JNCI Journal of the National Cancer Institute最新文献

Background: The Chronic Lymphocytic Leukemia (CLL) treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemo-free regimens. Frequentist network meta-analysis allows for both direct and indirect comparisons between different treatments.

Methods: Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease (MRD), objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities.

Results: 30 eligible trials involved 12,818 patients and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax (OV) in patients over 65 years old or with unmutated IGHV. In younger patients with comorbidities, Acalabrutinib-Obinutuzumab (AO) had superior PFS compared to Ibrutinib-Obinutuzumab (IO), Ibrutinib-Venetoclax (IV), and OV. For older patients with comorbidities, Acalabrutinib and AO both outperformed OV without significant difference between them. MRD-guided IV surpassed OV in patients without comorbidities. IO exhibited extended PFS benefits compared to OV in patients with mutated IGHV or with del(17p) and/or TP53 mutations. IV and IO have lower neutropenia rates than OV. IV have fewer infections than Acalabrutinib and AO. AO causes less diarrhea than IV but more headaches than IO and OV. OV has lower hypertension rates than IO. IV has fewer arthralgia than AO. For any grade secondary primary neoplasms, IV and OV is less than AO.

Conclusion: Tailored chemo-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different response spectra.

Background: Epidemiologic studies of risk factors for second primary breast cancer (SBC) have been conducted primarily in non-Hispanic White (NHW) women.

Methods: A racially- and ethnically-diverse population-based pooled cohort of 9,639 women with first primary stage I-III invasive breast cancer (FBC) was linked with the California Cancer Registry; 618 contralateral SBC (CSBC) and 278 ipsilateral SBC (ISBC), diagnosed >6 months after FBC, were identified. Using Fine and Gray models accounting for competing risks, we assessed associations of CSBC and ISBC risk with FBC clinical characteristics and epidemiologic factors.

Results: In younger women (FBC at age <50 years), higher CSBC risk was associated with ER/PR-negative FBC [hazard ratio (HR)=1.68], breast cancer family history (HR = 2.20), and nulliparity (HR = 1.37). In older women (FBC at age ≥50 years), higher risk was associated with breast cancer family history (HR = 1.32), premenopausal status (HR = 1.49), overweight (HR = 1.39), and higher alcohol consumption (HR = 1.34). For ISBC, higher risk was associated with married status (HR = 1.94) in younger women, and overweight (HR = 1.60) among older women. For CSBC, HR estimates were generally similar across racial and ethnic groups. Even after adjustment for these risk factors, compared with NHW women, risk remained elevated for CSBC in younger African American, Asian American, and Hispanic women, and for ISBC in older African American and Hispanic women with ER/PR-positive FBC.

Conclusions: Our findings support genetic risk evaluation, enhanced screening, and lifestyle changes in women at higher risk of SBC. Additional risk factors must contribute to the unequal burden of SBC across racial and ethnic groups.

Cancer and its care create substantial financial, time, and administrative burdens both for patients and their loved ones. While cancer-related financial burdens have been well documented in the past decade, time and administrative burdens of cancer care have received substantially less attention. We define time burdens as the burden patients and caregivers experience due to the time needed to complete cancer-related treatment and tasks that take away from other life responsibilities. Relatedly, we conceptualize administrative burdens as those burdens patients and caregivers experience due to cancer-related, resource-consuming bureaucratic and logistical tasks. Finally, financial hardship can be conceptualized as problems patients experience related to the cost of medical care. These burdens do not exist in isolation; time, administrative, and financial burdens intersect with and compound each other. Currently, we have limited evidence-based measures on the objective (e.g., scheduling time, transportation, wait time) and subjective (e.g., mental, emotional and physical stress) measures of time and administrative burden. We have even more limited evidence of the risk factors for and outcomes from increased time and administrative burdens, and how they differentially impact populations across social and demographic groups. In this commentary, we present a research agenda to map, measure, evaluate, and mitigate the time, administrative, and financial burdens of cancer and its care.

Background: Adolescent and young adult (AYA) cancer incidence rates are rising, and survivors are at risk for numerous cancer- and treatment-related consequences. Despite growing attention to this population, prevalence estimates are lacking.

Purpose: To estimate the number of individuals living in the United States with a history of cancer diagnosed during the AYA period.

Methods: Prevalence of cancer survivors diagnosed between the ages of 15 and 39 years was estimated using data from the Surveillance, Epidemiology, and End Results (SEER) program as of January 1, 2020. Limited duration prevalence data were also used to generate complete prevalence by sex, years since diagnosis (0-<1, 1-<5, 5-<10, 10-<15, 15-<20, 20+), and attained age (15-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70+) for the 15 most common AYA cancer sites.

Results: There were an estimated 2,111,838 survivors of AYA cancers in the United States as of January 1, 2020. More survivors were female (66%) and long-term (>5 years from diagnosis, 83%) or very long-term survivors (>10 years from diagnosis, 68.8%). A large percentage (44%) were more than 20 years from diagnosis. The most common cancer sites among females were breast (24%) and thyroid cancers (23%) and, among males, testicular cancer (31%). Across the population, the highest percentage of survivors of AYA cancers were 40- to 49-years of age (25.3%).

