5728 research outputs found
Sort by
The untapped potential of radiation and immunotherapy for hormone receptor-positive breast cancer.
No full textHormone receptor-positive breast cancers are a diverse group of tumours, with only some responding well to immunotherapy. Alternative combination strategies such as radiotherapy present an exciting opportunity to improve immunotherapy responses. We review an intriguing overlap between the impact of oestrogen signalling and radiation on multiple signalling pathways and immune cells that may be exploited for therapeutic gains in breast cancer. This is synthesised with the pre-clinical data and clinical trial landscape supporting the use of combined radiation and immunotherapy to derive insights for future neo-adjuvant trial design
Alcohol intake and pancreatic cancer risk: An analysis from 30 prospective studies across Asia, Australia, Europe, and North America.
No full textBACKGROUND: Alcohol is a known carcinogen, yet the evidence for an association with pancreatic cancer risk is considered as limited or inconclusive by international expert panels. We examined the association between alcohol intake and pancreatic cancer risk in a large consortium of prospective studies. METHODS AND FINDINGS: Population-based individual-level data was pooled from 30 cohorts across four continents, including Asia, Australia, Europe, and North America. A total of 2,494,432 participants without cancer at baseline (62% women, 84% European ancestries, 70% alcohol drinkers [alcohol intake ≥ 0.1 g/day], 47% never smokers) were recruited between 1980 and 2013 at the median age of 57 years and 10,067 incident pancreatic cancer cases were recorded. In age- and sex-stratified Cox proportional hazards models adjusted for smoking history, diabetes status, body mass index, height, education, race and ethnicity, and physical activity, pancreatic cancer hazard ratios (HR) and 95% confidence intervals (CI) were estimated for categories of alcohol intake and in continuous for a 10 g/day increase. Potential heterogeneity by sex, smoking status, geographic regions, and type of alcoholic beverage was investigated. Alcohol intake was positively associated with pancreatic cancer risk, with HR30-to-<60 g/day and HR≥60 g/day equal to 1.12 (95% CI [1.03,1.21]) and 1.32 (95% CI [1.18,1.47]), respectively, compared to intake of 0.1 to <5 g/day. A 10 g/day increment of alcohol intake was associated with a 3% increased pancreatic cancer risk overall (HR: 1.03; 95% CI [1.02,1.04]; pvalue < 0.001) and among never smokers (HR: 1.03; 95% CI [1.01,1.06]; pvalue = 0.006), with no evidence of heterogeneity by sex (pheterogeneity = 0.274) or smoking status (pheterogeneity = 0.624). Associations were consistent in Europe-Australia (HR10 g/day = 1.03, 95% CI [1.00,1.05]; pvalue = 0.042) and North America (HR10 g/day = 1.03, 95% CI [1.02,1.05]; pvalue < 0.001), while no association was observed in cohorts from Asia (HR10 g/day = 1.00, 95% CI [0.96,1.03]; pvalue = 0.800; pheterogeneity = 0.003). Positive associations with pancreatic cancer risk were found for alcohol intake from beer (HR10 g/day = 1.02, 95% CI [1.00,1.04]; pvalue = 0.015) and spirits/liquor (HR10 g/day = 1.04, 95% CI [1.03,1.06]; pvalue < 0.001), but not wine (HR10 g/day = 1.00, 95% CI [0.98,1.03]; pvalue = 0.827). The differential associations across geographic regions and types of alcoholic beverages might reflect differences in drinking habits and deserve more investigations. CONCLUSIONS: Findings from this large-scale pooled analysis support a modest positive association between alcohol intake and pancreatic cancer risk, irrespective of sex and smoking status. Associations were particularly evident for baseline alcohol intake of at least 15 g/day in women and 30 g/day in men
Exploiting collateral sensitivity in the evolution of resistance to tyrosine kinase inhibitors in soft tissue sarcomas.
No full textBroad-spectrum multi-target tyrosine kinase inhibitors (mTKIs) are clinically approved for the treatment of soft tissue sarcomas (STS). However, acquired resistance inevitably arises in the majority of STS patients. There is therefore an urgent need to identify new strategies to overcome resistance and achieve durable treatment responses. Here we show that STS cells that acquire resistance to clinically relevant mTKIs are cross-resistant to one another and sequential treatment does not delay the acquisition of drug resistance. Instead, we find that en route to acquiring drug resistance, STS cells develop collateral sensitivities to alternative drugs. We demonstrate that the mTKI sitravatinib rapidly induces collateral sensitivity to the FGFR inhibitor infigratinib which can be exploited for adaptive therapy to suppress STS cell growth. This study provides proof-of-principle that collateral sensitivity may be an effective strategy for overcoming resistance to mTKIs and this novel approach should be explored in the design of future trials
SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer.
