ctDNA detection before and during systemic therapy for inflammatory breast cancer.
Authors: Alexander Angela , Marx Angela , Wiley Jie , Kai Megumi , Valero Vicente , Woodward Wendy A. , Tin Tony , Kalashnikova Ekaterina , Bristow Sara L , Renner Derrick , Wu Hsin-Ta , Donahue Jeannine , Rodriguez Angel Augusto , Sethi Himanshu , Liu Minetta C. , George Mridula Annette , Cristofanilli Massimo , Lim Bora 
Published: June 2023

e12523

Background: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer and despite a multimodal treatment approach, it is associated with early recurrence and poor prognosis. There is a need for sensitive and reliable biomarkers for therapy response monitoring and early prediction of disease progression. The prognostic and predictive role of circulating tumor DNA (ctDNA) as a biomarker for molecular residual disease (MRD) following surgery has been established for several cancer types. In this study, we provide evidence that tumor-informed ctDNA assays can be used to monitor response to treatment and predict clinical outcomes in patients with IBC. Methods: This retrospective study included 18 newly diagnosed, stage III/IV (17 III, 1 IV) IBC pts (12 ER+/HER2-, 3 HER2+, 3 TNBC) who received standard neoadjuvant chemotherapy (NAC) followed by surgery, and adjuvant therapy with/without radiotherapy. Plasma samples were collected serially (n = 71) at the discretion of the physician, which included timepoints at diagnosis, during NAC, post surgery, during adjuvant therapy, and during surveillance. ctDNA was detected with a personalized, tumor-informed multiplex-PCR, NGS-based test (SignateraTM). Association of ctDNA dynamics during treatment with overall survival was evaluated (Log-rank method). Results: Independent ctDNA assays designed using both primary tumor tissue and sentinel lymph node tissue for 6 patients demonstrated intra- and inter-patient heterogeneous patterns of mutation acquisition and loss between primary tumor, lymph node metastasis, and ctDNA. Mutational profiles of detectable ctDNA shared features of tumor from both the breast and lymph node specimens. More importantly, ctDNA detection in plasma at each timepoint was concordant regardless of the source of tumor tissue for all 6 patients. Baseline ctDNA detection at the time of diagnosis was 100% (3/3 patients); 2 patients remained ctDNA-positive despite NAC and surgery. In patients with plasma available post surgery, prior to initiating adjuvant chemotherapy, 35% (5/14 patients) had detectable MRD. Over a follow-up period of 62 months, patients who did not achieve a complete molecular response (i.e., clear ctDNA), during systemic therapy, experienced disease progression ( p = 0.001, HR = 7.5). ctDNA was detectable up to 7.1 months (median 6.1) prior to radiologic findings. Conclusions: These findings demonstrate that the bespoke, tumor-informed ctDNA assay, Signatera, successfully tracks clonal mutations using primary tumor tissue or lymph node metastases for IBC patients. Presence of ctDNA after surgery and during adjuvant treatment is associated with inferior survival. Given the aggressive nature of the disease, serial monitoring of ctDNA during systemic therapy may serve as an early indicator of treatment response and can be used to support clinical decision making to improve patient outcomes.