293P - Ultra-sensitive ctDNA detection and monitoring in early breast cancer using PhasED-Seq

Background

Detection of circulating tumor DNA (ctDNA) after treatment in early-stage breast cancer (EBC) is associated with poor outcomes. However, first generation methods are often hampered by suboptimal sensitivity. We assessed the clinical validity of an ultrasensitive ctDNA MRD assay at key landmarks across various EBC subtypes.

Methods

The MSK-LINC study prospectively collected blood samples from EBC pts throughout their clinical care at MSK. The Foresight CLARITY assay was used to detect MRD. Whole genome sequencing of primary tumor and WBC samples was utilized to identify tumor-derived phased variants. Personalized PhasED-Seq assays were designed and applied to plasma to detect ctDNA MRD.

Results

Fifty pts were included: 22% stage I, 56% stage II, 22% stage III, 62% HR+/HER2-, 24% HER2+, and 14% triple-negative. All were treated by curative-intent surgery, and 44% and 48% received neoadjuvant or adjuvant chemotherapy, respectively. After a median follow-up of 69 months (range 14-94), 14% experienced distant recurrence. Baseline pretreatment ctDNA was detected in 72% of evaluable pts (n=46), with a median variant allele frequency of 0.01% (range 0.0008%-22.6%). 12/33 (36%) detected samples had ctDNA levels <0.01%. Of the 17 ctDNA+ pts at baseline who received neoadjuvant, 13 cleared ctDNA with 12/13 (92%) not experiencing a relapse. In pts with undetectable ctDNA pretreatment, none experienced relapse (0/13), compared to 21% (7/33) relapse with detectable pretreatment ctDNA. In landmark analysis, 8/49 (16%) of pts were MRD+ after surgery but before adjuvant therapy, and this was significantly associated with poor DFS (HR 14.0, p<0.0001). Among the 8 MRD+ pts after surgery, adjuvant therapy cleared MRD in 4 pts, none of whom experienced relapse. In contrast, one patient experienced relapse before adjuvant therapy and MRD+ persisted in the remaining 3 pts, all of whom experienced relapse. All pts experiencing recurrence were MRD+ before or at the time of distant relapse (7/7, sensitivity 100%).

