Abstract

Breast cancer is one of the main cause of cerebral and leptomeningeal metastases, the prognosis of which remains poor to this day. Most studies excluded patients with active brain metastases (BM) and particularly with leptomeningeal metastases (LM) explaining the lack of therapeutic innovation in this area. Currently, the standard management of patients with BM of breast cancer is based on the combination of surgery, radiotherapy and systemic treatments. Recently, third-generation of Antibody-Drug Conjugates (ADCs), have revolutionized the management of metastatic breast cancer. Trastuzumab deruxtecan and Sacituzumab govitecan have indeed shown significant improvements of survival outcomes and can now be used in a wide range of breast cancer subtypes. However, few data are available on the efficacy of third-generation ADCs on BM and LM of breast cancer. As the field of ADCs is rapidly evolving, with new constructs entering the late clinical development, in this review we describe the efficacy of approved and novel promising conjugates on patients with BM and LM of breast cancer.

Introduction

Brain metastases (BM) frequently occur in patients with advanced solid tumors, leading to significant morbidity and mortality. Although the incidence of BM varies across tumor histologies, it is estimated that 10 to 25% of patients with metastatic cancer will develop BM during the course of their disease [1], [2], [3]. Among these tumors, breast cancer (BC) ranks as the second most common cause of BM, following lung cancer. Autopsy studies, considering both symptomatic and asymptomatic lesions, estimate the incidence of BM in BC to be around 20 to 30% [4], [5]. Among metastatic breast cancers (mBC), HER2 positive and triple-negative subtypes are associated with a higher risk of BM (about 30% for each) than luminal subtype (15%) [5].Typically, BM is a late event in the disease course. The median time between the diagnosis of mBC and the onset of BM is approximately 53 months for luminal subtype, 34 months for HER2-positive subtype, and 25 months for triple-negative breast cancer (TNBC) [6]. With the availability of more effective systemic therapies for breast cancer, patients are living longer, resulting in a steady increase in the incidence of BM [7]. Despite therapeutic advancements, patients with BM from BC continue to have a poor prognosis. The median survival varies depending on tumor subtypes, ranging from 7 to 9 months for hormone-receptor positive (HR+)/HER2-negative BC, 16 to 19 months for HR+/HER2-positive BC, 11 to 13 months for hormone-receptor negative (HR-)/HER2-positive BC, and less than 5 months for TNBC [8], [9], [10].

Conclusions and perspectives

In recent years, the advent of novel ADC has significantly transformed the treatment landscape for metastatic breast cancer and holds great promise for improving survival outcomes [62].

However, the management of brain metastases remains a significant challenge. Many studies have either excluded patients with central nervous system involvement or failed to report specific intracranial data when included. Furthermore, there is a paucity of studies specifically investigating the efficacy of third-generation ADC in patients with active brain metastases or leptomeningeal disease.

Nonetheless, the limited available data thus far present promising findings, demonstrating notable activity of ADC in patients with active brain metastases. Given the poor prognosis associated with central nervous system involvement and the effectiveness of ADC, it is imperative to intensify the exploration of these novel treatments in this patient population. Therefore, substantial efforts should be dedicated to designing well-designed clinical trials in this context.