ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Five Years of Multidisciplinary Care in Hereditary Cancer: Our Experience in a Spanish University Hospital.

OBJECTIVE: To analyse the evolution of a multidisciplinary heredofamilial cancer unit (HFCU) in a university hospital. METHODS: This was a retrospective analysis of the activity of our HFCU in its first 5 years of existence. RESULTS: Between July 2010 and July 2015, 1,518 patients from 1,318 families attended our HFCU. Genetic testing was offered to 862 patients. Of those, 833 (96.6%) accepted testing, with available results for 636 (76.4%). Pathogenic mutations in BRCA1 and BRCA2 were found in 175 patients. Lynch syndrome and adenomatous polyposis were the most frequent syndromes diagnosed (151/175, 86.3%) among 17 different syndromes studied. Of the 404 patients without a previous genetic diagnosis in the family, 62 (15.3%) were found to have mutations in disease-causing genes. Prophylactic surgery and follow-up (33.7%) or follow-up only (66.3%) was proposed for mutation carriers according to international guidelines and patients' preferences. CONCLUSION: We have a high mutation detection rate, genetic test acceptance, and compliance with risk reduction strategies. However, there is room for improvement, especially in genetic testing timing, considering that an increase in the indications for genetic testing is expected.

MicroRNA-based molecular classification of non-BRCA1/2 hereditary breast tumours.

BACKGROUND: Hereditary breast cancer comprises 5-10% of all breast cancers. Mutations in two high-risk susceptibility genes, BRCA1 and BRCA2, along with rare intermediate-risk genes and common low-penetrance alleles identified, altogether explain no more than 45% of the high-risk breast cancer families, although the majority of cases are unaccounted for and are designated as BRCAX tumours. Micro RNAs have called great attention for classification of different cancer types and have been implicated in a range of important biological processes and are deregulated in cancer pathogenesis. METHODS: Here we have performed an exploratory hypothesis-generating study of miRNA expression profiles in a large series of 66 primary hereditary breast tumours by microarray analysis. RESULTS: Unsupervised clustering analysis of miRNA molecular profiles revealed distinct subgroups of BRCAX tumours, 'normal-like' BRCAX-A, 'proliferative' BRCAX-B, 'BRCA1/2-like' BRCAX-C and 'undefined' BRCAX-D subgroup. These findings introduce a new insight in the biology of hereditary breast cancer, defining specific BRCAX subgroups, which could help in the search for novel susceptibility pathways in hereditary breast cancer. CONCLUSION: Our data demonstrate that BRCAX hereditary breast tumours can be sub-classified into four previously unknown homogenous groups characterised by specific miRNA expression signatures and histopathological features.

Venous thromboembolism incidence in cancer patients with germline BRCA mutations.

BACKGROUND: Germline BRCA (gBRCA) mutations predispose to an increased risk of breast and ovarian cancer among other neoplasms. Recently, several genomic alterations such as ALK and ROS-1 rearrangements have been described as molecular drivers of venous thromboembolism (VTE). The association of gBRCA mutations and VTE is unknown. MATERIALS AND METHODS: We performed an observational, retrospective, single-center study to determine the VTE incidence in consecutive patients with gBRCA mutations and cancer diagnosis attended in the multidisciplinary heredofamiliar cancer unit (HFCU) of Hospital General Universitario Gregorio Marañón, Spain, from 2010 to 2019. RESULTS: One-hundred and forty-one patients were included in the analysis. The overall VTE incidence was 12.8%. The highest incidence was reported in ovarian cancer patients (20.0%), followed by patients with both ovarian and breast cancers (16.6%) and the lowest was found in breast cancer (4.9%). No difference in the type of gBRCA mutation (1 or 2) in terms of VTE rate was observed. Sixty one percent of the patients were receiving anti-cancer therapy at the time of VTE diagnosis and the majority of the events (83.3%) were diagnosed in ambulatory setting. Khorana score was of limited value to detect high-risk patients. CONCLUSIONS: The VTE incidence observed in our study is consistent with prior data described in general population of breast and ovarian cancer. The risk of VTE in these patients seems to be driven by the type of cancer. We have not observed any significant interaction of gBRCA mutation status and cancer-associated thrombosis.

