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Supplementary Figure 1. Study flowchart

Supplementary table 1. Main characteristics of patients receiving different dose levels

Supplementary table 3. Multivariate model for Overall Survival (Cytotoxic Agents)

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

Supplementary table 2. Multivariate model for overall survival (Molecularly Targeted Agents).

IFNγsignalling underpins host responses to infection, inflammation and anti-tumour immunity. Mutations in the IFNγsignalling pathway cause immunological disorders, haematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer, however the function of most clinically observed variants remain unknown. Here, we systematically investigate the genetic determinants of IFNγresponse in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations with clinical precedence, including causal variants in haematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumour organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumour-reactive T cells. By classifying > 300 missense variants altering IFNγ pathway activity, we demonstrate the utility of base editing for mutagenesis at scale, and generate a resource to inform genetic diagnosis.

Immunotherapy is a fundamental pillar in the treatment of lung cancer but remains inefficient in half of the treated patients. Recent clinical trials showed synergistic effects of combining chemotherapy and immunotherapy for lung cancer, suggesting that increased DNA damage imposed by chemotherapy modulates the tumor microenvironment to aid the efficacy of immunotherapy. But the immunological mechanisms related to this remains to be fully elucidated. The cGAS-STING pathway senses cytosolic DNA introduced by DNA-damaging agents such as chemotherapy. Activation of this pathway and induction of inflammatory cytokines may contribute to better immunotherapy efficacy. In particular, the release of type I IFN is a hallmark for STING pathway activation. However, we also know that IFNλ – a type III IFN – can be induced by STING-signaling. Despite the relevance of IFNλ in controlling inflammatory responses, its contribution in cancer remains unclear. Here, we investigated cGAS-STING expression and signaling in a panel of lung cancer cells. We identified IFNλ1 as an alternative hallmark for cGAS-STING DNA-sensing with higher expression after DNA-stimulation than IFNb in 6 out of 8 cell lines with one cell line having no IFNb expression at all. We then tested IFN induction after chemotherapeutic treatment in three different NSCLC cell lines and saw significant increase in both IFNb and IFNλ1 expression across four different chemotherapeutics, but with a higher fold change for IFNλ1. The induction of both IFNb and IFNλ1 was abolished when STING KO cell lines were treated with doxorubicin pointing to a STING-dependent response. To access the effect of IFNλ1 on macrophages, a prevalent cell type in the tumor microenvironment expressing IFNLR1, we performed RNA-sequencing on four primary human macrophage donors stimulated with IFNλ1. This stimulation led to a significant increase in well-known interferon-stimulated genes including the chemokines CXCL10 and CXCL11. We also explored whether IFNλ1 stimulation led to increased macrophage-dependent activation of autologous CD8+ T-cells. Interestingly, we found increased expression of both IFNg (p = 0.0215, n = 6) and Granzyme B (p = 0.0033, n = 6) measured by flow cytometry and ELISA (p > 0.0001, n = 6 for both). The addition of IFNλ1 during direct co-culture of macrophages and lung tumor organoids furthermore dampened the induction of the signal regulatory protein-a (SIRPa), a phagocytosis-inhibiting receptor, (p = 0.0041, n = 4) otherwise induced by the tumor organoids, but not matched healthy organoids. In support of this, there was an increased activation of CD8+ T-cells measured by IFNg production in an organoid-macrophage-CD8+ T-cell co-culture model. To summarize, we demonstrate that IFNλ1 may be a strong and broad marker of STING activation induced by chemotherapy in NSCLC and that IFNλ1 has the ability to prime a wider immune response by targeting macrophages. Hence, we propose that an IFNλ1 induced immune response has the potential to support and boost the response induced by existing immunotherapies. Citation Format: Kristine R Gammelgaard, Stine H Godsk, Albert G Olivier, Maria Riedel, Silke D Nielsen, Allard van Renterghem, Trine V Larsen, Anders Etzerodt, Emile Voest, Martin R Jakobsen. IFNλ1 is a marker of DNA damage-triggered STING-signaling in lung cancer that induces immune activation through macrophage stimulation [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A50.

With the increasing use of genomic profiling for diagnosis and therapy guidance in many tumor types, precision oncology is rapidly reshaping cancer care. However, the current trajectory of drug development in oncology results in a paradox: if patients cannot access advanced diagnostics, we may be developing drugs that will reach few patients. In this Perspective, we outline the major challenges to the implementation of precision oncology and discuss critical steps toward resolving these, including facilitation of equal access to genomics tests, ensuring that clinical studies provide robust evidence for new drugs and technologies, enabling physicians to interpret genomics data, and empowering patients toward shared decision-making. A multi-stakeholder approach to evidence generation, value assessment, and healthcare delivery is necessary to translate advances in precision oncology into benefits for patients with cancer globally.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd.

There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal (MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers.

