Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells.

BACKGROUND: Hepatocellular carcinoma (HCC) growth relies on angiogenesis via vascular endothelial growth factor (VEGF) release. Hypoxia within tumour environment leads to intracellular stabilisation of hypoxia inducible factor 1 alpha (Hif1α) and signal transducer and activator of transcription (STAT3). Melatonin induces apoptosis in HCC, and shows anti-angiogenic features in several tumours. In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate the anti-angiogenic effects of melatonin. METHODS: HepG2 cells were treated with melatonin under normoxic or CoCl2-induced hypoxia. Gene expression was analysed by RT-qPCR and western blot. Melatonin-induced anti-angiogenic activity was confirmed by in vivo human umbilical vein endothelial cells (HUVECs) tube formation assay. Secreted VEGF was measured by ELISA. Immunofluorescence was performed to analyse Hif1α cellular localisation. Physical interaction between Hif1α and its co-activators was analysed by immunoprecipitation and chromatin immunoprecipitation (ChIP). RESULTS: Melatonin at a pharmacological concentration (1 mM) decreases cellular and secreted VEGF levels, and prevents HUVECs tube formation under hypoxia, associated with a reduction in Hif1α protein expression, nuclear localisation, and transcriptional activity. While hypoxia increases phospho-STAT3, Hif1α, and CBP/p300 recruitment as a transcriptional complex within the VEGF promoter, melatonin 1 mM decreases their physical interaction. Melatonin and the selective STAT3 inhibitor Stattic show a synergic effect on Hif1α, STAT3, and VEGF expression. CONCLUSION: Melatonin exerts an anti-angiogenic activity in HepG2 cells by interfering with the transcriptional activation of VEGF, via Hif1α and STAT3. Our results provide evidence to consider this indole as a powerful anti-angiogenic agent for HCC treatment.

Electronic health records and patient registries in medical oncology departments in Spain.

PURPOSE: We aimed to evaluate the current situation of electronic health records (EHRs) and patient registries in the oncology departments of hospitals in Spain. METHODS: This was a cross-sectional study conducted from December 2018 to September 2019. The survey was designed ad hoc by the Outcomes Evaluation and Clinical Practice Section of the Spanish Society of Medical Oncology (SEOM) and was distributed to all head of medical oncology department members of SEOM. RESULTS: We invited 148 heads of oncology departments, and 81 (54.7%) questionnaires were completed, with representation from all 17 Spanish autonomous communities. Seventy-seven (95%) of the respondents had EHRs implemented at their hospitals; of them, over 80% considered EHRs to have a positive impact on work organization and clinical practice, and 73% considered that EHRs improve the quality of patient care. In contrast, 27 (35.1%) of these respondents felt that EHRs worsened the physician-patient relationship and conveyed an additional workload (n = 29; 37.6%). Several drawbacks in the implementation of EHRs were identified, including the limited inclusion of information on both outpatients and inpatients, information recorded in free text data fields, and the availability of specific informed consent. Forty-six (56.7%) respondents had patient registries where they recorded information from all patients seen in the department. CONCLUSION: Our study indicates that EHRs are almost universally implemented in the hospitals surveyed and are considered to have a positive impact on work organization and clinical practice. However, EHRs currently have several drawbacks that limit their use for investigational purposes. CLINICAL TRIAL REGISTRATION: Not applicable.

Correction to: Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

A sentence under 'Results' heading in the Abstract section was published incorrectly. The correct sentence should read as follows.

Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

INTRODUCTION: This study aimed to describe the efficacy of fulvestrant 500 mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. MATERIALS AND METHODS: Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500 mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. RESULTS: A total of 263 women were evaluated (median age, 65.8 years). At a median follow-up of 21.5 months, median PFS and OS were 10.6 and 43.2 months, respectively. PFS according to 1st, 2nd, 3rd, and ≥ 4th lines were 11.5, 10.6, 9.9, and 8.5 months, respectively (p = 0.0245). PFS in patients with visceral involvement was 10 months vs 10.6 months in patients without visceral involvement (p = 0.6604), 9.6 months in patients with high Ki67 vs 10 months in patients with low Ki67 (p = 0.7224), and 10.2 months in HER2+ patients vs 10.3 months in HER2- patients (p = 0.6809). The CBR was 56.5% and the DoCB was 18.4 months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). CONCLUSIONS: Fulvestrant 500 mg administered in clinical practice was shown to be effective (PFS, 10.6 months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

Suspected extragonadal germ-cell cancer syndrome presenting with an orbital mass and elevation of serum CEA, CA 19-9 and CA50 levels.

