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Cancer Prevalence across Vertebrates.
No full textCancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes. See related commentary by Metzger, p. 14
PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma.
No full textIdentification of ARID1A/ATR synthetic lethality led to ATR inhibitor phase II trials in ovarian clear cell carcinoma (OCCC), a cancer of unmet need. Using multiple CRISPR-Cas9 mutagenesis and interference screens, we show that inactivation of protein phosphatase 2A (PP2A) subunits, including PPP2R1A, enhance ATRi sensitivity in ARID1A mutant OCCC. Analysis of a new OCCC cohort indicates that 52% possess oncogenic PPP2R1A p.R183 mutations and of these, one half possessed both ARID1A as well as PPP2R1A mutations. Using CRISPR-prime editing to generate new isogenic models of PPP2R1A mutant OCCC, we found that PPP2R1A p.R183W and p.R183P mutations cause ATRi-induced S phase stress, premature mitotic entry, genomic instability and ATRi sensitivity in OCCC tumour cells. p.R183 mutation also enhanced both in vitro and in vivo ATRi sensitivity in preclinical models of ARID1A mutant OCCC. These results argue for the assessment of PPP2R1A mutations as a biomarker of ATRi sensitivity
A Phase I Clinical Trial of Intrahepatic Artery Delivery of TG6002 in Combination with Oral 5-Fluorocytosine in Patients with Liver-Dominant Metastatic Colorectal Cancer.
Get PDFPURPOSE: Effective treatment for patients with metastatic cancer is limited, particularly for those with colorectal cancer with metastatic liver lesions, in which accessibility to numerous tumors is essential for favorable clinical outcomes. Oncolytic viruses (OV) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoral administration routes. PATIENTS AND METHODS: We conducted a multicenter, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral prodrug 5-fluorocytosine to 15 patients with metastatic colorectal cancer. RESULTS: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by the virus within tumor biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumor, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to the virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer antigens and neoantigens, with elevated functional activity, may be associated with improved anticancer activity. Despite these findings, no clinical efficacy was observed. CONCLUSIONS: In summary, these data demonstrate the delivery of OV to tumor via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data support the need for future studies using IHA administration of OVs
Multidisciplinary evidence-based consensus statements on salvage surgery for recurrent head and neck cancer (International Centre for Recurrent Head and Neck Cancer).
No full textBACKGROUND: Recurrent head and neck squamous cell carcinomas are an understudied subgroup, lacking high-quality evidence and thus gold standard management recommendations, resulting in major variations in practice. The aim of this project was to deliver a national multidisciplinary expert consensus on patients with recurrent head and neck squamous cell carcinoma managed by curative salvage surgery. METHODS: The Appraisal of Guidelines for Research and Evaluation II (AGREEII) protocol guided the Delphi process. Best practice statements were developed after literature review on the perioperative management and surgical salvage of major recurrent head and neck squamous cell carcinoma subsites. Members of the International Centre for Recurrent Head and Neck Cancer network and other UK-based professional stakeholder organizations were invited into an online Delphi study. Participants voted on statements over 3 rounds, with items modified in response to vote thresholds and comments. RESULTS: A total of 28 experts participated, including 11 otolaryngologists, 7 oncologists, 9 oral and maxillofacial surgeons, and 1 speech and language therapist. Consensus was achieved on 73 statements, with 29 (39.7%) achieving unanimous (threshold = 100%) and 25 (34.2%) very strongly supported (threshold > 90%) agreement. CONCLUSIONS: Salvage surgeries for recurrent head and neck squamous cell carcinoma are challenging cases that require intensive multidisciplinary input to achieve cure while balancing impact on function and quality of life. In this article, we provide a large series of statements based on UK-wide expert consensus that will guide clinicians through the complex intra- and perioperative management of patients undergoing surgical salvage
Association between socioeconomic position and lung cancer incidence in 16 countries: a prospective cohort consortium study.
