Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence.

We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs. We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial. Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort. Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools.

Déclaration de conflit d'intérêts

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians Open Payments. Aziz Nazha Honoraria: DCI Consulting or Advisory Role: Karyopharm Therapeutics, Tolero Pharmaceuticals Speakers’ Bureau: Novartis, Incyte Research Funding: Jazz Pharmaceuticals Mikkael A. Sekeres Consulting or Advisory Role: Celgene, Millennium Pharmaceuticals, Syros Pharmaceuticals Research Funding: Takeda Pharmaceuticals (Inst), Pfizer (Inst) Rafael Bejar Honoraria: Celgene, Alexion Pharmaceuticals, Abbvie/Genentech, Astex Pharmaceuticals, NeoGenomics Laboratories, Daiichi Sankyo, Forty Seven Consulting or Advisory Role: Celgene, Foundation Medicine, NeoGenomics Laboratories, Abbvie/Genentech, Astex Pharmaceuticals, Daiichi Sankyo Research Funding: Celgene, Takeda Pharmaceuticals Travel, Accommodations, Expenses: Celgene Megan Othus Consulting or Advisory Role: Celgene, Glycomimetics, Cascadia Laboratories Rami S. Komrokji Stock and Other Ownership Interests: Abbvie Consulting or Advisory Role: Celgene, Novartis, Daiichi Sankyo, Pfizer, Janssen Pharmaceuticals, Agios, Incyte Speakers’ Bureau: Novartis, Alexion Pharmaceuticals, Jazz Pharmaceuticals Travel, Accommodations, Expenses: Celgene, Incyte, Alexion Pharmaceuticals, Novartis, Jazz Pharmaceuticals, Daiichi Sankyo David P. Steensma Stock and Other Ownership Interests: Array BioPharma (I) Honoraria: Daiichi Sankyo, Summer Road, Stemline Therapeutics Consulting or Advisory Role: Pfizer Amy DeZern Consulting or Advisory Role: Acceleron Pharma, Syros, Otsuka US Gail Roboz Consulting or Advisory Role: Amphivena, Janssen, Amgen, Astex Pharmaceuticals, Celgene, Genoptix, MedImmune, Novartis, Pfizer, Abbvie, Argenx, Array BioPharma, Bayer AG, Celltrion, Jazz Pharmaceuticals, Orsenix, Genentech/Roche, Sandoz, Actinium Pharmaceuticals, Astellas Pharma, Eisai, Daiichi Sankyo, MEI Pharma, Otsuka, Takeda Pharmaceuticals, Roche, Agios, Trovagene Research Funding: Abbvie (Inst), Agios (Inst), Astex Pharmaceuticals (Inst), Celgene (Inst), CTI (Inst), Karyopharm Therapeutics (Inst), MedImmune (Inst), MEI Pharma (Inst), Moffitt (Inst), Novartis (Inst), Onconova Therapeutics (Inst), Pfizer (Inst), Sunesis Pharmaceuticals (Inst), Tensha Therapeutics (Inst), Cellectis (Inst), Cellectis, Janssen (Inst), Amphivena (Inst) Travel, Accommodations, Expenses: Amphivena, Astex Pharmaceuticals, Janssen, Pfizer, Array BioPharma, Novartis, Abbvie, Jazz Pharmaceuticals, Celgene, Celltrion, Roche/Genentech, Sandoz, Bayer AG, Clovis Oncology, Amgen, Sunesis Pharmaceuticals, Eisai, Agios Guillermo Garcia-Manero Honoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, Abbvie Consulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals Research Funding: Celgene, Astex Pharmaceuticals Harry Erba Consulting or Advisory Role: Agios, Astellas Pharma, Amgen, Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz Pharmaceuticals, Macrogenics, Novartis, Pfizer, Seattle Genetics Speakers’ Bureau: Agios, Celgene, Incyte, Jazz Pharmaceuticals, Novartis Research Funding: Agios (Inst), Amgen (Inst), Daiichi Sankyo (Inst), Glycomimetics (Inst), Immunogen (Inst), Janssen Oncology (Inst), Juno Therapeutics (Inst), Pfizer (Inst), Seattle Genetics (Inst), Takeda Pharmaceuticals (Inst) Other Relationship: Glycomimetics, Celgene Benjamin L. Ebert Consulting or Advisory Role: GRAIL Research Funding: Celgene, Deerfield Management Patents, Royalties, Other Intellectual Property: Patents related to the prediction of risk of cardiovascular disease (Inst) No other potential conflicts of interest were reported.