JNCI Cancer Spectrum最新文献

Background: Treatment response to immune checkpoint inhibitors (ICIs) varies considerably, a phenomenon known as treatment effect heterogeneity (HTE). While HTE is explored via one-variable-at-a-time subgroup analyses in randomised controlled trials (RCTs), this method has limitations, which the risk-modelling approach seeks to address.

Methods: Applying the risk-modelling approach, individual patient data from ten RCTs (six supporting FDA atezolizumab label: OAK, IMpower130, IMpower150, IMpower133, IMbrave150, IMspire150; four unlabelled indications: IMpower131, and IMpower132, IMmotion151, IMvigor211) were analysed by an extreme gradient-boosting algorithm to predict pre-treatment prognosis for overall survival. The predicted risk scores were evaluated as efficacy modifiers categorically (high, intermediate, low risk groups) and continuously in Cox models with treatment-by-risk-group interaction terms. Sensitivity and exploratory analyses investigated absolute and meta-analysed treatment effect and compared the results with established prognostic tools and treatment effect predictors. Statistical significance tests are two-sided.

Results: Among the ten RCTs (N = 7053), one trial-IMvigor211 - showed significant HTE by pre-treatment prognosis across all evaluations (risk groups, risk scores, sensitivity analyses: p < .001). Amongst other trials, no significant HTE was detected (risk group and risk score analysis interaction test: OAK p = .61, 0.77; IMpower130 p = .13, 0.52; IMpower131: p = .21, 0.02; IMpower150: p = .14, 0.36; IMpower133: p = .38, 0.12; IMbrave150: p = .15, 0.08; IMspire150: p = .24, 0.6; IMpower132: p = .15, 0.81; IMmotion151: p = .48, 0.21).

Conclusion: The risk-modelling approach showed no clear link between pre-treatment prognosis and ICI efficacy in most RCTs, particularly those supporting atezolizumab's FDA label. In IMvigor211, patients with better pre-treatment prognosis were more likely to benefit from atezolizumab treatment for platinum-refractory metastatic urothelial carcinoma.

Background: A growing population of older adult cancer survivors faces competing cancer and non-cancer health risks. There are limited real-world data on recurrence patterns beyond five years post-treatment.

Methods: This was a SEER-Medicare retrospective cohort study of patients aged ≥66 with stage I-III breast, colon, or rectal cancer who received definitive surgery and survived ≥5 years from diagnosis without recurrence or second primary malignancy. Late recurrence (5-10 years post-diagnosis) was identified using a validated algorithm to detect treated recurrence in Medicare claims. Demographic and clinical characteristics collected at cancer diagnosis were assessed as predictors of late treated recurrence using restricted mean survival time (RMST) regression.

Results: The sample included 12,859 breast, 17,329 colon, and 4,427 rectal cancer survivors. The cumulative incidence of late treated recurrence 5-10 years post-diagnosis was 5.0% in breast, 4.4% in colon, and 8.0% in rectal cancer survivors. In all cohorts, stage was associated with shorter RMST. The absolute risk difference between stage I and III was greatest in breast (2.% vs 18.1%), followed by rectal (5.2% vs. 10.3%) and colon (2.7% vs 6.7%) cancer survivors (P < .001 for all cohorts). Though their effect on RMST was modest (<5%), higher grade, node-positive, and ER-positive disease in breast, left-sided tumors in colon, and radiation in rectal cancer were associated with late treated recurrence. Across all cohorts, the incidence of other-cause mortality (24.1%-34.0%) exceeded cancer-specific mortality (2.9%-6.2%).

Conclusions: Late treated recurrence in older long-term survivors is uncommon, but risk remains elevated 5 years post-diagnosis in those with more advanced stage.

Introduction: Health-related quality of life (HRQoL) is not routine in early phase clinical trials (EP-CTs), which focus on dose-limiting toxicities and safety. However, for clinicians, understanding the impact of such trials on HRQoL is fundamental to consent patients, especially when the benefits on tumor response may be unknown.