SEOM clinical guideline for the management of cutaneous melanoma (2020).

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.

Prognostic significance of sentinel node biopsy status in cutaneous melanoma: a 21-years prospective study from a single institution.

AIM: To analyze the accuracy of the sentinel lymphatic node biopsy (SLNB) and to investigate predictive factors for sentinel node (SN) status and prognostic factors for recurrence-free survival (RFS) and disease-specific survival (DSS) in patients with melanoma. MATERIAL AND METHODS: Between June 1997 and June 2017, 440 consecutive patients, who underwent SLNB by a single surgical team, were prospectively included. Descriptive and survival analysis were performed. RESULTS: 119 of 440 patients (26%) had positive SN. SLNB's false-negative rate was 6.3%. Breslow thickness, Clark´s level, ulceration and histological subtype were statistically significant predictive factors of SN metastases. In a multivariate analysis, positive SN (HR = 2.21, p = 0.01), deeper Breslow thickness (HR = 2.05, p = 0.013), male gender (RR = 2.05, p = 0.02), and higher Clark's level (HR = 2.30, p = 0.043) were significantly associated with decreased RFS; and positive SN (HR = 2.58, p < 0.001), deeper Breslow thickness (HR = 2.57, p = 0.006) and male gender (HR = 1.93, p = 0.006) were associated with lower DSS. CONCLUSION: SLNB is a reliable and reproducible procedure with high sensitivity (93.7%). Positive SN metastases, Breslow thickness and male gender were statistically associated with poorer outcomes. Male gender was an independent prognostic factor of tumor thickness or SN status.

Efficacy and safety of immune checkpoint inhibitor immunotherapy in elderly cancer patients.

PURPOSE: There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years. METHODS/PATIENTS: The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated. RESULTS: In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p = 0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope = 0.218, p = 0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs. CONCLUSIONS: The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.

Utility of PET/CT in patients with stage I-III melanoma.

PURPOSE: To study the utility of positron emission tomography with computerized tomography (PET/CT) in patients with a stage I-III melanoma. PATIENTS AND METHODS: PET/CT findings from all patients with a stage I-III melanoma attended at our hospital from September 2011 to November 2015 were reviewed. RESULTS: Data from 83 patients with a stage I-III melanoma, 39 patients with a positive sentinel lymph node biopsy (SLNB) and 35 patients with locoregional recurrences were analyzed. Sensitivity of PET/CT in clinical stage I-III patients was 5%, with a 14% of false positives. In patients with a positive SLNB, PET/CT previous to complete lymph node dissection had a 23% of false negatives. In patients with clinical locoregional recurrences, PET/CT findings revealed asymptomatic visceral distant metastasis in 25.7%. CONCLUSIONS: PET/CT has a significant rate of false positive and negative results in patients with a stage I-III melanoma. Utility in patients with nodal locoregional recurrences seems higher than in patients with skin metastases.

Prospective, multicenter study on the economic and clinical impact of gene-expression assays in early-stage breast cancer from a single region: the PREGECAM registry experience.

INTRODUCTION: The aim of this study is to evaluate the cost-effectiveness and impact of gene-expression assays (GEAs) on treatment decisions in a real-world setting of early-stage breast cancer (ESBC) patients. METHODS: This is a regional, prospective study promoted by the Council Health Authorities in Madrid. Enrolment was offered to women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, node-negative or micrometastatic, stage I or II breast cancer from 21 hospitals in Madrid. Treatment recommendations were recorded before and after knowledge of tests results. An economic model compared the cost-effectiveness of treatment, guided by GEAs or by common prognostic factors. RESULTS: 907 tests (440 Oncotype DX® and 467 MammaPrint®) were performed between February 2012 and November 2014. Treatment recommendation changed in 42.6% of patients. The shift was predominantly from chemohormonal (CHT) to hormonal therapy (HT) alone, in 30.5% of patients. GEAs increased patients' confidence in treatment decision making. Tumor grade, progesterone receptor positivity and Ki67 expression were associated with the likelihood of change from CHT to HT (P < 0.001) and from HT to CHT (P < 0.001). Compared with current clinical practice genomic testing increased quality-adjusted life years by 0.00787 per patient and was cost-saving from a national health care system (by 13.867€ per patient) and from a societal perspective (by 32.678€ per patient). CONCLUSION: Using GEAs to guide adjuvant therapy in ESBC is cost-effective in Spain and has a significant impact on treatment decisions.