No full textElucidating the complex network of communication between tumour cells is central to understanding cell fate decisions and progression of pancreatic ductal adenocarcinoma (PDAC)1,2. We previously showed that constant suppression of BMP activity by the BMP antagonist GREM1 secreted by mesenchymal PDAC cells is essential for maintaining the fate of epithelial PDAC cells3. Here we identify SPP1 (also known as osteopontin)4 as a key regulator of mesenchymal cell fate in pancreatic cancer. Proteomic analysis of plasma from patients with PDAC showed that SPP1 is substantially upregulated in late-stage disease. Inactivation of Spp1 led to a delay in tumorigenesis in mouse PDAC models and abolished metastasis formation. Spp1 was expressed in epithelial PDAC cells, and Spp1 inactivation resulted in a conversion of mesenchymal to epithelial PDAC cells. Mechanistically, SPP1 bound the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression, and GREM1 inhibition of BMP signalling was required for Spp1 expression in epithelial cells, thereby forming an intercellular regulatory loop. Concomitant inactivation of Grem1 reverted the epithelial phenotype of Spp1 knockout to fully mesenchymal PDAC. Conversely, Grem1 heterozygosity combined with Spp1 knockout resulted in wild-type PDAC histology, a result that confirmed the direct antagonistic functions of these factors. Hence, mesenchymal and epithelial PDAC cell fates are determined by the reciprocal paracrine regulation of the soluble factors GREM1 and SPP1
Analysis of more than 400,000 women provides case-control evidence for <i>BRCA1</i> and <i>BRCA2</i> variant classification
No full textDevelopment and validation of a risk prediction model for premenopausal breast cancer in 19 cohorts.
No full textBACKGROUND: Incidence of premenopausal breast cancer (BC) has risen in recent years, though most existing BC prediction models are not generalizable to young women due to underrepresentation of this age group in model development. METHODS: Using questionnaire-based data from 19 prospective studies harmonized within the Premenopausal Breast Cancer Collaborative Group (PBCCG), representing 783,830 women, we developed a premenopausal BC risk prediction model. The data were split into training (2/3) and validation (1/3) datasets with equal distribution of cohorts in each. In the training dataset variables were chosen from known and hypothesized risk factors: age, age at menarche, age at first birth, parity, breastfeeding, height, BMI, young adulthood BMI, recent weight change, alcohol consumption, first-degree family history of BC, and personal history of benign breast disease (BBD). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression using age as time scale, stratified by cohort. Given that complete information on all risk factors was not available in all cohorts, coefficients were estimated separately in groups of cohorts with the same available covariate information, adjusted to account for the correlation between missing and non-missing variables and meta-analyzed. Absolute risk of BC (in situ or invasive) within 5 years, was determined using country-, age-, and birth cohort-specific incidence rates. Discrimination (area under the curve, AUC) and calibration (Expected/Observed, E/O) were evaluated in the validation dataset. We compared our model with a literature-based model for women < 50 years (iCARE-Lit). RESULTS: Selected model risk factors were age at menarche, parity, height, current and young adulthood BMI, family history of BC, and personal BBD history. Predicted absolute 5-year risk ranged from 0% to 5.7%. The model overestimated risk on average [E/O risk = 1.18 (1.14-1.23)], with underestimation of risk in lower absolute risk deciles and overestimation in upper absolute risk deciles [E/O 1st decile = 0.59 (0.58-0.60); E/O 10th decile = 1.48 (1.48-1.49)]. The AUC was 59.1% (58.1-60.1%). Performance was similar to the iCARE-Lit model. CONCLUSION: In this prediction model for premenopausal BC, the relative contribution of risk factors to absolute risk was similar to existing models for overall BC. The discriminatory ability was nearly identical (< 1% difference in AUC) to the existing iCARE-Lit model developed in women under 50 years. The inability to improve discrimination highlights the need to investigate additional predictors to better understand premenopausal BC risk
The Spectrum of IDH- and H3-Wildtype High-Grade Glioma Subgroups Occurring across Teenage and Young Adult Patient Populations.