Conclusions

PhasED-Seq is highly sensitive and specific for MRD detection in this EBC cohort. Post-surgical ctDNA MRD+ was associated with recurrence while MRD negativity at baseline or MRD clearance by (neo)adjuvant therapy was associated with improved outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D. Kurtz: Financial Interests, Personal, Full or part-time Employment: Foresights Diagnostics; Financial Interests, Personal, Advisory Role: Foresights Diagnostics, Roche, Genentech, Adaptive Biotechnologies; Financial Interests, Personal, Stocks or ownership: Foresights Diagnostics; Financial Interests, Personal, Other, Patents: Stanford University. S. Love Stowell: Financial Interests, Personal, Full or part-time Employment: Foresights Diagnostics. D. Maloney: Financial Interests, Personal, Full or part-time Employment: Foresights Diagnostics. H.I. Scher: Financial Interests, Personal, Other, Honoraria: Physician Education Resource; Financial Interests, Personal, Advisory Role: Bayer, Pfizer, Regeneron Pharmaceuticals, Sanofi (Genzyme Corporation), WIRB-Copernicus Group; Non-Financial Interests, Personal, Advisory Role: AIQ Global Inc, Janssen Research & Development, Promontory Therapeutic; Financial Interests, Institutional, Funding: AIQ Solutions, Astrin Biosciences, Biodesix, Janssen; Financial Interests, Personal, Royalties: Elucida Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bayer, Biodesix, Promontory Therapeutics, Prostate Cancer Foundation, WIRB-Copernicus Group. M. Morrow: Financial Interests, Personal, Invited Speaker, tumor board participant for medical education company, honoraria received: Precisa; Financial Interests, Personal, Invited Speaker, speaker at meeting. Honoraria received: roche; Financial Interests, Personal, Invited Speaker, speaker at satellite symposia, honorarium received.: exact sciences; Financial Interests, Personal, Royalties, textbook editor: Lippincott. S. Chandarlapaty: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Effector, Nuvalent, Genesis Therapeutics, Prelude Therapeutics, SAGA Diagnostics, Neogenomics, Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares, Company with PI3K inhibitor asset - will not be discussed at all in the conference.: Totus Medicines; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Paige.ai, AstraZeneca; Financial Interests, Institutional, Steering Committee Member: Lilly; Non-Financial Interests, Advisory Role: Breast Cancer Research Foundation. J. Chabon: Financial Interests, Personal, Stocks or ownership: Foresights Diagnostics; Financial Interests, Personal, Full or part-time Employment: Foresights Diagnostics. A. Alizadeh: Financial Interests, Personal, Other, Consultant: ADCT, Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, Roche; Non-Financial Interests, Personal, Advisory Board: Lymphoma Research Foundation; Non-Financial Interests, Personal, Member: American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, Leukemia & Lymphoma SocietyLeukemia & Lymphoma Society; Financial Interests, Institutional, Funding: National Cancer Institute, National Heart, Lung, Blood Institute, National Institutes of Health, National Institutes of Health, Celgene, BMS, Pfizer; Financial Interests, Personal, Royalties, Patents: FortySeven; Financial Interests, Personal, Other, Patent: Foresight, MARIA, CiberMed, idiotype vaccines; Financial Interests, Personal, Royalties, Patent: Roche; Financial Interests, Personal, Ownership Interest: CiberMed Inc, Foresight Diagnostics, FortySeven Inc, CARGO Therapeutics. B.T. Li: Financial Interests, Personal, Royalties, Intellectual property rights as a book author: Karger Publishers, Shanghai Jiao Tong University Press; Financial Interests, Institutional, Other, Inventor on institutional patents at MSK (US62/685,057, US62/514,661): Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Institutional clinical trials funding to Memorial Sloan Kettering Cancer Center: Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui, Lilly; Financial Interests, Institutional, Funding, Institutional clinical trial funding to Memorial Sloan Kettering Cancer Center: Revolution Medicines; Non-Financial Interests, Advisory Role, Uncompensated advisor and consultant: Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Lilly; Non-Financial Interests, Other, Academic travel support, but without compensation: MORE Health, Jiangsu Hengrui Pharmaceuticals; Non-Financial Interests, Member: American Society of Clinical Oncology, International Association for the Study of Lung Cancer. G. Plitas: Financial Interests, Personal, Advisory Role: Merck, Tizona, Paige AI; Financial Interests, Personal, Principal Investigator: Takeda. M. Diehn: Financial Interests, Personal, Advisory Board: AstraZeneca, Genentech, Illumina, Gritstone Bio, Boehringer Ingelheim, Regeneron, Roche Diagnostics, Foresight Diagnostics, Celgene; Financial Interests, Personal, Other, Honorarium: Novartis, Bristol Myers Squibb; Financial Interests, Personal, Other, Consultant: BioNTech, RefleXion, Roche; Financial Interests, Personal, Ownership Interest: CiberMed, Foresight Diagnostics; Financial Interests, Personal, Stocks/Shares: Gritstone Bio; Financial Interests, Institutional, Coordinating PI: Varian, AstraZeneca; Financial Interests, Other, Reagents: Illumina; Non-Financial Interests, Member of Board of Directors: Foresight Diagnostics. P. Razavi: Financial Interests, Personal, Advisory Board: Odyssey Biosciences, Myriad Genetics; Financial Interests, Personal, Advisory Role: Guardant Health, Paige.ai, SAGA Diagnosticsagnostics, Tempus, Natera, Inivata, Foundation Medicine, Epic Sciences, Prelude Therapeutics, Lilly/Loxo, Pfizer, AstraZeneca, Novartis; Financial Interests, Institutional, Funding: Myriad Genetics, Personalis, Guardant Health, Biovica, Inivata, Tempus, Biotheranostics, Invitae/ArcherDx, Epic Sciences, AstraZeneca, Novartis, Illumina, Grail. All other authors have declared no conflicts of interest.