Presentation of all work packages at the TANGO project mini symposium in 2018, includes milestone achievements and preliminary results., The "Technology Assessment of Next Generation Sequencing in Personalized Oncology" (TANGO) project is funded by the ZonMw Personalised Medicine Programme under Dossier number: 846001002 in collaboration with KWF and Zilveren Kruis. The project period is 31 December 2016 – 31 May 2021.

The author reviews the recently published article, ‘Facilitating a culture of responsible and effective sharing of cancer genome data’ (Nat Med 2016;22:464–71), considering why data sharing is important, and explaining the obstacles and problems involved. The need to identify common bioinformatics pipelines, and resolving outstanding legal, ethical and technical issues are highlighted. Particular attention is given to emerging issues around informed consent and the handling of electronic patient records. There is now an urgent need to address all these issues on multiple levels in order to fulfil the promise of personalised medicine. The author further considers the work of the Global Alliance for genomics and health across cancer and rare diseases, and in the emerging field of infectious diseases genomics. Finally, the potential impact of cancer genomic data on clinical practice is considered and the enormous potential for it to inform good decision-making is underscored.

Non

The utilization of archived, formalin-fixed paraffin-embedded (FFPE) tumor samples for massive parallel sequencing has been challenging due to DNA damage and contamination with normal stroma. Here, we perform whole genome sequencing of DNA isolated from two triple-negative breast cancer tumors archived for >11 years as 5m FFPE sections and matched germline DNA. The tumor samples show differing amounts of FFPE damaged DNA sequencing reads revealed as relatively high alignment mismatch rates enriched for CG>TA substitutions compared to germline samples. This increase in mismatch rate is observable with as few as one million reads, allowing for an upfront evaluation of the sample integrity before whole genome sequencing. By applying innovative quality filters incorporating global nucleotide mismatch rates and local mismatch rates, we present a method to identify high-confidence somatic mutations even in the presence of FFPE induced DNA damage. This results in a breast cancer mutational profile consistent with previous studies and revealing potentially important functional mutations. Our study demonstrates the feasibility of performing genome-wide deep sequencing analysis of FFPE archived tumors of limited sample size such as residual cancer after treatment or metastatic biopsies. © The Author(s) 2012.

The von Hippel-Lindau (VHL) tumor suppressor gene encodes an adaptor protein that regulates an array of transcription-dependent and -independent cellular and physiological processes. Mutations in this gene cause VHL disease, congenital polycythemia, and several sporadic tumor types. The last 15 years of fundamental and clinical research have helped define the phenotypic spectrum of VHL-associated diseases and have introduced new cellular functions for pVHL. Here, we review the current knowledge of VHL function, and the different animal models for VHL disease, with a particular focus on the zebrafish. Zebrafish vhl mutants develop key aspects of the human disease condition, including activation of the hypoxia-inducible factor (HIF) signaling pathway, polycythemia, excessive neovascularization, macular edema, and pronephric abnormalities. The zebrafish vhl model offers a platform for the identification of genetic pathways, modifiers, and interactors involved in the development of VHL-associated neoplasms. Vhl mutants represent a unique and clinically relevant in vivo model for studying genotype-phenotype correlations and the identification of prognostic biomarkers. The amenability of zebrafish for chemical genetic screens will not only be helpful to identify novel therapeutic agents but may also reveal novel processes that require regulation by VHL.

Purpose To evaluate and compare health-related quality of life (HRQOL) after conventional- and high-dose adjuvant chemotherapy in patients with high-risk breast cancer. Patients and Methods Patients were randomly assigned to either a conventional or high-dose chemotherapy regimen; both regimens were followed by radiotherapy and tamoxifen. HRQOL was evaluated until disease progression using the Short Form-36 (SF-36), Visual Analog Scale, and Rotterdam Symptom Checklist and assessed every 6 months for 5 years after random assignment. For the SF-36, data from healthy Dutch women with the same age distribution served as reference values. Results Eight hundred four patients (conventional-dose chemotherapy, n = 405; high-dose chemotherapy, n = 399) were included. Median follow-up time was 57 months. Directly after high-dose chemotherapy, HRQOL decreased more compared with conventional chemotherapy for all SF-36 subscales. After 1 year, the reference value of healthy women was reached in both groups. Small differences were observed between the two groups in the role-physical and role-emotional subscales, but 1 year after treatment, these differences were minor and not clinically relevant. During follow-up, patients with a lower educational level and many complaints before chemotherapy experienced a worse HRQOL. Conclusion Shortly after high-dose chemotherapy, HRQOL was more affected than after conventional-dose chemotherapy. One year after random assignment, differences were negligible. Identifying patients who have a higher chance of persistent impaired quality of life after treatment (which, in the present study, included patients with a lower educational level and many complaints before chemotherapy) is important and may open the way for better patient-tailored prevention strategies.