Resistance to CDK4/6 inhibitors (CDK4/6i): The clinical usefulness of liquid biopsy in metastatic breast cancer (mBC).

Abstract

Retraction The abstract by Raimondi et al entitled, “Resistance to CDK4/6 inhibitors (CDK4/6i): The clinical usefulness of liquid biopsy in metastatic breast cancer (mBC),” published in Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 1053-1053, was retracted by the Journal of Clinical Oncology.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, and Arianna Di Rocco did not respond to our queries. Author Giuseppe Naso is deceased. This abstract was retracted on November 9, 2021. 1053 Expression of Concern The abstract by Raimondi et al entitled, “Resistance to CDK4/6 inhibitors (CDK4/6i): The clinical usefulness of liquid biopsy in metastatic breast cancer (mBC),” published in Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 1053-1053, 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: Palbociclib (P) in combination with fulvestrant (F) or letrozole (L), is used globally to treat metastatic breast cancer but despite therapeutic improvements most patients acquire resistance to CDK4/6i. KRAS tumor mutations (mutKRAS) have been associated with worse PFS in several tumor types but have not been analysed extensively in breast cancer. To understand the molecular mechanisms of resistance to CDK4/6i and their clinical behavior, using liquid biopsy, we evaluated the opportunity to reveal the onset of resistance to CDK4/6i detecting mutKRAS ctDNA. Methods: We studied the KRAS mutation status of 211 patients with mBC treated with CDK4/6i plus L or F as first-line metastatic therapy. Using Bio-Rad QX200 droplet digital polymerase chain reaction (ddPCR) system we determined KRAS ctDNA levels in plasma. Using logistic and Cox regression, a predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed. The PFS and the OS were estimated by the Kaplan–Meier method and compared with use of the log-rank test. Results: In 38% (81 patients, 24 in treatment with L and 57 in treatment with F) we observed mutKRAS ctDNA before starting CDK4/6i: the detection of mutKRAS significantly correlated with the onset of resistance to CDK4/6i within 6months from the evidence of KRAS mutation and worse PFS ( p<0.001). OR was seen in 84 of 130 KRAS wild-type (WT) patients versus 0 of 81 in KRAS mutants. At 24-month follow up, median PFS was significantly better in KRAS WT versus mutants (3.1 [range: 1-6months,95%CI 0.9-3.6] versus NA months; p<0.001). Correlating the results of liquid biopsy both to tumoral burden and patients clinical features, we observed a higher mutKRAS circulating copies-number in those patients with two or more metastatic sites( p<0.001). Conclusions: Despite the study’s limitations, our data suggest mutKRAS ctDNA status leads to CDK4/6i resistance acquisition within 6 months from the detection and provide critical information for the prediction of therapeutic responses in mBC. Monitoring KRAS status with liquid biopsy, we could predict who will take advantage from CDK4/6i, decreasing wastes of resources ensuring the best patients’ quality of life.