No full textBACKGROUND: Studies have reported higher lung cancer incidence among groups with lower socioeconomic position (SEP). However, it is not known how this difference in lung cancer incidence between SEP groups varies across different geographical settings. Furthermore, most prior studies that assessed the association between SEP and lung cancer incidence were conducted without detailed adjustment for smoking. Therefore, we aimed to assess this relationship across world regions. METHODS: In this international prospective cohort consortium study, we used data from the Lung Cancer Cohort Consortium (LC3), which includes 20 prospective population cohorts from 16 countries in North America, Europe, Asia, and Australia. Participants were enrolled between 1985 and 2010 and followed for cancer outcomes using registry linkages and/or active follow-up. We estimated hazard ratios (HRs) for the association between educational level (our primary measure of SEP, in 4 categories) and incident lung cancer using Cox proportional hazards models separately for participants with and without a smoking history. The models were adjusted for age, sex, cohort (when multiple cohorts were included), smoking duration, cigarettes per day, and time since cessation. FINDINGS: Among 2,487,511 participants, 53,830 developed lung cancer during a 13.5-year median follow-up (IQR = 6.5-15.0 years). Among participants with a smoking history, higher education was associated with decreased lung cancer incidence in nearly every cohort after detailed smoking adjustment. By world region, this association was observed in North America (HR per one-category increase in education [HRtrend] = 0.88, 95% CI = 0.87-0.89), Europe (HRtrend = 0.89, 95% CI = 0.88-0.91), and Asia (HRtrend = 0.91, 95% CI = 0.86-0.96), but not in the Australian study (HRtrend = 1.02, 95% CI = 0.95-1.09). By histological subtype, education associated most strongly with squamous cell carcinoma and more weakly with adenocarcinoma (p-heterogeneity 0.05), except the USA Southern Community Cohort Study (HRtrend = 0.75, 95% CI = 0.62-0.90). INTERPRETATION: Based on longitudinal data from 2.5 million participants from 16 countries, our findings suggest that higher educational attainment was associated with lower lung cancer risk among participants with a smoking history, but not among participants who never smoked. Limitations of our study include that cohort participants cannot fully represent the general populations of the geographical regions included, and education was the only measure of SEP consistently available across our consortium. FUNDING: This study was supported in part by the National Cancer Institute (NCI), the Lung Cancer Research Foundation (LCRF), and the World Cancer Research Fund (WCRF)
Clinical challenges and proposed solutions for patients with invasive lobular breast cancer.
No full textBACKGROUND: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer and is increasingly recognized as a separate entity from invasive breast cancer of no-special type. Here, we present the current standings and challenges of clinical ILC research and discuss possible solutions to address these challenges. DESIGN: European and United States experts on ILC have summarized the recent developments, ongoing endeavors and remaining challenges concerning the histopathological diagnosis, imaging and treatment of ILC. RESULTS: Recent endeavors have led to guidelines for a more uniform and standardized pathological diagnosis of ILC. Future efforts are needed to refine the histological and biological subclassification and determine the indications for use of artificial intelligence for pathological diagnosis. Since standard-of-care imaging tools are suboptimal for ILC screening and local and systemic staging, new modalities such as contrast-enhanced mammography, novel positron emission tomography tracers and diffusion-weighted magnetic resonance imaging are under investigation. An alternative to the currently used RECIST v1.1 criteria is needed for clinical trial response assessment, as it is not uniformly applicable for patients with metastatic ILC. The use of liquid biopsies for detecting disease progression needs dedicated research. Regarding treatment, the efficacy of novel breast cancer therapies needs to be examined specifically for ILC, and evaluation of drugs targeting ILC-specific or enriched targets is warranted. CONCLUSIONS: While great progress has been made in ILC research, many challenges remain and require further investigation in the clinic to optimize treatment and outcomes for those diagnosed with this common tumor type
CODAK: Real-World Clinical Outcomes of Patients With Unresectable, Stage III Non-Small Cell Lung Cancer Treated With Durvalumab After Chemoradiotherapy in the United Kingdom.
