310P - Longitudinal evaluation of circulating tumour DNA in early breast cancer using a plasma-only methylation-based assay

Background

Plasma-only ctDNA detection is a strategy to identify molecular residual disease (MRD) in early breast cancer (EBC). MRD-positivity in the absence of clinical/radiographic disease may have prognostic implications and enable intervention prior to clinical recurrence.

Methods

Plasma samples from baseline, perioperative, adjuvant and follow-up timepoints were collected in patients with estrogen receptor positive/HER2-negative (ER+) and triple-negative (TN) breast cancer treated with neoadjuvant chemotherapy (2015 onward). Samples were analyzed using the Guardant Reveal pan-tumor assay on the INFINITY^TM platform. Clinical/pathologic characteristics and recurrence outcomes were collected. ctDNA/MRD-positivity was defined as a methylation score > 0.

Results

270 timepoints (median 3 per patient, range: 1-9) were analyzed from 83 patients with ER+ (n=38) and TN (n=45) EBC; 95% (256/270) produced successful results. Baseline positivity rate was 67.5% (54/80) in all patients (66.7% in ER+, 68.2% in TN). Nine patients had a mutation called at baseline (7 PIK3CA; 1 of TP53, FGFR1, BRAF, GATA3, or NOTCH2). Larger tumor size (p=0.014) and nodal involvement (p=0.011) were associated with baseline test positivity. 17/83 (20.5%) patients have had a clinical recurrence (13 distant, 4 local). 14/17 (82.3%) patients with recurrence had a positive test at baseline (2 negative, 1 fail) and baseline methylation scores were higher in patients with recurrence (p=0.0032). Seven of 8 patients with recurrence had a positive sample collected at or prior to clinical recurrence with lead time of up to 5.1 months. Four patients with no documented recurrence had a positive test at their last follow up [range: 4.7-19.1 months from last test] with methylation scores lower than those of patients with recurrence (p=0.012). Any ctDNA positivity in follow up after surgery was strongly associated with a risk of recurrence (HR = 7.02, 95%CI: 1.82-27.2, p=0.001).

Conclusions

This longitudinal evaluation of a plasma-only methylation based ctDNA assay demonstrates ctDNA detection and dynamic changes in a large EBC cohort. Potential prognostic and predictive applications warrant further evaluation.

Clinical trial identification

NCT03702309.

Editorial acknowledgement

Copy editing assistance was provided by Meditech Media.

Legal entity responsible for the study

University Health Network - Princess Margaret Cancer Centre - Cancer Genomics Program.

Funding

The Princess Margaret Cancer Foundation, The Ontario Institute for Cancer Research (OICR), BMO Financial Group Chair in Precision Genomics, GSK.

Disclosure

P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen, Medicenna; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. E. Amir: Financial Interests, Institutional, Funding: Novartis. M. Annan, A. Silvestro, Q. Zhang, R. Cheikh, J. Kim, O. Barbash : Financial Interests, Personal, Full or part-time Employment, Recently retired: GSK; Financial Interests, Personal, Stocks/Shares: GSK. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus, Tubulis, LTZ Therapeutics; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, Merck, GSK, Roche/Genentech, AstraZeneca, Astellas, Amgen, Shattucks, EMD Serono; Financial Interests, Institutional, Coordinating PI: Bayer, Symphogen, Intensity Therapeutics; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center. D. Cescon: Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Novartis, GSK, Merck, Gildead Sciences, Eisai, Inflex Ltd, Lilly, SAGA diagnostics; Financial Interests, Institutional, Funding: Merck, Roche/Genentech, GSK, Pfizer, Inivata / NeoGenomics, AstraZeneca, Gilead Sciences, Knight Therapeutics; Other, Personal, Other, Patent (US62/675,228) for methods of treating cancers characterized by a high expression of spindle and kinetochore associated complex subunit 3 (SKA3): Patent. All other authors have declared no conflicts of interest.