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Best Overall Response-Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.
No full textPURPOSE: This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. EXPERIMENTAL DESIGN: RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation. RESULTS: A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e-7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. CONCLUSIONS: The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended
First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.
No full textPURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts
Age-Specific Cancer Mortality in the US During the COVID-19 Pandemic, March to December 2020.
No full textBACKGROUND: It is important to understand the impact of the COVID-19 pandemic on cancer death rates in 2020 in the US. We estimated whether there were larger-than-expected changes in cancer mortality rates from March to December 2020 after accounting for temporal and seasonal patterns using data from January 2011 to February 2020 by cancer type and age. METHODS: We obtained death counts and underlying causes of death by cancer type, month/year (2011-2020), and age group from the National Center for Health Statistics and population estimates from the US Census Bureau. Poisson regression was used to test for significant changes in cancer death rates from March to December 2020 compared with prior years. RESULTS: After accounting for temporal trends and seasonal patterns, total cancer death rates were significantly lower than expected during March to December 2020 among 55- to 64-year-olds and ≥75-year-olds, but not in other age groups. Cancer death rates were 2% lower than expected from March to June among 55- to 64-year-olds and 2% to 3% lower from March to July and December among ≥75-year-olds. Among ≥75-year-olds, colorectal cancer death rates were lower from March to June [rate ratios (RR) = 0.94-0.96; P < 0.05]; however, lung cancer death rates were 5% lower across each month (all RRs = 0.95; P < 0.05). CONCLUSIONS: In the US, cancer death rates based on the underlying cause of death were broadly similar to expected rates from March to December 2020. However, cancer death rates were lower than expected among 55- to 64-year-olds and ≥75-year-olds, likely due to COVID-19 as a competing cause of death. IMPACT: Cancer mortality rates from 2020 should be interpreted with caution
Cross-sectional analyses of online appointment booking and repeat prescription ordering user characteristics in general practices of England in the years 2018-2020.
No full textOBJECTIVES: To explore the characteristics of the General Practice Patient Survey (GPPS) respondents using the different functionalities of the online services in the context of England's National Health Service General Practices. We hypothesised that respondents who are older, with lower socioeconomic status and non-white ethnicity would be less likely to use online services, while long-term conditions might increase their usage. DESIGN: Cross-sectional study using respondent-level data from the GPPS in England of the years 2018, 2019 and 2020. We assessed the association between online services use and respondent characteristics using two-level mixed-effects logistic regression. PARTICIPANTS: Survey respondents of the GPPS 2018-2020. PRIMARY OUTCOME MEASURES: Online appointment booking and online repeat prescription ordering. RESULTS: 1 807 049 survey respondents were included in this study. 15% (n=263 938) used online appointment booking in the previous 12 months, and 19% (n=339 449) had ordered a repeat prescription in the previous 12 months. Respondents with a long-term condition, on regular multiple medications, who have deafness or hearing loss and who are from the lowest deprivation quintile were more likely to have used online services. Male respondents (compared with females) and respondents with black and other ethnicity compared with white ethnicity were less likely to use online services. Respondents over 85 years old were less likely to use online appointment booking and online repeat prescription ordering compared with the younger age groups. CONCLUSIONS: Specific groups of respondents were more likely to use online services such as patients with long-term conditions or those with deafness or hearing loss. While online services could provide efficiency to patients and practices it is essential that alternatives continue to be provided to those that cannot use or choose not to use online services. Understanding the different patients' needs could inform solutions to increase the uptake and use of the services
Topographic analysis of pancreatic cancer by TMA and digital spatial profiling reveals biological complexity with potential therapeutic implications.
No full textPancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-β axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer
Proteomic features of soft tissue tumours in adolescents and young adults.
No full textBACKGROUND: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes. METHODS: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8). RESULTS: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. CONCLUSIONS: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients
Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project.
No full textTesticular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression
Final analysis of the ALTTO trial: adjuvant trastuzumab in sequence or in combination with lapatinib in patients with HER2-positive early breast cancer [BIG 2-06/NCCTG N063D (Alliance)].