No full textAIMS: The aim of this study was to describe the clinical outcomes, demographics, and clinical characteristics of patients with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) treated with durvalumab as part of the UK early access programme or post reimbursement. MATERIALS AND METHODS: CODAK (NCT04667312) was a multicentre, noninterventional, cohort study of patients (N = 114) with locally advanced, unresectable, stage III NSCLC initiated on durvalumab between 1 September 2017 and 31 December 2019 following concurrent or sequential chemoradiotherapy (CRT) in the UK, with retrospective data collection from 10 clinical centres. The primary outcome was the real-world overall survival (rwOS) rate at 12 and 24 months post durvalumab initiation. RESULTS: Of the 114 patients included, 47 (41.2%) were aged ≥70 years and 67 (58.7%) were male. Median follow-up time from durvalumab initiation was 22 months. The 12-month rwOS rate was 80.2% (95% confidence interval [CI]: 73.1-88.0), and the 24-month rate was 63.0% (54.1-73.4). Median rwOS was 35.9 months (95% CI: 35.9 to not reached [NR]) in the overall cohort. Before durvalumab initiation, 85.1% (97/114) received concurrent CRT and 13.2% (15/114) received sequential CRT (two unknown). In the overall cohort, median real-world progression-free survival was 28.5 months (95% CI: 16.4-NR). The median time to durvalumcab treatment discontinuation was 8.7 months (95% CI: 6.2-11.2). Thirty-three patients (28.9%) discontinued durvalumab treatment due to adverse events (AEs). Pneumonitis/interstitial lung disease (ILD) was the most common AE leading to discontinuation among all patients (19/114 [16.7%]). Eleven patients (9.6%) had at least one interruption due to pneumonitis/ILD. CONCLUSION: CODAK provides data from the UK that add to real-world evidence showing that durvalumab following CRT is an effective standard of care for patients with unresectable, stage III NSCLC
CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
No full textThe energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy
Effect of prior and first-line immunotherapy on baseline immune biomarkers and modulation of the tumor microenvironment in response to nivolumab and relatlimab combination therapy in patients with melanoma from RELATIVITY-020.
No full textBACKGROUND: Some patients with melanoma experience disease progression during immunotherapy (IO) and may benefit from novel combinations of immune checkpoint inhibitors (ICIs). We report results from exploratory biomarker analyses to characterize the responses of patients with advanced melanoma to treatment with nivolumab (anti-programmed cell death-1 (PD-1)) and relatlimab (anti-lymphocyte-activation gene 3 (LAG-3)) combination therapy in RELATIVITY-020 (NCT01968109). METHODS: Tumor biopsies collected at baseline and ≤4 weeks after treatment initiation were evaluated for % LAG-3-positive and % CD8-positive immune cells and % programmed death-ligand 1 (PD-L1) expression on tumor cells. Baseline biomarker expression was compared among patients with IO-refractory melanoma based on last prior therapy and IO-resistance type, and between patients with IO-refractory and IO-naïve melanoma. Change in biomarker expression after treatment was evaluated in patients with IO-refractory and IO-naïve melanoma. Immune-related gene expression was compared among resistance groups and by the last prior treatment. RESULTS: Among patients with IO-refractory melanoma (N=505), elevated baseline LAG-3, PD-L1, and CD8 expression (p≤0.01, p≤0.05, p≤0.001, respectively) was observed in patients whose last prior therapy was IO versus non-IO, and in those who responded (complete/partial per Response Evaluation Criteria in Solid Tumors V.1.1) to nivolumab and relatlimab combination therapy versus those who did not (stable/progressive disease). Inflammation-related gene expression was significantly higher (p<0.05) in patients with secondary versus primary resistance to prior IO treatment, and in those whose last prior therapy was IO versus non-IO. IO-refractory patients whose tumors responded to nivolumab and relatlimab combination therapy had higher inflammation-related gene expression than non-responders (p<0.05); proliferation and hypoxia-related gene expression were enriched in non-responders. During treatment with nivolumab and relatlimab combination therapy, LAG-3 expression increased significantly in patients with IO-refractory (p≤0.01) and IO-naïve melanoma (p≤0.001), and PD-L1 and CD8 increased significantly (p≤0.01 and p≤0.05, respectively) in patients with IO-naïve melanoma. CONCLUSIONS: Nivolumab and relatlimab combination therapy can modulate the tumor microenvironment in patients with both IO-refractory and IO-naïve melanoma. Further research is needed to identify patients who will most benefit from anti-LAG-3/PD-(L)1 agents, and to elucidate the mechanisms of action of, and resistance to, this combination therapy in patients with advanced melanoma. TRIAL REGISTRATION NUMBER: NCT01968109