Patients with extragonadal germ-cell cancer syndrome (EGCCS) represent a subgroup of patients with poorly differentiated carcinoma or adenocarcinoma of an unknown primary site for whom potentially curative therapy is available. We report the case of a young man presenting an orbital tumor and high serum levels of CEA, CA 19-9 and CA50 for whom an initial diagnosis of metastatic poorly differentiated carcinoma was made. Suspecting EGCCS, he was treated as for a germ-cell tumor. While in treatment, he underwent residual orbital mass resection, and the histologic diagnosis was embryonal carcinoma based on alpha-fetoprotein immunoperoxidase staining. We discuss the rare location at diagnosis, the impressive increase in the commonly considered gastrointestinal markers that he showed, and the potential utility of these markers for such patients.

FoxO proteins: regulation and molecular targets in liver cancer.

Human forkhead box class O (FoxO) transcription factors, activated in response to a wide range of external stimuli, like growth factors, insulin, nutrient levels and oxidative stress, are able to control several specific geneexpression programs. Besides their clear implication in metabolic processes, they appear to play a relevant role in tumour suppression by upregulation of genes involved in cell cycle arrest or apoptosis. Recent research efforts provide new insights into the molecular modulation of FoxO in liver cancer and disclose potential opportunities for developing new antitumor drugs. Through an intricate regulatory model, achieved via several post-translational modifications, including phosphorylation, acetylation, and ubiquitination, which control their subcellular localization and DNA binding activity, FoxO factors act as tumour suppressors. Low levels of FoxOs are associated with poor prognosis in cancer patients, and seem to confer chemotherapy resistance. Within FoxO members, FoxO3a appears to present anti-tumour properties in hepatocellular carcinoma, inducing the expression of pro-apoptotic genes, or interfering with signaling cascades commonly altered in this disease such as Wnt/ß-catenin, PI3K/AKT/mTOR or MAPKs pathways. Here, we describe the main mechanisms of FoxO proteins regulation, and their cross-link with altered pathways in liver cancer. Moreover, based on the current knowledge of FoxO modulation, emphasis is placed on the development of novel agents which specifically activate FoxO family members and could be useful in the treatment of hepatocarcinoma.

Breast cancer management in the elderly.

The increase in life expectancy in the western world means that we are faced with patients diagnosed with breast cancer in old age with increasing frequency. The management of these cases is a challenge for the oncologist, who must take into account the conditions associated with advanced age and the lack of trials in this population. In this review, we addressed the incorporation of geriatric assessment methods that may be useful in making decisions, the particular biological characteristics of breast cancer in elderly patients and their treatment in both localized and advanced disease. Finally, we collected recommendations based on scientific evidence regarding the monitoring and life-style after finishing treatment.

Clinical guideline SEOM: cancer of unknown primary site.

Cancer of unknown primary site is a histologically confirmed cancer which is manifested in advanced stage, with no identifiable primary site after the use of standard diagnostic procedures. Patients are initially placed into one of categories based upon the examination of the initial biopsy: adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma and poorly differentiated carcinoma. Appropriate patient management requires an understanding of several clinicopathologic features that help to identify several subsets of patients with more responsive tumors.

Management of patients with metastatic breast cancer.

Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Aromatase inhibitors (AI) have been extensively studied in this setting. This section summarizes the key data regarding the use of AI in advanced breast cancer. In postmenopausal women, AI are the first line of treatment for untreated patients, or those who had prior AI treatment and progress after 12 months of adjuvant therapy. A longer disease-free interval and absence of visceral disease is associated with a better response. If tumors recur in less than 12 months, it is recommended that tamoxifen (TAM) or the estrogen-receptor antagonist fulvestrant (FUL) treatment be initiated. In the second-line setting, the best option after progression is the administration of either FUL or TAM. In the third-line setting, reintroduction of AI is considered an acceptable option. In premenopausal women who have not received prior treatment or who have progressed after 12 months following adjuvant treatment, it is recommended to initiate therapy with a combination of TAM and a luteinizing hormone-releasing hormone (LHRH) analog. If there is treatment failure with the use of this combination, megestrol acetate or an LHRH agonist plus an AI may be reasonable alternatives. Intensive research is ongoing to understand the mechanisms of resistance to hormone therapy. In human epidermal growth factor receptor 2 positive-patients, combinations with HER2 antagonists are associated with significant clinical activity.