90P - Clonal haematopoiesis of indeterminate potential (CHIP) might mislead interpretation of ATM and CHEK2 alterations detected on liquid biopsies

Background

Large populations blood-based sequencing studies have revealed that somatic mutations in hematopoietic cells are acquired during aging. This phenomenon, in the absence of cytopenias and dysplastic haematopoiesis, is known as clonal haematopoiesis of indeterminate potential (CHIP). Genes involved in CHIP include ATM and CHEK2, encoding key regulators of DNA repair. These genes are associated with response to anticancer treatments, e.g. poly-ADP ribose polymerase (PARP) inhibitors, and used as biomarkers within clinical trials. We evaluated CHIP mutation frequency in a cohort of patients undergoing evaluation for early phase trials.

Methods

Blood samples (≤60 mL) were taken from patients with solid tumours within the TARGET National study (NCT04723316). Circulating tumour DNA (ctDNA) was sequenced using Foundation Medicine Liquid CDx. Patients consented at Newcastle Hospitals were identified on the TARGET National database. Aberrations in DNMT3A, TET2, JAK2, CHEK2 and ATM that were flagged as not tumoral by the study Molecular Tumour Board were considered as CHIP.

Results

Of 382 patients with 42 different cancer types, 162 (43%) had ≥1 mutation considered as CHIP. CHIP was most frequent in patients aged 50-70 years, showing significant association with ageing (p=0.0016). Mutations were most frequent in lung (17%), prostate (13%) and colorectal (9%) cancer. Alterations of DNMT3A were most common (57%), followed by TET2 (20%), CHEK2 (10%), ATM (9%) and JAK2 (4%). Among patients with CHIP, 109 (67%) had previous platinum-based chemotherapy. No significant relationship was found between CHIP and Platinum-based chemotherapy (p=0.0665). However, in this cohort CHEK2 (80%) and ATM (78%) were the most frequent CHIP alterations (p>0.05).

Conclusions

CHIP was highly prevalent in cancer patients likely due to genotoxic stress and ageing. The rate of mutations was dependant on cancer types and treatment context. The prevalence of mutated DNA repair genes CHEK2 and ATM was increased post-cisplatin exposure. Therefore, the clinical relevance of these alterations as therapeutic targets in patients post platinum-based chemotherapy requires cautious interpretation.

Clinical trial identification

NCT04723316.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Sir Bobby Robson Foundation.

Disclosure

P. Rescigno: Financial Interests, Advisory Board: AstraZeneca, Janssen, Pfizer. C. Oing: Financial Interests, Personal, Invited Speaker, Renal Cancer Expert Panel Case Presentation: Ipsen; Financial Interests, Personal, Invited Speaker, Talk on Pain Management in GU Cancer Patients: Medac; Financial Interests, Personal, Invited Speaker, Case Presentation Soft Tissue Sarcoma: Roche; Financial Interests, Personal, Advisory Board, Ad Board on discussing novel educational events for young haematologists: Novartis; Financial Interests, Personal, Invited Speaker, Science Slam with a presentation on young professional support from oncological societies in Germany: AstraZeneca; Financial Interests, Personal, Advisory Board, AdBoard assessing educational needs for oncology professionals regarding G-CSF use: Sandoz; Financial Interests, Personal, Invited Speaker, Presentation on Burnout and Resilience in medical oncology professionals: Asklepios Hamburg; Financial Interests, Personal, Advisory Board, Larotrectinib use in sarcoma: Bayer; Financial Interests, Personal, Advisory Board, Experiences with Cabo/Nivo as first-line treatment for metastatic RCC: Ipsen; Financial Interests, Personal, Advisory Board, Workshop series on improving customer experience: Pfizer; Non-Financial Interests, Other, Clinical Advisory role in early drug discovery with a fellowship position affiliated with Astex Pharmaceuticals, Cambridge, UK: Astex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples, Cytotoxic Agent for Preclinical Experiments: PharmaMar. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Fabre, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo, Incyte; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences, AstraZeneca; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Local PI: MSD; Financial Interests, Institutional, Coordinating PI: Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Advisory Role: National Institute for Health and Clinical Excellence; Non-Financial Interests, Leadership Role, Steering Committee member: British Thoracic Oncology Group; Other, Clinical Lead for Cancer (paid position): North East England and Yorkshire Genomic Laboratory Hub. All other authors have declared no conflicts of interest.