Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.

Tregs are able of suppressing tumor-specific effector cells, such as lymphocytes CD8+, CD4+ and Natural Killer cells. Different drugs, especially different schedules of administration, like metronomic chemotherapy (mCHT), seem to be able to increase anticancer immunity, by acting on downregulation of Tregs. Most of the data available regarding the immunomodulating effect of mCHT have been obtained with Cyclophosphamide (CTX). Aim of the present study was to explore the effects of mVRL and mCAPE administration, alone or in combination, on T cells. Observation of 13 metastatic breast cancer patients lasted controlling for 56 days, where Treg frequencies and function, spontaneous anti-tumor T-cell responses were monitored, as well as the clinical outcome. No depletion in Treg absolute numbers, or percentage of T lymphocytes, was observed. Only in 5 patients, a modest and transient depletion of Tregs was observed during the first 14 days of treatment. To better describe the effect on Tregs, we subsequently looked at the variations in Memory, Naïve and Activated Treg subpopulations: we observed a trend in reduction for memory Treg (Treg MEM) and an increase for Treg Naïve (Treg NAIVE) and Treg Activated (Treg ACT) components. We finally analyzed the average trend of Treg in the Treg depleted patients and non-depleted ones, without fiding any significant differences. The trend of the Treg MEM appeared different, showing a reduction during the first 14 days, followed by an increase at the levels before treatment at Day 56 in the group of depleted patients and a progressive substantial reduction in the group of non-depleted patients along the entire course of treatment. Opposed to the data known, treatment with mVRL w/o mCAPE did not show any effect on Tregs.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT’s activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75–98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3–4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Background: MBC is an incurable disease and chemotherapy (CHT) represents one option of treatment upfront, in TNBC pts, or at failure of an endocrine therapy + targeted agents in HR+ ones. mCHT was extensively studied in different types of ABC pts and is largely used in clinical practice. 18FDG-PET is often used as a tool for disease staging at baseline and for disease restaging during treatment. Different quantitative and semi-quantitative 18FDG-PET parameters have been investigated as predictive and prognostic biomarkers in NSCLC and other tumours. Aim of the present study is to evaluate the role of baseline SUVmax , global SUVmean, SUVpeak, Metabolic Tumour Volume (MTV) and Total Lesion Glycolysis (TLG) as predictive factors of response to mCHT. Patients and Methods: We identified 36 MBC pts treated with mCHT between 2014 and 2021, with at least two separate 18FDG-PET evaluations. Patients and biological tumour characteristics, previous treatments, site of relapse as well as quantitative pre-treatment 18FDG-PET parameters have been collected. Tumour response was assessed using PERCIST Criteria. Median and mean ± SD 18FDG-PET parameters have been reported according to the type of response. Complete and Partial responses have been grouped together with Stable Disease. Results: Median age was 69 (33-82). Luminal pts were 25 (67.6%), TNBC pts were 16.2%); most were heavily pre-treated for their metastatic disease (≥ 3 lines: 14, 37.8%) and presented ≥ 3 metastatic sites (14, 37.8%). All pts received mCHT, 26 (70.3%) as combination therapy (VRL+CAPE or VRL+CAPE+CTX), or single agent (VRL, 11). Bone was the commonest metastatic site (62.2%). ORR was 43.2%; 7 pts had SD (18.9%), the remaining developed PD (37.8%). Similar values have been observed between the 2 groups in terms of SUVmax , global SUVmean and SUVpeak,. Mean MTV was higher in responder (n=22) vs non responder (n=14) pts, as TLG. Details are reported in Table 1. Conclusions: High mean baseline MTV and TLG seem to be related to response to mCHT in MBC pts. Our observation is in contrast to what is described for other cancer types, especially NSCLC, and for standard neoadjuvant treatment of BC. Considering the peculiar mechanisms of action of mCHT, our preliminary findings warrant further exploration in a larger series of BC pts. Table 1 Baseline 18FDG-PET uptake values in responder and non responder patients Citation Format: Marco Meazza Prina, Irene Gotuzzo, Marina Elena Cazzaniga, Elisabetta De Bernardi, Pietro Cafaro, Serena Capici, Viola Cogliati, Francesca Fulvia Pepe, Federica Cicchiello, Francesca Riva, Nicoletta Cordani, Maria Grazia Cerrito, Elia Anna Turolla, Claudio Landoni, Federica Elisei, Cinzia Crivellaro, Leonardo Virdone, Lavinia Monaco, Alessandro Guidi, Luca Guerra. BASELINE 18FDG-PET METABOLIC TUMOUR VOLUME (MTV) AS A POTENTIAL PREDICTIVE FACTOR OF RESPONSE TO METRONOMIC CHEMOTHERAPY (mCHT) IN HR+/HER2- METASTATIC BREAST CANCER (MBC) PATIENTS (pts). PRELIMINARY RESULTS OF THE METRO-PET STUDY [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-42.