Aims and methods: The PEARLER (Patient diversity And experience in eaRLy phase cancEr clinical tRials) study was conducted with a key aim of focusing on assessing HRQoL in participants undergoing EP-CTs using a multi-center prospective cohort setting. All participants completed a baseline demographic survey on Cycle 1 Day 1 with EORTC-QLQ-C30 on Day 1 of Cycles 1 through 6 or end of treatment (EoT).

Results: Overall, 122 participants were recruited with median age 62. Median baseline Global Health Status (GHS) was 67 and remained unchanged throughout EP-CT (P = .188). GHS deterioration occurred in 29/122 (24%) while improvement occurred in 16/122 (13%). Median baseline Physical Function Score (PFS) was 87. PFS deterioration occurred in 30/122 (25%) while improvement occurred in 6/122 (5%). Baseline median CFS was 84. Cognitive Function Score (CFS) deterioration occurred in 25/122 (20%) while improvement occurred in 20/122 (16%). Baseline median Emotional Function Score (EFS) was 77. EFS deterioration occurred in 14/122 (11%) while improvement occurred in 14/122 (11%). Presence of liver metastases was a negative predictive marker for GHS, CFS, and EFS over time (P = .01, P < .01, and P < .01).

Conclusion: PEARLER is the first prospective cohort study investigating change in HRQoL over time in patients undergoing EP-CTs. Reassuringly, almost three-quarters of participants who undertake EP-CTs either sustain or improve their GHS or PFS. Presence of liver metastases appears to be a negative predictive marker of HRQoL.

Background: The 2024 American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology practice guidelines recommend early salvage radiation therapy (RT) for biochemical recurrence after radical prostatectomy and androgen deprivation therapy for high-risk features. Increasingly, men with high-risk disease are undergoing radical prostatectomy. We therefore characterized contemporary RT and androgen deprivation therapy practices within the Michigan Radiation Oncology Quality Consortium and Michigan Urological Surgery Improvement Collaborative.

Methods: Patients receiving postprostatectomy RT from June 9, 2020, to June 9, 2024, were eligible. Prospectively collected data included surgical pathology, RT, and androgen deprivation therapy details. RT was adjuvant (pre-RT prostate-specific antigen [PSA] <0.1 ng/mL), consolidative (persistent PSA ≥0.1), or salvage (all others). Multivariable analyses evaluated associations between clinicopathologic features and androgen deprivation therapy use.

Results: Among 345 patients across 26 centers, 56% had at least 1 high-risk feature: pT3b/T4 (24%), pN1 (6%), grade group 4/5 (30%), pre-RT PSA greater than 0.5 ng/mL (27%). RT was adjuvant (10%), consolidative (28%), or salvage (62%), initiated at median PSA of 0.07 ng/mL (interquartile range [IQR] = 0.03-0.09 ng/mL), 0.5 ng/mL (IQR = 0.3-1.5 ng/mL), and 0.3 ng/mL (IQR = 0.2-0.5 ng/mL), respectively. Median time to RT was 8, 6, and 29 months. A minority were recommended 24 months of androgen deprivation therapy (17%), and very few were recommended intensification with AR-pathway inhibitors (5%). On multivariate analysis, androgen deprivation therapy was associated with pT3b/T4 (odds ratio [OR] = 2.77, 95% confidence interval [CI] = 1.34 to 5.93), pN1 (OR = 6.22, 95% CI = 1.35 to 47.57), grade group 4/5 (OR = 2.87, 95% CI = 1.51 to 5.56), and pre-RT PSA more than 0.5 (OR = 2.11, 95% CI = 1.17 to 3.91).

Conclusions: Within the Michigan Radiation Oncology Quality Consortium, more than half who received postprostatectomy RT had high-risk features; nearly 30% required consolidation for persistently positive PSA. Androgen deprivation therapy was associated with high-risk features, but few received androgen deprivation therapy prolongation or intensification. Studies are needed to personalize androgen deprivation therapy, especially for those with persistent PSA, who are frequently treated yet underrepresented in trials.

Background: We examined late effects clustering among adolescent and young adult (AYA; age 15-39 years at diagnosis) Hodgkin lymphoma (HL) survivors and identified characteristics associated with each cluster.

