Showing papers by "Jan Budczies published in 2023"
TL;DR: In this article , the authors proposed a harmonized framework for health technology assessment across the European Union (EU) to facilitate the extraction of real-world data (RWD) suitable for approval and pricing with minimal effort.
Abstract: Leveraging real‐world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low‐prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or “best” supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan‐European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient‐reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient‐level data) suitable for approval and pricing with minimal effort. For an EU‐wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off‐label use could potentially also be harmonized across EU‐states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.
1 citations
TL;DR: The European Parliament and the Council of the European Union (EC) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament, the Council and the EU Council on 5 April 2017 and came into force on 26 May 2017 as discussed by the authors .
Abstract: Abstract Background Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. A new amending regulation, which introduces a phased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices (IVDs) and a later date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021. The combined use of CE-certified IVDs (CE-IVDs), in-house IVDs (IH-IVDs), and research use only (RUO) devices are a cornerstone of diagnostics in pathology departments and crucial for optimal patient care. The IVDR not only regulates the manufacture and placement on the market of industrially manufactured IVDs, but also imposes conditions on the manufacture and use of IH-IVDs for internal use by healthcare facilities. Objectives Our work provides an overview of the background and structure of the IVDR and identifies core areas that need to be interpreted and fleshed out in the context of the legal framework as well as expert knowledge. Conclusions The gaps and ambiguities in the IVDR crucially require the expertise of professional societies, alliances, and individual stakeholders to successfully facilitate the implementation and use of the IVDR in pathology departments and to avoid aberrant developments.
TL;DR: In this paper , a cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein-Gensler (BG) risk model.
Abstract: The prognostic significance of tumour budding (TB) and minimal cell nest size (MCNS) was shown in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC). However, the optimisation of cutpoints, the prognostic impact in HPV-positive HNSCC, and the comparison with other histopathological grading systems are insufficiently investigated.TB and MCNS were analysed digitally in 1 and 10 high-power fields (HPF) of 331 HPV-positive and HPV-negative cases from TCGA. Optimising the cutpoints a new cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein-Gensler (BG) risk model.The two-tiered CDG system based solely on TB yielded optimal prognostic stratification with shortened overall survival for CDG-high cases. Optimal cut-offs were two buds (1 HPF) and six buds (10 HPF), respectively. Analysing MCNS did not add prognostic significance to quantifying TB. CDG was a significant prognostic marker in HPV-negative and HPV-positive tumours and prognostically superior to the WHO and BG systems. High CDG was associated with clinically occult lymph-node metastases.The most comprehensive study of TB in HNSCC so far confirmed its prognostic impact in HPV-negative tumours and for the first time in HPV-positive tumours. Further studies are warranted to evaluate its applicability for therapy guidance in HNSCC.
TL;DR: In this article , an expression-based analysis of breast cancer tumors was performed to determine if it is prognostic and/or predictive of response to paclitaxel-based therapy in the GeparSepto (G7) trial.
Abstract: Abstract Purpose: Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426). Experimental Design: Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA “hot,” “warm,” or “cold” by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined. Results: iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low. Conclusions: Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.
TL;DR: Budczies et al. as discussed by the authors performed a comprehensive mRNA expression analysis in 24 cancer types of the TCGA to extract a consensus expression signature shared across TP53 mutation types and cancer types, and differential gene expression patterns between different TP53 mutations such as LOF, GOF, as well as dominant negative mutations, and cancer type specific gene expression pattern.
Abstract:
TP53 mutations are the most common single gene alteration in human cancer with diagnostic and prognostic implications in some cancer types. While no TP53-targeting therapeutics have been approved in the USA or Europe yet, drugs tailored to specific TP53 mutations, restoring the functionality of mutated TP53 (TP53mut), and protecting TP53 from negative regulation are being explored in preclinical studies and clinical trials. We performed a comprehensive mRNA expression analysis in 24 cancer types of the TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between different TP53 mutation types such as LOF, GOF, as well as dominant-negative mutations, and (iii) cancer types specific gene expression patterns. Mutational hotspots showed a similar pattern across cancer types, but at the same time prevalence was significantly different between cancer types for about half of the most prevalent hotspots. Both can be explained in part by the mutational processes operational for example the clock-like process behind SBS1 that is operational across cancer types and aflatoxin exposure assocated with SBS24 that ist operational in liver hepatocellular carcinoma. Virtually no genes were differential between tumors harboring different types of TP53 mutations in none of the cancer types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus gene list of 178 common over- and 32 common underexpressed genes was shared between at least two-thirds of the 24 cancer types. Analysis of the immune tumor microenvironment revealed exclusively decreased immune cell populations in the TP53mut tumors in six, a mixed pattern in four, exclusively increased immune cell populations in two, and no significant alterations in 20 cancer subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and support the development of novel strategies for therapeutic targeting of TP53mut.
Citation Format: Jan Budczies, Eva Romanovsky, Klaus Kluck, Iordanis Ourailidis, Michael Menzel, Susanne Beck, Markus Ball, Daniel Kazdal, Petros Christopoulos, Peter Schirmacher, Thorsten Stiewe, Albrecht Stenzinger. Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by comprehensive mRNA expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2607.
TL;DR: In this paper , a series of 100 poorly differentiated ovarian carcinoma samples was analyzed using whole exome sequencing (WES) and genotyping, and tumor purity was determined using conventional pathology, digital pathology, and two bioinformatic methods.
TL;DR: In this article , a retrospective study included all NSCLC patients with KRAS mutated non-small-cell lung cancer (NSCLC) treated in the Thoraxklinik Heidelberg from 01/2014 until 01/2021.