No full textPURPOSE: High-grade gliomas (HGG) occur in any central nervous system location and at any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterize these tumors to support accurate stratification of patients. EXPERIMENTAL DESIGN: 207 histone/IDH wild-type tumors from patients aged 13 to 30 years were collected. DNA methylation profiling [Illumina EPIC BeadArrays, brain tumor classifier (MNPv12.8 R package)] classified cases against reference cohorts of HGG. Calibrated scores guided characterization workflows [RNA-based ArcherDx fusion panel (n = 92), whole-exome sequencing (n = 107), and histology review). RESULTS: 53.4% (n = 86) matched as pediatric-type subgroups [pedHGG_RTK1A/B/C (31.7%, n = 51, PDGFRA, CDKN2A/B, SETD2, and NF1 alterations), pedHGG_MYCN (8.1%, n = 13, MYCN/ID2 amplifications), and pedHGG_RTK2A/B (7.5%, n = 12, TP53, BCOR, ATRX, and EGFR alterations)]. Eighteen percent (n = 29) classified as adult-type subgroups [GBM_MES (15.5%, n = 25, enriched for RB1, PTEN, and NF1 alterations) and GBM_RTK1/2 (2.5%, n = 4, CDK4 amplifications)]. Twenty-three cases (14.7%) classified as novel, poorly characterized subgroups with distinct methylation profiles and molecular features [pedHGG_A/B (n = 10 6.2%), HGG_E (n = 6 3.7%), HGG_B (n = 2 1.0%), and GBM_CBM (n = 5 3.1%)] with variable histologic morphology. Eight cases (5.1%) showed hypermutator phenotypes, enriched in HGG_E, one of which was associated with constitutional mismatch repair deficiency, and their sibling, who was diagnosed with the same syndrome, was diagnosed with a tumor that classified as a pedHGG_RTK1B. HGGs that have developed on a background of previous treatment for a childhood cancer are detected in the TYA population, classifying most frequently as pedHGG_RTK1 and contributing to the poor prognosis of this subgroup. Age distribution/molecular profile comparisons using publicly available methylation/sequencing data (and from local diagnostic cohorts) for HGG_B (n = 19), GBM_CBM (n = 35), and GBM_MES_ATYP (n = 102), irrespective of age, show that HGG_B is a TYA-specific subgroup (median age 29 years) and that GBM_CBM and GBM_MES_ATYP show a peak of distribution in the TYA population but also have a wider age distribution (median age 35.7 and 50.5 years, respectively), with the latter showing distinct differences in copy-number profiles compared with older adults in the same subgroup and containing fewer chr7 gains, chr10 losses, more CDKN2A/B deletions and MET amplifications, and a worse survival compared with adult-specific GBM_MES_TYP. CONCLUSIONS: TYA HGGs comprise novel methylation subgroups with distinct methylation and molecular profiles. Accurate stratification of these patients will open opportunities to more effective treatments, including immune checkpoint, MAPK pathway, and PDGFRA inhibitors. See related commentary by Ritzmann et al., p. 3110
Multiparametric magnetic resonance imaging for radiotherapy response evaluation in high-risk soft tissue sarcoma: A pilot study.
No full textBACKGROUND AND PURPOSE: Soft tissue sarcomas (STS) are rare mesenchymal tumors for which no clinically validated quantitative magnetic resonance imaging (qMRI) parameters exist yet.This study explores repeatability and association with histopathology of qMRI parameters during and after neo-adjuvant angiogenesis inhibition (oral pazopanib) and radiotherapy for localized, high-risk STS. MATERIALS AND METHODS: For fifteen patients, qMRI parameters, including apparent diffusion coefficient (ADC), volume transfer constant (Ktrans) and T2 relaxation times were acquired twice at baseline (B1 and B2), twice during neo-adjuvant treatment and pre-surgery. For all three parameters, the mean was determined per tumor. Subsequently, repeatability coefficient (RC or %RC) was assessed from B1 and B2 mean values. Mixed models were estimated to study the association between percentage viable cells from histopathology and absolute change from baseline (ΔqMRI) for ADC mean and percentage change from baseline (%ΔqMRI) for T2 and Ktrans at each time point. RESULTS: RC was 0.17 × 10-3 mm2/s for ADC and %RC was, 5 % and 65 % for T2 and Ktrans, respectively.The changes in mean ADC and T2 showed both increases and decreases at each timepoint, whereas mean Ktrans predominantly showed decreases. ΔqMRI for ADC mean, %ΔqMRI for T2 mean and %ΔqMRI for Ktrans mean showed no statistically significant association with % viable cells. CONCLUSION: This pilot study reported relatively low repeatability coefficients for ADC and T2 and a higher repeatability coefficient for Ktrans and showed heterogeneous changes in qMRI parameters in fifteen STS patients, however with no association between these parameters and percentage viable cells
The Breast International Group (BIG) Patient Partnership: Embedding meaningful patient involvement in the design and conduct of breast cancer clinical research.
No full textInvolving those with a lived experience of the relevant condition in the design of clinical research ensures that studies address real-world needs and priorities, enabling more relevant, ethical, and impactful outcomes. In 2019, the Breast International Group (BIG) established the BIG Patient Partnership to facilitate the meaningful involvement of people affected by breast cancer in the design and conduct of its studies. The members provide a strong international patient voice in academic breast cancer research. The partnership is based on 4 pillars: foundational and ongoing training, meaningful and systematic involvement, patients as a strategic driving force in BIG's research, and promoting the value of the patients' voice in research. In this paper, we describe a model to enable performing transnational clinical research for and with patient partners. We hope to inspire organizations and people who are burdened by cancer from different cultural backgrounds to develop an interactive, engaging, and empowering process for researchers and patient partners to work together
Somatic evolution following cancer treatment in normal tissue.
No full textThe extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing1 (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305-2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution