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Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance...
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A terapia endócrina (TE) é o tratamento padrão para pacientes com câncer de mama receptor hormonal (RH) positivo e HER-2 negativo metastático.
Background:
The quest to comprehend the real-world efficacy of CDK4/6 inhibitors (CDKis) in breast cancer continues, as patient responses vary significantly.
Methods:
This single-center retrospective study evaluated CDKi use outside the trial condition from November 2016 to May 2020. Progression-free survival (PFS), time-to-treatment failure (TTF), short-term and prolonged treatment benefit (≥4 and ≥10 months), as well as prognostic and predictive markers were assessed with Kaplan-Meier and multivariate regression analyses.
Results:
Out of 86 identified patients, 58 (67.4%) had treatment failure of which 40 (46.5%) were due to progression. Median PFS and TTF were 12 and 8.5 months, respectively. A total of 57 (66.3%) and 42 (48.8%) patients experienced short-term and prolonged treatment benefit. Independent, significant predictors for PFS were progesterone receptor expression (HR: 0.88), multiple metastatic sites (HR: 2.56), and hepatic metastasis (HR: 2.01). Significant predictors for TTF were PR expression (HR: 0.86), multiple sites (HR: 3.29), adverse events (HR: 2.35), and diabetes (HR: 2.88). Aside from tumor biology and adverse events, treatment modifications like pausing and switching of CDKi were predictive for short-term (OR: 6.73) and prolonged (OR: 14.27) therapeutic benefit, respectively.
Conclusions:
These findings emphasize the importance of tailored treatment strategies, highlighting the role of PR expression, metastatic burden, and therapeutic adjustments in optimizing patient outcomes in real-world breast cancer management.
The circadian clock controls the expression of a large proportion of protein‐coding genes in mammals and can modulate a wide range of physiological processes. Recent studies have demonstrated that disruption or dysregulation of the circadian clock is involved in the development and progression of several diseases, including cancer. The cell cycle is considered to be the fundamental process related to cancer. Accumulating evidence suggests that the circadian clock can control the expression of a large number of genes related to the cell cycle. This article reviews the mechanism of cell cycle‐related genes whose chromatin regulatory elements are rhythmically occupied by core circadian clock transcription factors, while their RNAs are rhythmically expressed. This article further reviews the identified oscillatory cell cycle‐related genes in higher organisms such as baboons and humans. The potential functions of these identified genes in regulating cell cycle progression are also discussed. Understanding how the molecular clock controls the expression of cell cycle genes will be beneficial for combating and treating cancer.
Citation: Cordani, N.; Mologni, L.; Piazza, R.; Tettamanti, P.; Cogliati, V.; Mauri, M.; Villa, M.; Malighetti, F.; Di Bella, C.; Jaconi, M.; et al. TWIST1 Abstract: Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival in hormone-receptor-positive (HR+), human-epidermal-growth-factor-receptor-type-2-negative (HER2−) metastatic luminal breast cancer (mLBC). Several studies have shown that in patients with endocrine-sensitive or endocrine-resistant LBC, the addition of CDK4/6 inhibitors to endocrine therapy significantly prolongs progression-free survival. However, the percentage of patients who are unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers have been validated to select a priori responders or refractory patients. The selection of mutant clones in the target oncoprotein is the main cause of resistance. Other mechanisms such as oncogene amplification/overexpression or mutations in other pathways have been described in several models. In this study, we focused on palbociclib, a selective CDK4/6 inhibitor. We generated a human MCF-7 luminal breast cancer cell line that was able to survive and proliferate at different concentrations of palbociclib and also showed cross-resistance to abemaciclib. The resistant cell line was characterized via RNA sequencing and was found to strongly activate the epithelial-to-mesenchymal transition. Among the top deregulated genes, we found a dramatic downregulation of the CDK4 inhibitor CDKN2B and an upregulation of the TWIST1 transcription factor. TWIST1 was further validated as a target for the reversal of palbociclib resistance. This study provides new relevant information about the mechanisms of resistance to CDK4/6 inhibitors and suggests potential new markers for patients' follow-up care during treatment.
