cholangiocarcinoma. These findings support further investigation of this regimen as a neoadjuvant treatment strategy.

Tobacco smoking has a strong influence on DNA methylation (DNAm), enabling the development of DNAm-based smoking predictors, yet external evaluations of these have remained limited. We aimed to assess six DNAm-based smoking predictors in a large sample of middle-aged and older Australians for (i) their accuracy and reliability, and (ii) their association with risk of smoking-related cancers. We used blood DNAm data from the Melbourne Collaborative Cohort Study to calculate six DNAm-based smoking predictors (EpiSmokEr, Elliott-183, McCartney-233, DNAmPACKYEARS, PCPACKYEARS, and mCigarette). Accuracy with respect to self-reported smoking pack-years (N = 2875, median age: 61 years) was assessed using Pearson's correlations, explained variance, and area under the curve (AUC). Reliability was assessed using intraclass correlation coefficients (ICCs) in 364 duplicated samples. Conditional logistic regression was used to assess associations with lung (N_cases = 332) and urothelial (N_cases = 426) cancer risk in two nested case-control studies. All smoking predictors showed excellent reliability (ICC > 0.9) and ability to distinguish current from never smokers (AUCs: 0.94-0.98), explaining 35%-50% variance of smoking pack-years. The predictors were positively associated with smoking-related cancer risk, with strongest adjusted associations observed for mCigarette with lung cancer (per SD, rate ratio [RR] = 2.18, 95% CI: 1.57-3.02) and for PCPACKYEARS with urothelial cancer (RR = 1.62, 95% CI: 1.27-2.07). This translated into prediction gains compared with models solely based on questionnaire-collected smoking variables. In middle-aged and older Australians, DNAm-based smoking predictors showed very good reliability and accuracy in predicting smoking exposure, and strong positive associations with smoking-related cancer risk beyond self-reported smoking information. This highlights their potential utility as an alternative or addition to self-reported smoking information for cancer risk stratification.

Twenty-five percent of colon cancer patients having curative surgery will recur. Most of them will die from distant metastasis partly due to shortcomings of routine histopathological analysis, that is, undetected tumor cells in the regional lymph node field. We have developed ColoNode, an mRNA test in which five biomarkers are quantified and related to a house-keeping gene. Thereby, four different risk groups are defined from low to very high-risk of recurrence being highly valuable as various indicators of the risk of occult tumor cell dissemination and their aggressiveness. Here we report results of the 5-year survival analysis of a prospective study involving nine Swedish hospitals comparing ColoNode with routine histopathology. The study involves 186 colon cancer patients. The following four conclusions can be drawn: (1) ColoNode surpassed histopathology by identifying all 20 patients who were found by histopathology and an additional seven patients who recurred. Multivariate analysis provided a hazard ratio of 6.7 (p = 0.002) while histopathology lost its significance (HR: 1.3; p = 0.60). Only perineural invasion remained as an independent risk factor apart from ColoNode, with a hazard ratio of 2.7 (p = 0.038). (2) Patients belonging to medium-risk group apparently benefited from adjuvant chemotherapy treatment. (3) A total of 113 patients (≈60%) belonged to the low-risk group and can be considered cured by surgery alone. (4) Four patients were missed by both ColoNode and histopathology. Possible reasons for this are discussed. The results suggest that the ColoNode test should be added to the arsenal of prognostic tools, maybe even replacing histopathological lymph node analysis.

Prior studies suggest that proportional-hazards violations (PHVs) occur in oncology randomized controlled trials (RCTs) and may affect conclusions, but evidence has largely focused on initial reports rather than updated analyses. We examined PH testing practices, frequency, patterns, and statistical implications of PHVs in updated oncology RCTs. We focused on oncology RCTs supporting US Food and Drug Administration approvals. Phase II-III oncology RCTs supporting FDA approvals between 2006 and 2025 were identified. Individual patient data were reconstructed from Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. Treatment effects were analyzed with Cox proportional-hazards models, log-rank tests, MaxCombo, and restricted mean survival time difference (RMSD). Two hundred seventy endpoint comparisons (150 overall survival [OS], 120 non-OS) from 168 RCTs were included. PH testing dropped from 24.1% in initial reports to 11.5% in updates (McNemar p < 0.001). Although PH testing increased over the past decade in initial publications (Wald p < 0.001), no trend in updates (Wald p = 0.29). PHV frequency was numerically higher in updated than initial analyses (38.9% vs. 33.0%). Non-OS endpoints, metastatic settings, and immunotherapy or targeted-therapy regimens were associated with PHVs. Among updated analyses, nominal significance differences between PH-dependent and alternative methods were more frequent with PHVs (MaxCombo: 11.4% vs. 3.6%, chi-square p = 0.012; RMSD: 8.6% vs. 2.4%, chi-square p = 0.021). PHV patterns were diminishing effects (35.2%), delayed separation (27.6%), and crossing hazards (27.6%). PH testing declined in updated analyses despite numerically more frequent PHVs. Although updates are descriptive and do not invalidate original conclusions, unrecognized non-proportionality may affect long-term benefit interpretation, supporting PH diagnostics and prespecified complementary analyses.

Neoadjuvant mitomycin C plus cisplatin (MP) previously demonstrated promising activity in high-grade serous ovarian cancer in a single-arm study of BRCA1 pathogenic variant (PV) carriers. This prospective, open-label, randomized Phase II trial (NCT04747717) compared MP with standard paclitaxel-carboplatin (TCbP) in women with germline BRCA1/2 PVs. Here, we report a per-protocol analysis of the BRCA1 subgroup involving 29 MP and 31 TCbP patients. Grade III-IV anemia and thrombocytopenia were more frequent with MP, while other adverse events showed similar distribution. RECIST v1.1 response rates did not differ between treatment arms. Surgery was undertaken for 25 MP and 28 TCbP patients. Complete cytoreduction was achieved in 20/25 (80%) MP and 19/28 (68%) TCbP cases. All MP patients underwent complete debulking after 3-4 neoadjuvant cycles, while six out of 19 women from the TCbP arm required more than 4 cycles to achieve surgical clearance of tumor lumps (p = 0.008). MP outperformed TCbP in the improvement of the peritoneal cancer index (p = 0.001). Complete absence of tumor cells in the omentum was documented in 4/25 (16%) MP patients and 6/28 (21%) TCbP patients (p = 0.73). Maintenance olaparib, complete cytoreduction, resolution of carcinomatosis, and TP53 mutation type (loss-of-function (LOF) versus non-LOF) were associated with improved disease-free interval (DFI). At a median follow-up of 44.8 months, multivariate analysis revealed no differences in progression-free survival or DFI between treatment arms. In conclusion, MP showed no significant efficacy advantage over TCbP but produced a rapid and profound reduction of tumor burden, thus warranting further evaluation. Trial Registration: ClinicalTrials.gov (identifier: NCT04747717).