Triple-negative breast cancer (TNBC), a biologically diverse subtype of breast cancer, is associated with poor prognosis. Patients (pts) with TNBC who achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have improved disease free and overall survival. We investigated whether early circulating tumor DNA (ctDNA) measurements could predict response to NAC.
ctDNA was detected in 94 serial plasma samples (n) from 37 pts (N) with TNBC (stage I=2, II=19, III=16) with a tumor-informed ctDNA assay (SignateraTM, bespoke mPCR-NGS). Pts received standard NAC; plasma was collected pre-NAC (n=30), 12 weeks after NAC initiation (mid-NAC, n=34), after NAC prior to surgery (n=15), and after surgery (n=15). Associations between ctDNA and ultrasound (US) imaging and response to NAC were evaluated. Circulating tumor cells (CTCs) were also assessed using CellSearch. pCR was defined as the absence of invasive tumor in the breast and axillary lymph nodes in surgical specimens. P values were measured using Student t-test, and correlation between variables used Pearson analysis.
At diagnosis, ctDNA was detected in 90% (27/30) of patients, of whom 76% (19/25) had early ctDNA clearance by mid-NAC. Imaging at mid-NAC showed that 95% (18/19) of cases with undetectable ctDNA had evidence of partial or complete response (PR/CR), while 1 case had progressive disease. After completion of NAC, all 19 cases had PR, CR, or stable disease. Importantly, 58% (11/19) of cases who were ctDNA-negative at their mid-NAC blood draw achieved pCR, while none of the pts with ctDNA detectable at mid-NAC (N=6) had pCR. ctDNA clearance at mid-NAC was significantly associated with pCR (P=0.0304). ctDNA dynamics early in the treatment course correlated with pCR rates (P=0.009) and tumor volume reduction based on US (P=0.008). CTCs were detected in 36% (11/30) of pts pre-NAC, 47% (16/34) mid-NAC, 40% (6/15) post-NAC, and 20% (3/15) after surgery and were not associated with pCR.
Early clearance of ctDNA at mid-treatment but not CTCs during NAC was associated with a higher rate of pCR in TNBC. Personalized ctDNA monitoring during NAC is feasible and may help predict response and guide treatment.
The authors.
The study was funded by Academic and Foundation funding, including The Wintermann Foundation, The Shiela Prenowitz Research Endowment, and the John Wayne Cancer Foundation.
E. Kalashnikova, D. Renner, A.A. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. D. Tripathy: Financial Interests, Personal, Advisory Board, Serving on Steering Committee for TrialsEducational Lectures: Novartis; Financial Interests, Personal, Advisory Board, Steering Committee for and ongoing trial: Pfizer; Financial Interests, Personal, Advisory Board, Advisory council for design and interpretation of trials: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Educational Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, To discuss and interpret clinical trial data: Immunomedics; Financial Interests, Personal, Advisory Board, Advice on clinical trial design: OncoPep; Financial Interests, Personal, Invited Speaker, Lecture on gene profiling: Exact Sciences; Financial Interests, Personal, Advisory Board, Consulting: Sermonix; Financial Interests, Personal, Advisory Board, Consultant: Personalis, Puma Biotechnology, Gilead; Financial Interests, Institutional, Research Grant, Funding for laboratory experiments on the inhibition of CXCR4 in breast cancer cells: Polyphor; Financial Interests, Institutional, Invited Speaker, Global PI on one trial and local PI on another trial: Novartis. M.C. Liu: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera; Financial Interests, Institutional, Research Grant: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax; Financial Interests, Personal, Other, Travel reimbursement: AstraZeneca, Genomic Health, Ionis. S.L. Moulder: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. All other authors have declared no conflicts of interest.