Abstract 5468: Which are the clinicopathological characteristics useful to define the metastatic breast cancer patients that will respond to CDK4/6 inhibitors and hormone therapy? An Italian real-world experience
Authors: Bravaccini Sara , Roncadori Andrea , Balzi William , Martinelli Giovanni , Montella Maria Teresa , Palleschi Michela , Maltoni Roberta 
Published: June 2023

Abstract
The development of CDK4/6 inhibitors has changed the therapeutic management of hormone receptor positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a high proportion of patients will present disease progression due to the resistance of cancer cells to CDK4/6 inhibitors. Loss of retinoblastoma function, dysregulation of several signaling pathways and overexpression of CDK6, CDK7 and cyclin E have been described as main actors in the development of resistance to CDK4/6 inhibitors. Despite these findings on the role of new emerging biomarkers, we wondered if the clinicopathological characteristics could be useful to identify the patients that will respond to CDK4/6 inhibitors by the analysis of a retrospective case series of patients with HR+ mBC treated with hormone therapy plus CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib) at IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori" (Meldola, Italy). 177 mBC patients 66 of whom were treated with CD4/6 inhibitors plus letrozole and 111 treated with CDK4/6 inhibitors and fulvestrant were enrolled in the study. The median age was 63 years (range 38-92), of whom 103 younger than 65 years. 152 were in postmenopausal status. Among the clinical characteristics, neutropenia was developed in 80 patients. ki67 was low (&lt;20%) in 85 patients. 21 (23.3%) patients had bone metastases, 36 visceral metastases (23.3%) and 33 (36.7%) in other organs. The multivariable Cox PH model showed that having received a prior adjuvant treatment and the number of metastases were the only factors associated with the progression-free survival (PFS). Furthermore, when introducing the presence of neutropenia as a potential predictor of PFS in the Cox PH model, it resulted to be a risk predictor of progression. To better describe the mechanism linking PFS and neutropenia a multistate model was developed. Low body surface area and older age were associated with an increased risk of developing neutropenia. High Ki67, the presence of visceral metastases and the absence of a prior adjuvant chemotherapy were prognostic factors of progression/death. As expected, among neutropenic patients, those with multiple previous lines of treatment were at higher risk of disease progression/death. Finally, the neutropenia status was associated with a more than double risk of progression/death with respect to patients without neutropenia (HR=2.311; p=0.025). Given that we identified a set of factors associated with the probability to develop neutropenia and considering that neutropenia itself is associated with an increased risk of progression, these baseline characteristics should be taken into account in order to reduce the occurrence of both neutropenia and disease progression.
Citation Format: Sara Bravaccini, Andrea Roncadori, William Balzi, Giovanni Martinelli, Maria Teresa Montella, Michela Palleschi, Roberta Maltoni. Which are the clinicopathological characteristics useful to define the metastatic breast cancer patients that will respond to CDK4/6 inhibitors and hormone therapy? An Italian real-world experience. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5468.