ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain metabolized in the liver via cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Methods: A narrative review of the literature was conducted by searching MEDLINE and PubMed databases up to October 2025, using the English language as the only restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in the CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition using concomitant drugs or compounds (herbal or food) are variability factors in drug response that may be predictable. Conclusion: This review article provides an overview of the role of pharmacogenetics and opioid interactions as a rationale for multimodal approaches aimed at optimizing treatment in clinical practice, in particular opioids should be tailored to each clinical indication and patients should be stratified to receive the appropriate dose.