Methods: We included AYAs with HL in 2006-2018 from the California and Utah Cancer Registries linked to statewide hospitalization, emergency department, and ambulatory surgery visit data. We identified severe late effects >2 years after cancer diagnosis in 9 late effects categories. Latent class analysis (LCA) was used to identify late effects clusters. Multinomial logistic regression models estimated adjusted associations of demographic and treatment characteristics with LCA late effect group.

Results: We identified 4635 AYA HL survivors with median follow-up of 8.2 years and 4 late effects groups: 77.1% had a low probability of any late effect (Low Morbidity), 12.8% had high probability of Thyroid disorders, 8.0% had high probability of Cardiovascular Disease (CVD), and 2.1% had high probability of Multiple Conditions (CVD, diabetes/pancreatic, thyroid, and renal diseases). Publicly insured AYAs were more likely than those with private insurance to be in the CVD (OR = 1.53, 95% CI = 1.18 to 1.98) and Multiple Conditions (OR = 2.17, 95% CI = 1.29 to 3.66) than the Low Morbidity group. AYAs with radiation were more likely to be in the Multiple Conditions (OR = 2.31, 95% CI = 1.41 to 3.78) and Thyroid (OR = 2.81, 95% CI = 2.20 to 3.58) groups. Hematopoietic cell transplantation was associated with Multiple Conditions (OR = 9.50, 95% CI = 5.82 to 15.50), CVD (OR = 3.82, 95% CI = 2.96 to 4.93), and Thyroid (OR = 2.86, 95% CI = 2.12 to 3.85) groups.

Conclusions: While most AYA HL survivors were in the Low Morbidity group, those with public insurance or intense treatment may be at higher risk for multiple conditions.

Background: There are substantial historical racial and ethnic differences in treatment survival for patients with hepatocellular carcinoma (HCC) that may have changed with approval of 9 novel systemic HCC therapies between 2017 and 2022.

Methods: This retrospective cohort study included patients from the Flatiron Health Research Database who received systemic therapy between 2011 and 2023. We identified receipt of systemic therapy, including novel systemic therapies receiving US Food and Drug Adminstration approval ≥2017, and determined overall survival (OS) from start of first-line systemic therapy until death. Multivariable models adjusted for sociodemographic and clinical factors.

Results: The study included 4198 patients who were 53.0% White, 11.8% Black, and 5.2% Asian, and 11.2% were Hispanic. Asian patients were more likely than White patients to receive novel systemic therapies (odds ratio [OR] = 1.78, 95% confidence interval [CI] = 1.12 to 2.83), while Black and Hispanic patients had similar receipt of treatment. Asian and Hispanic patients had median OS of 10.3 and 10.5 months compared with 8.0 and 8.3 months for White and non-Hispanic patients. Asian (HR = 0.79, 95% CI = 0.65 to 0.96) and Hispanic patients (HR = 0.72, 95% CI = 0.62 to 0.83) had better OS than White and non-Hispanic patients, respectively, which did not substantially change with stepwise adjustment. Racial differences in survival worsened over time. Receipt of novel therapy was associated with improved survival.

Conclusions: Asian and Hispanic patients had the best survival, and Asian patients were more likely to receive novel therapies. As adjustment for many social and clinical factors had minimal impact on these findings, additional research is needed to understand these survival differences.

Background: Diagnosis, treatment, and outcomes of colon cancer in the United States differ between patients younger than age 50 (early-onset colon cancer [EOCC]) and those age 50 or older (average-onset [AOCC]) and may be impacted by access to care. Less is known about surgical quality and postoperative outcomes between patients with EOCC and AOCC. This study aimed to compare patients with EOCC and AOCC in surgical aspects and 30-day postoperative complications and readmissions in the Military Health System.

Methods: The cohort included patients diagnosed with stage I-III colon adenocarcinoma between 2001 and 2014 who received surgery. Poisson regression with robust standard errors estimated the adjusted risk ratios (ARRs) and 95% confidence intervals (CIs) in association with age at diagnosis for the outcomes.

