<p>Supplementary Figure S2. CC-90011 Dose Response in a Kasumi-1 Cell Line Model of Acute Myeloid Leukemia (A) and a Normal Human Fibroblast Cell Line Model (B). CellTiter 96® aqueous cell proliferation assay results shown.</p>
Reliable evaluation of treatment benefit in early phase clinical trials is necessary. The time to progression ratio (TTPr), which compares successive TTP in a single patient, is a powerful criteria for determining targeted or immune therapies efficacy.
Introduction: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumors is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.Materials and Methods: On-purpose tumor biopsies from pts with metastatic solid tumors enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using Whole Exome Sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumor board. Clinical characteristics and outcome were collected.Results: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumors. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumor samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1 – 10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA.Conclusions: Epigenetic alterations occur frequently in metastatic solid tumors. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analyzed in molecular profiling studies.Declaration of Interests: PMR: Consultant/Advisory fees from Roche and AbilityPharma; CB declares Consulting BMS, GSK, AZ and Funding from BMS; LV reports personal fees from Adaptherapy, is CEO of RESOLVED, non personal fees from Pierre-Fabre and Servier, grants from Bristol-Myers Squibb, all outside the submitted work; AV is an employee and stakeholder of Astrazeneca since August 2020; JCS received consultancy fees from Relay Therapeutics; was an employee of AstraZeneca 2017–2019; has shares in AstraZeneca, Daiichi Sankyo, Gritstone; he is an employee of Amgen since August, 2021; CM is a consultant/Advisory fees from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. SPC declares honoraria from Amgen, AstraZeneca, BMS, EISAI, Janssen, MSD, Novartis and Roche, advisory Board from Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Oncovita, Seagen, UltraHuman and Travel and congress support from AstraZeneca, MSD, Ose Pharma, Roche, Sotio. JMM declares participating in advisory board from BMS - Celgene, GSK, MSD, Roche; As part of the Drug Development Department (DITEP) the authors principal investigator/ sub-Investigator from Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Bioalliance Pharma, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene 21 Corporation, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, Xencor; Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. The other authors declare no potential conflicts of interest.
Abstract Introduction: Precision medicine has shown to improve outcomes of cancer patients by identifying oncogenic alterations and actionable mutations. Yet, most tests perform DNA sequencing and are not able to discriminate which tumor driving signaling pathways (SP) are functionally active. OncoSignal pathway analysis tests quantitatively measure activity of SP such as estrogen receptor, androgen receptor, PI3K, MAPK, TGF-β, Notch on fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissue samples, while mutation analysis provides complementary information related to the genomic alteration in the SP. Combined information is expected to improve choice of the optimal effective targeted therapy to improve patients' outcome and quality of life as well as to reduce unnecessary side effects/costs due to unnecessary therapy. In this study OncoSignal pathway analysis was performed on a series of samples from the Moscato trial (1), with the aim of assessing clinically actionable SP activity. Methods: OncoSignal pathway analysis (ER, AR, PI3K, MAPK, HH, Notch, TGF-β) was performed blinded by Molecular Pathway Dx (Philips, Eindhoven) on tumor tissue samples from 5 breast and 31 prostate tumors, all proven to be hard to treat and obtained from the Moscato study. Results were sent back to Institut Gustave Roussy for clinical annotation and analysis. For breast and prostate cancer, pathway activity scores were determined for each SP in healthy breast (n=7) and prostate (n=9) tissues (GEO datasets: GSE17951 and GSE10780) and compared with pathway activity scores in cancer tissue samples (multiple GEO datasets: n=133 and n=1712). Increased activity of a pathway in cancer tissue (>95th percentile of healthy tissue pathway activity) was considered as tumor-driver function for the respective pathway and thus clinically actionable. Subsequently, for each individual Moscato sample, alterations were considered as tumor driving pathways if the sample pathway activity score exceeded the 95th percentile of normal (primary) tissue pathway activity. Results: Identified tumor driving SP in breast cancer were ER, AR, MAPK-AP1, HH, and PI3K pathway whereas in prostate cancer identified SP were the AR and PI3K pathway. Of the 5 breast cancer metastasis samples (lung, head/neck, skin, liver, lymph node; average tumor content 40%), all had at least one clinically actionable tumor driving pathway. Of the 30 prostate cancer metastasis samples (bone, liver, lymph nodes; average tumor content 62%), 29 (97%) had a clinically actionable tumor driving pathway. Conclusion: OncoSignal pathway analysis enabled identification of clinically potentially actionable signaling pathway activity in 97-100% of analyzed breast and prostate cancer samples. Citation Format: Patricia Martin-Romano, Sieglinde Neerken, Anja Van de Stolpe, Eveline Den Biezen-Timmerman, Maud Ngo, Claudio Nicotra, Martijn Akse, Alexander Eggermont, Paul Van de Wiel, Christophe Massard, Fabien Calvo. First results of the EIT PACMAN Study: OncoSignal pathway analysis to identify clinically actionable signal transduction pathway activity in a variety of cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1331.