Conclusion: There are over 2.1 million cancer survivors diagnosed in the AYA period who are living in the United States; most are more than 10 years from diagnosis.

Background: The effects of usual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites, and breast cancer risk.

Methods: Physical activity levels were assessed using doubly labeled water, accelerometers, and 24-hr recalls in the IDATA study (N = 707 participants, ages 50-74 years, 51% women), with 1-6 assessments over 12 months and two blood sample collections. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of metabolites with postmenopausal breast cancer in a nested case-control study (621 cases, 621 controls), all statistical tests were 2-sided.

Results: Physical activity was associated with 164 metabolites spanning numerous pathways, including amino acid and fatty acid metabolism. Twelve of these metabolites were also associated with breast cancer risk, ten of which supported a protective role of physical activity. Notably, higher physical activity was associated with lower 16alpha-hydroxy DHEA 3-sulfate (androgen) and adipoylcarnitine (fatty acid), both of which were associated with increased breast cancer risk (OR per 1 standard deviation (SD)=1.34, 95% CI = 1.16-1.55 and 1.26,1.11-1.42, respectively). Higher physical activity energy expenditure was also associated with lower sphingomyelin (d18:1/20:1, d18:2/20:0), which was associated with a reduced breast cancer risk (0.82,0.73-0.93).

Conclusion: Physical activity is associated with a broad range of metabolites, many of which are consistent with a protective effect against breast cancer. Our findings highlight potential metabolic pathways for cancer prevention.

A new era of cancer management is underway in which treatments are being developed for the entire continuum of the disease process. The availability of genetically engineered and naturally occurring preclinical models serve as instructive platforms for evaluating therapeutic mechanisms. However, a major clinical challenge is that the entire malignancy process occurs across multiple scales including genetic mutations, malignant changes in cell behavior, dysregulated tumor microenvironments, and systemic adaptations in the host. A multi-disciplinary group of investigators coalesced at the National Cancer Institute Oncology Models Forum (NCI-OMF) with the overall goal to provide updates on the use of precision preclinical models of cancer. The benefits and limitations of preclinical models were discussed in order to identify strategies for maximizing opportunities in modeling that could inform future cancer prevention and treatment approaches. Our shared perspective is that the continuum of single cell, multi-cell, organoid, and in situ models are remarkable resources for the clinical challenges ahead. We provide a roadmap for parsing already available models and include preliminary recommendations for the application of next generation preclinical modeling in cancer intervention.

Background: Determining whether screening with multicancer detection (MCD) tests saves lives requires randomized controlled trials (RCTs). To inform RCT design, we estimated cancer-mortality outcomes from hypothetical MCD RCTs.

Methods: We used the Hu-Zelen model, previously used to plan the NLST, to estimate mortality reductions, sample-size, and power for 9 cancers for different RCT design parameters and MCD test parameters.

Results: Our base-case RCT with 5 yearly screens and 100,000 people ages 60-74 in each arm, who also undergo standard-of-care screens, has 87-89% power to detect an 9-10% mortality reduction (NNS = 578-724) over 7-9 years. The majority of prevented deaths were from lung-cancers (base-case (64-66%) and all sensitivity analyses), 8-10% from colorectal-cancer, and 26% from the other 7-cancers, mostly from stomach/ovary/esophagus (due to excellent stage-1 survival) and less from liver/pancreas (poor stage-1 survival) or head/neck-cancer/lymphoma (excellent stage-4 survival). There was limited power for mortality reductions at most individual cancer sites. Base-case findings were sensitive to test sensitivity, stage-shifts, and mean sojourn times in the preclinical state (especially for lung-cancer), but 90% power could be recovered by recruiting a substantially higher risk population.

Conclusions: Large-scale MCD RCTs would have 89% power to detect a ∼10% cancer-mortality reduction over a relatively short 7-9 year timeframe from trial entry. The estimated NNS for MCD RCTs compares favorably to mammographic screening. Most prevented cancer-deaths in a well-powered MCD RCT would likely be from lung-cancer. Non-lung/CRC cancer sites could be a meaningful proportion of prevented cancer-deaths but power is insufficient to isolate non-lung-cancer mortality reductions.

The Affordable Care Act (ACA) eliminated patient cost-sharing for USPSTF recommended services. However, if the US Court of Appeals for the Fifth Circuit fully upheld a US District Court ruling in Braidwood Management v. Becerra, 666 F. Supp. 3d 613 (N.D. Tex 2023), cost-sharing for USPSTF recommendations made after ACA passage would have been reinstated for over 150 million people. The case could still reinstate cost-sharing for colorectal cancer (CRC) screening for ages 45-49 years and for polyp removal during (diagnostic) colonoscopy across all ages. Using the MISCAN-Colon model, we simulated the potential impact on CRC outcomes, assuming early-onset CRC trends, and lower screening participation. An 8-percentage-points decline in screening participation could increase CRC incidence by 5.1%, and CRC mortality by 9.1%, with slightly lower costs due to increased cost-sharing. Larger decreases in screening participation can result in higher costs from increased incidence and delayed diagnoses.

Background: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor.

Methods: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action.

Results: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype.

Conclusion: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.