Introduction: Previous studies have shown that levels of circulating tumor DNA (ctDNA) during therapy and post-surgery can stratify patients who exhibit effective responses versus those showing minimal residual disease. In this study, we performed longitudinal tracking of plasma TP53 and PIK3CA mutations prespecified from NGS analysis of tumor tissue specimens of HER2-positive and triple-negative (TN) breast cancer (BC) patients in order to demonstrate that ctDNA clearance during neoadjuvant treatment (NAT) correlates with effective response to treatment. Initially, we examined the degree to which clearance of TP53 and PIK3CA mutations in ctDNA during NAT correlated with pathologic complete response (pCR) in the resected specimen. Our findings suggest that effective ctDNA clearance may predict pCR. Moreover, these findings prompt further investigative trials that explore more fully the value of ctDNA monitoring to identify those patients who may avoid surgery following NAT.
Patients and Methods: In initial analyses, tumor tissue samples from 18 TN or HER2 BC patients whoreceived NAT and showed significant response were analyzed for TP53 and PI3KCA mutations (Qiasymphony DNA midi and DNA Tissue Kits, respectively, QIAGEN). Plasma samples were obtained from all of these patients at diagnosis, after the 1st treatment cycle, during the middle of treatment, and prior to surgery. All TP53 and PIK3CA ctDNA analyses were carried out using the plasma SafeSEQ technology (Sysmex Inostics) and were only carried out on patient samples in which a specific TP53 or PIK3CA mutation had been initially identified in that patient’s tissue. All patients underwent a surgical excision after NAT.
Results: Of the 18 patients, only 8 were found to have either a TP53 or a PIK3CA mutation (6 TP53 and 2 PI3KCA mutations). PI3KCA mutations were only detected in HER2-positive patients, whereas TP53 mutations were detected predominantly in TN patients (88%). After the 1st cycle of NAT, no mutations were detected in 6 (75%) patients while the 2 remaining (25%) demonstrated mutation clearance at the middle of treatment. Interestingly, one patient showed a TP53 baseline mutation (TP53 p.R273L) that was no longer detected after the 1st cycle of NAT, but a new mutation was detected at the time of surgery (TP53 p.R267W). Seven out of these 8 patients showing mutation clearance in ctDNA (88%) reached a pCR.
Conclusions: ctDNA detected in plasma of patients with TN or HER2-positive BC showed a sharp decrease from the first cycle of NAT, reaching undetectable levels until the time of surgery and correlating with pCR. However, new mutations not previously present appeared, which may reflect the adaptation of the tumor to treatment. We are currently extending our analyses to reanalyze with an alternative NGS platform those tissue specimens for which no mutations were detected. Also, additional patient plasma and tissue specimens are undergoing analysis to evaluate the relationship between molecular MRD as determined by ctDNA and pCR.
Citation Format: Nikaoly Ciriaco, Esther Zamora, Santiago Escrivá, Rosa Somoza, Javier Hernández-Losa, Santiago Ramón y Cajal, Martín Espinosa-Bravo, Vicente Peg. Clearance of ctDNA in triple-negative and Her2-positive breast cancer patients during neoadjuvant treatment is correlated with pathologic complete response [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B63.