Abstract: 9090 Background: Interest has surged for KRAS mutated ( KRASmut) non-small-cell lung cancer (NSCLC) after approval of the covalent KRASG12C inhibitors sotorasib and adagrasib. It remains unclear, how prognosis of these tumors is influenced by co-mutations and which cases could benefit most from novel drugs alongside immunotherapy (IO) or chemo-immunotherapy (CHT-IO). Methods: This retrospective study included all NSCLC patients with KRASmut NSCLC treated in the Thoraxklinik Heidelberg from 01/2014 until 01/2021. For molecular profiling, PCR-based next-generation sequencing (NGS) was performed with a 40-gene panel, including TP53, KEAP1 and STK11. Date of progression was verified through reevaluation of radiologic images by the investigators according to RECIST v1.1. Stratification was performed according to the type of KRAS mutation (G12C vs. other), presence of TP53, STK11 and KEAP1 co-mutations ( vs. wild-type [WT] status), and the PD-L1 tumor proportion score (TPS < 1 aka PD-L1neg, vs. TPS 1-49, vs. TPS 50+ aka PD-L1high). Results: Among 370 identified patients, no differences (all p-values > 0.08) were observed between KRASG12C (n = 163) and KRASnon-G12C (n = 207) regarding clinicopathological features, like age (median 65 years), sex, smoking status, initial ECOG performance status, PD-L1 TPS, type of treatment in any line, number of treatment lines, and overall survival (OS, 19.4 months in median; details in the poster). In contrast, there was a strong association of PD-L1 TPS with OS (20.2 vs. 9.7 months for PD-L1high vs. PD-L1neg, p = 0.011) and progression-free survival (PFS, 5.7 vs. 1.9 months, p = 0.004) under IO. In addition, specifically within the PD-L1neg subset, OS was longer for KRASG12C compared to KRASother patients (22.6 months vs. 12.1 months, p = 0.032). This was driven by the longer PFS under CHT-IO (9.7 vs. 4.5 months for KRASG12C vs. KRASother, p = 0.005), particularly in the absence of TP53 mutations (8.5 vs. 4.0 months with p = 0.004 for TP53wt patients; p > 0.50 for TP53mut) and KEAP1 mutations (11.3 vs. 5.1 months with p = 0.01 for KEAP1wt patients; p > 0.70 for KEAP1mut). Also, across all patients, KEAP1mut cases showed a trend for shorter PFS under CHT-IO (2.7 vs. 8.0 months, p = 0.07) and IO (1.9 vs. 3.9 months, p = 0.081), as well as shorter OS (15.9 vs. 19.5 months, p = 0.068) compared to KEAP1wt, in contrast to STK11mut cases (p = 0.42-0.92 for the same comparisons). Overall, KRASmut NSCLC after chemotherapy and immunotherapy showed poor prognosis under standard therapies with a median PFS of 3 months, and a median OS of 6.8 months. Conclusions: In PD-L1neg NSCLC, KRASG12C is associated with better outcome under CHT-IO and longer OS compared to KRASother, especially in the absence of TP53 and KEAP1 co-mutations. KEAP1, but not STK11 mutations are associated with impaired benefit from (CHT-)IO in KRASmut NSCLC. Treatment of KRASmut NSCLC after chemo-immunotherapy represents an unmet medical need.
TL;DR: In this paper , the authors performed multi-region sampling (2-4 samples per tumor; total of 55 samples) from a cohort of 19 untreated stage IA-IIIB lung adenocarcinomas (n = 11 KRAS mutant, n = 1 ERBB2 mutant and n = 7 KRAS wildtype).
Abstract: Objective Intratumoral heterogeneity was found to be a significant factor causing resistance to lung cancer therapies, including immune checkpoint blockade. Lesser is known about spatial heterogeneity of the tumor microenvironment (TME) and its association with genetic properties of the tumor, which is of particular interest in the therapy-naïve setting. Materials and methods We performed multi-region sampling (2–4 samples per tumor; total of 55 samples) from a cohort of 19 untreated stage IA-IIIB lung adenocarcinomas (n = 11 KRAS mutant, n = 1 ERBB2 mutant, n = 7 KRAS wildtype). For each sample the expression of 770 immunooncology-related genes was analyzed using the nCounter platform, while the mutational status was determined by hybrid capture-based next-generation sequencing (NGS) using a large panel covering more than 500 genes. Results Global unsupervised analyses revealed clustering of the samples into two groups corresponding to a ‘hot’ or ‘cold’ immunologic tumor contexture based on the abundance of immune cell infiltrates. All analyzed specific immune cell signatures (ICsig) showed a significantly higher intertumoral than intratumoral heterogeneity (p < 0.02), as most of the analyzed cases (14/19) showed a very homogenous spatial immune cell profile. PD-L1 exhibited a significantly higher intertumoral than intratumoral heterogeneity (p = 1.03e−13). We found a specific association with ‘cold’ TME for STK11 (11/14, p < 0.07), but not KRAS, TP53, LRP1B, MTOR, U2AF1 co-mutations, and validated this finding using The Cancer Genome Atlas (TCGA) data. Conclusion Early-stage lung adenocarcinomas show considerable intertumoral, but limited intratumoral heterogeneity, which is clinically highly relevant as assessment before neoadjuvant treatment is based on small biopsies. STK11 mutations are specifically associated with a ‘cold’ TME, which could affect the efficacy of perioperative immunotherapy.
TL;DR: In this paper , a comprehensive mRNA expression analysis in 24 cancer types of TCGA was performed to extract a consensus expression signature shared across TP53 mutation types and cancer types, and differential gene expression patterns between tumors harboring different TP53 mutations such as loss of function, gain of function or dominant negative mutations, and cancer-type specific patterns of gene expression and immune infiltration.
Abstract: Abstract TP53 is the most frequently mutated gene in human cancer. While no TP53 -targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.