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Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial

Françoise Rothé, Maria Joao Silva, David Venet, Christine Campbell, Ian Bradburry, Ghizlane Rouas, Evandro De Azambuja, Marion Maetens, Debora Fumagalli, Vanessa Rodrik-Outmezguine, Serena Di Cosimo, Daniela Rosa, Stephen Chia, Andrew Wardley, Takayuki Ueno, Wolfgang Janni, Jens Huober, José Baselga, Martine Piccart, Sherene Loi, Christos Sotiriou, Sarah-Jane Dawson & Michail Ignatiadis

abstract

PURPOSE
In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2-targeted therapy.

EXPERIMENTAL DESIGN
Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for and mutation detection.

RESULTS
A total of 69 of 455 (15.2%) patients had a and/or mutation detected in the baseline tumor sample and evaluable ctDNA results from baseline samples. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15; 95% CI, 0.034-0.7; = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR.

CONCLUSIONS
ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.
   
citation Rothé F, Silva M J, Venet D, Campbell C, Bradburry I, Rouas G, de Azambuja E, Maetens M, Fumagalli D, Rodrik-Outmezguine V, Di Cosimo S, Rosa D, Chia S, Wardley A, Ueno T, Janni W, Huober J, Baselga J, Piccart M, Loi S, Sotiriou C, Dawson S J, Ignatiadis M. Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial. Clin Cancer Res 2019; 25:3581-3588.
   
type journal paper/review (English)
date of publishing 12-03-2019
journal title Clin Cancer Res (25/12)
ISSN electronic 1557-3265
pages 3581-3588
PubMed 30862692
DOI 10.1158/1078-0432.CCR-18-2521