Results: Among 333 patients with EOCC and 1369 patients with AOCC, there were no statistically significant differences in surgical delay, positive margins, or inadequate lymphadenectomy. Patients with EOCC had statistically higher adjusted 30-day risk of any complication (ARR = 1.31, 95% CI = 1.05 to 1.63), inclusive of general surgical (ARR = 1.64, 95% CI = 1.14 to 2.38) and gastrointestinal (ARR = 1.29, 95% CI = 1.00 to 1.65) complications, relative to patients with AOCC. There was no statistically significant difference in 30-day readmission for patients with EOCC (ARR = 1.30, 95% CI = 0.84 to 202) compared with patients with AOCC.

Conclusion: In the Military Health System, patients with EOCC had higher adjusted 30-day risk of complications following surgery compared with patients with AOCC. This finding may have implications for care delivery and postoperative management of patients with EOCC to reduce complication burden and achieve optimal outcomes.

Background: Cancer-related cognitive impairment is a significant concern, yet data assessing long-term changes from pretreatment baselines are limited.

Methods: In this large nationwide study, patients with breast cancer and lymphoma and controls were assessed at pre-chemotherapy, post-chemotherapy, 6-month, 1-year, and 2-year follow-ups. Cognitive function was measured using self-reported and performance-based assessments. The analysis included 225 participants: breast cancer (41 patients/36 controls) and lymphoma (73 patients/75 controls). Cognitive trajectories were estimated using longitudinal linear mixed models, adjusting for demographic, clinical, and psychosocial factors. A minimal clinically important difference cutoff identified changes over time in perceived cognitive impairment.

Results: Patients with breast cancer reported greater cognitive complaints than controls, with declines in FACT-Cog Total (β = -17.17, P < .001), Perceived Cognitive Impairment (β = -11.09, P < .001), and Perceived Cognitive Abilities (β = -3.60, P = .03) from pre-chemotherapy to 2-year follow-up. Declines were observed in memory (Rey Auditory Verbal Learning Test [RAVLT] Immediate Recall: β = -1.53, P = .04) and executive function (phone fluency: β = -1.53, P = .02) at 1 year. Patients with lymphoma also showed more complaints, with declines in Perceived Cognitive Impairment (β = -6.19, P = .01), poorer RAVLT Immediate (β = -1.62, P < .001), Delayed Recall (β = -1.72, P < .001), and phone fluency (β = -2.46, P < .001) from pre-chemotherapy to 1-year follow-up.

Conclusion: Compared with controls, patients with breast cancer and lymphoma showed persistent cognitive worsening up to 1-year posttreatment, and patients with breast cancer reported perceived impairment at 2 years compared with controls.

Background: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.

Methods: Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests.

Results: In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC.

Conclusions: Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.

Background: In the development of breast cancer and ovarian cancer there may be an influence of lifestyle and environmental factors. This influence could be relevant also in patients with genetic predisposition such as in carriers of germline pathogenic variants in the BRCA genes. However, this issue has been addressed in only a few studies so far.

Methods: In this retrospective, multicenter case-control study, we enrolled participants with a pathogenic variant BRCA gene and divided into 2 groups: group 1, patients with breast cancer and/or ovarian cancer, and group 2, subjects without cancer. We compared these groups regarding demographic data as age, body mass index, smoking habits, estroprogestinic use, Mediterranean diet, and physical activity. Multivariable analyses were used to identify predisposing factors. All evaluations were 2-tailed and considered statistically significant if the P value was less than .05.

Results: We enrolled 281 participants, 135 (79.4%) with breast cancer, 32 (18.8%) with ovarian cancer, 3 (1.8%) with both, and 111 unaffected (39.5%) women. Independent risk factors associated with cancer were age (P < .0001); body mass index (P = .007); family history (P = .002); occupation (P = .003); smoking habits (P = .012), number of cigarettes smoked (P = .016), and pack-year index (P = .022); and estroprogestinic use (P = .032) and years of estroprogestinic use (P = .029). At multivariate analysis, age (odds ratio [OR] = 1.062; P < .0001), family history (OR = 0.129; P = .001), number of cigarettes smoked (P = .014), and estroprogestinic use (OR = 2.009; P = .025) were statistically significant risk factors associated with cancer development.

Conclusions: In the development of breast cancer and ovarian cancer, lifestyle and environmental factors seem to play a statistically significant role in the presence of genetic predisposition associated with BRCA1 and BRCA2 gene mutations.