No full textBACKGROUND: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial. PATIENTS AND METHODS: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety. RESULTS: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups. CONCLUSIONS: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy
Advanced Imaging for the assessment of Colorectal Liver Metastases
No full textThis thesis explores the deployment of advanced imaging techniques in the management of patients with colorectal liver metastases, emphasizing the role of artificial intelligence (AI), abbreviated MRI protocols, quantitative CT and MRI assessment for the assessment of colorectal liver metastasis at disease diagnosis and follow-up. The research aims to improve diagnostic accuracy, treatment planning, and outcome assessment through innovative imaging approaches.
First, the application of AI in MRI reconstructions is evaluated. AI algorithms are being employed to swiftly reconstruct higher-resolution images from MRI scans, thereby reducing scan times and improving imaging efficiency. This advancement has the potential to improve patient discomfort through reducing acquisition time in clinical practice, while maintaining or enhancing diagnostic accuracy.
Second, acknowledging the growing demands for using MRI, the performance of a 10-15 minute long abbreviated liver MRI protocol following the initial diagnosis of liver metastases on CT is assessed. Although abbreviated MRI protocols have been shown effective for assessing response and segmental liver involvement for the follow-up of colorectal liver metastasis, their use for the initial baseline assessments to evaluate the presence and site of liver metastases is unclear. This research seeks to address this gap and assess the benefits for disease and surgical staging.
Third, the application of quantitative MRI to evaluate treatment response of SBRT is examined. SBRT represents a significant advancement in radiation therapy, enabling the precise delivery of high doses of radiation to tumours while sparing surrounding healthy tissue. Despite its promise in treating colorectal liver metastases, challenges remain in disease response assessment. This research aims to identify imaging parameters for identifying response and treatment benefits.
Last, the potential surgical impact of hepatic steatosis assessed using CT imaging on pre-operative imaging is also investigated. Hepatic steatosis, which can be prevalent in the general population but specifically in patients with colorectal cancer due to neoadjuvant systemic treatments, is associated with an increased risk of postoperative complications. Anecdotally, surgeons report that steatotic livers bleed more than non-steatotic livers during surgery which may further increase morbidity. The study will explore hepatic steatosis as a potential risk factor for peri-operative morbidity and blood loss, which can contribute to more informed surgical decision-making.
In summary, in this project, I will evaluate non-invasive and novel approaches by applying different state-of- the-art imaging techniques to improve the detection of metastatic liver lesions, in the preoperative mapping of colorectal liver metastases (both before and after neoadjuvant chemotherapy), for the assessment of treatment response and for informing perioperative complications
YAP activation is robust to dilution.
Get PDFThe concentration of many transcription factors exhibits high cell-to-cell variability due to differences in synthesis, degradation, and cell size. Whether the functions of these factors are robust to fluctuations in concentration, and how this may be achieved, is poorly understood. Across two independent panels of breast cancer cells, we show that the average whole cell concentration of YAP decreases as a function of cell area. However, the nuclear concentration distribution remains constant across cells grouped by size, across a 4-8 fold size range, implying unperturbed nuclear translocation despite the falling cell wide concentration. Both the whole cell and nuclear concentration was higher in cells with more DNA and CycA/PCNA expression suggesting periodic synthesis of YAP across the cell cycle offsets dilution due to cell growth and/or cell spreading. The cell area - YAP scaling relationship extended to melanoma and RPE cells. Integrative analysis of imaging and phospho-proteomic data showed the average nuclear YAP concentration across cell lines was predicted by differences in RAS/MAPK signalling, focal adhesion maturation, and nuclear transport processes. Validating the idea that RAS/MAPK and cell cycle regulate YAP translocation, chemical inhibition of MEK or CDK4/6 increased the average nuclear YAP concentration. Together, this study provides an example case, where cytoplasmic dilution of a protein, for example through cell growth, does not limit a cognate cellular function. Here, that same proteins translocation into the nucleus