Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC).
Authors: Raimondi Lucrezia , Naso Giuseppe , Lazzeroni Rachele , Di Benedetto Laura , Raimondi Filippo Maria , Di Rocco Arianna , Giaconi Laura , Rossi Luigi , Spinelli Gian Paolo 
Published: June 2021

Retraction The abstract by Raimondi et al entitled, “Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC),” published in Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 507-507, was retracted by the Journal of Clinical of Oncology (JCO). An Expression of Concern was previously issued by JCO on June 16, 2021. Subsequent to publication of the abstract, questions about the data were brought to JCO’s attention. The data were provided by author Giuseppe Naso, who has since died. As the source of the data and methods of data collection cannot be verified, the abstract is being retracted. A copy of this Retraction Notice was sent to the last known email addresses for the authors. Authors Lucrezia Raimondi, Laura Giaconi, and Gian Paolo Spinelli agreed to the retraction. Authors Rachele Lazzeroni, Laura Di Benedetto, Filippo Maria Raimondi, Arianna Di Rocco, and Luigi Rossi did not respond to our queries. Author Giuseppe Naso is deceased. This abstract was retracted on November 9, 2021. 507 Expression of Concern The abstract by Raimondi et al entitled, “Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC),” published in Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 507-507, is under further review. Questions have been raised regarding the integrity of the methods, results, and analysis of the reported abstract. Until the authors and their institutions can fully provide additional information, readers should interpret the findings presented with caution. An update will be provided when our investigation is complete. Background: Despite improvements in treatments, patients diagnosed with TNBC still have poor prognosis for a higher tendency of developing BrM. Identifying patients at high risk of BrM, enabling to predict who will take advantage from appropriate additional treatment, remains a critical problem. ctDNA represents a valuable tool associated with the outcome and the aggressiveness of breast cancer but no prognostic and predictive biomarker has been identified to predict the development of BrM in TNBC. We studied the usefulness of assessment of CSF-ctDNA for early identification of the risk of BrM in TNBC. Methods: Between January 2016 and December 2020, 323 newly diagnosed non-metastatic TNBC patients who underwent neoadjuvant therapy+surgery(NACT) with complete response(CR)were prospectively enrolled. After surgery, samples of CSF measuring ctDNA were obtained from all patients: CSF-ctDNA was extracted with the QIAamp Circulating Nucleic Acid Kit (Qiagen, Valencia, CA, USA) and ctDNA levels were measured. Survival curves were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression was used to identify the risk of mortality at three years. Results: After NACT, CSF-ctDNA was detectable in 126/323 (39%) patients, 101/126 (80%) were diagnosed at III stage. 124 of 126 (98.4%) ctDNA+ patients subsequently developed BrM. In contrast, only 2 (2/197, 1%) ctDNA- patients subsequently developed BrM and the 195 other patients remain in a CR (p < 0.001, Fisher's exact test). CSF-ctDNA did associate with PFS and OS: undetectable ctDNA was associated with superior PFS (HR 0.3; p = 0.002) and OS (HR 0.2; p < 0.01), indicating survival is largely determined by the onset of BrM. With a median follow-up of 3 years, median PFS of ctDNA+ vs ctDNA- patients was 13 months vs not reach, p = 0.004 (by Log-rank test). Median OS for ctDNA+ vs ctDNA- patients was 16 months after NACT vs not reach, p = 0.0016 (by Log-rank test). At multivariate analysis detectable CSF-ctDNA emerged as the best predictor of the develop of BrM and 24-month mortality (HR:3.62; p < 0.0001). Age, stage, Ki67% and response to chemotherapy were not significantly associated with the prognosis. Conclusions: After NACT, detectable CSF-ctDNA significantly associates with PFS and OS, identifying early at-risk patients to develop BrM in TNBC.