Context: The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. Patients and Methods: From 1997–2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. Results: Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2–6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2–6 months. Conclusions: Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.

Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

Saverio Minucci, Giancarlo Pruneri, Luca Magnani and colleagues identify acquired CYP19A1 amplification as a mechanism of resistance to aromatase inhibitors in ERα metastatic breast cancer. Mechanistically, they show that CYP19A1 amplification results in increased aromatase activity and estrogen-independent ERα binding to target genes. Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy2, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases. We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer–associated genes, including ESR1 and CYP19A1. Notably, CYP19A1amp cells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.

Introduction: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. Patients and Methods: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. Results: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 μg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). Conclusions: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Objective: Cabergoline (CAB) has been found to be associated with increased risk of cardiac valve regurgitation in Parkinson's disease, whereas several retrospective analyses failed to detect a similar relation in hyperprolactinemic patients. The current study aimed at investigating cardiac valve disease before and after 24 and 60 months of continuous treatment with CAB only in patients with hyperprolactinemia.Subjects and methods: Forty patients (11 men and 29 women, aged 38.7±12.5 years) newly diagnosed with hyperprolactinemia entered the study. Cumulative CAB dose ranged from 12 to 588 mg (median 48 mg) at 24 months and 48–1260 mg (median 149 mg) at 60 months. All patients underwent a complete trans-thoracic echocardiographic examination. Valve regurgitation was assessed according to the American Society of Echocardiography.Results: At baseline, the prevalence of trace mitral, aortic, pulmonic, and tricuspid regurgitations was 20, 2.5, 10, and 40% respectively, with no patient showing clinically relevant valvulopathy. After 24 months, no change in the prevalence of trace mitral (P=0.78) and pulmonic (P=0.89) regurgitations and of mild aortic (P=0.89) and tricuspid (P=0.89) regurgitations was found when compared with baseline. After 60 months, the prevalence of trace tricuspid regurgitation was only slightly increased when compared with that after 24 months (37.5%; P=0.82), but none of the patients developed significant valvulopathy. No correlation was found between cumulative dose and prevalence or grade of valve regurgitation at both evaluations. Prolactin levels normalized in all patients but one.Conclusion: CAB does not increase the risk of significant cardiac valve regurgitation in prolactinomas after the first 5 years of treatment.