The RANK-RANKL axis: an opportunity for drug repurposing in cancer?

Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

A retrospective chart review study describing metastatic melanoma patients profile and treatment patterns in Spain.

PURPOSE: To describe patient characteristics by disease stage, resectability status and current treatment management after first diagnosis of IIIB to IV1c advanced (AM)/metastatic melanoma (MM). METHODS/PATIENTS: Multicentre, retrospective study based on data from medical charts of patients > 18 years at MM first diagnosis, visited by oncologists at 4 reference centres in Spain: Hospital Universitario Gregorio Marañón (Madrid), Hospital General de Valencia (Valencia), Clínica Universidad de Navarra (Pamplona), and Hospital Clínic (Barcelona). RESULTS: Metastatic non-visceral melanoma (IIIB, IIIC, IV M1a) was reported in 139 (48.6%) patients and 40.9% (n = 117) were diagnosed with IV-M1c disease. 160 (55.9%) metastases were resectable. Available therapies under clinical practice were used in 210 patients; 74 were treated under clinical trials (CT). Intention-to-cure surgery (47.6%) was the most common treatment at time of MM diagnosis. Systemic (45.1% overall) therapy included chemo-, targeted- and immunotherapy (19.6%, 14.3%, 8.4%, respectively). At time of data collection, 26 patients were still alive and 120 had progressed to IV-M1c. Median overall survival (OS) was significantly larger in IIIB patients, 28.9 m (25.2-32.7); the shortest for IV-M1c patients, 11.0 m (8.7-13.3). CONCLUSIONS: Novel treatments are undoubtedly a major step forward in AM/MM, however these are often only available in the CT setting because early stages of development or country-specific regulations. Further prospective studies and multifactorial analysis should be performed to clearly identify possible clinical associations for outcome in Spanish patients with AM/MM.

SEOM clinical guideline for the management of malignant melanoma (2017).

All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

Venous thromboembolism incidence in cancer patients with germline BRCA mutations

BackgroundGermline BRCA (gBRCA) mutations predispose to an increased risk of breast and ovarian cancer among other neoplasms. Recently, several genomic alterations such as ALK and ROS-1 rearrangements have been described as molecular drivers of venous thromboembolism (VTE). The association of gBRCA mutations and VTE is unknown.Materials and methodsWe performed an observational, retrospective, single-center study to determine the VTE incidence in consecutive patients with gBRCA mutations and cancer diagnosis attended in the multidisciplinary heredofamiliar cancer unit (HFCU) of Hospital General Universitario Gregorio Marañón, Spain, from 2010 to 2019.ResultsOne-hundred and forty-one patients were included in the analysis. The overall VTE incidence was 12.8%. The highest incidence was reported in ovarian cancer patients (20.0%), followed by patients with both ovarian and breast cancers (16.6%) and the lowest was found in breast cancer (4.9%). No difference in the type of gBRCA mutation (1 or 2) in terms of VTE rate was observed. Sixty one percent of the patients were receiving anti-cancer therapy at the time of VTE diagnosis and the majority of the events (83.3%) were diagnosed in ambulatory setting. Khorana score was of limited value to detect high-risk patients.ConclusionsThe VTE incidence observed in our study is consistent with prior data described in general population of breast and ovarian cancer. The risk of VTE in these patients seems to be driven by the type of cancer. We have not observed any significant interaction of gBRCA mutation status and cancer-associated thrombosis.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension.

Calcitonin gene related peptide (CGRP), a 37 amino acid neuropeptide, is the most potent vasodilator known. Participation of CGRP in hypertension and related diseases, such as preeclampsia or vasospasm after subarachnoid haemorrage, is one of the most studied topics. In this review we summarize the published roles of CGRP in pathophysiology of hypertension in humans and in experimental models. We also discuss the effects of direct administration of CGRP in the treatment of hypertension and of anti-hypertensive drugs that enhance the release or response of endogenous calcitonin gene-related peptide: angiotensin converting enzyme inhibitors, selective antagonists for the angiotensin II receptor, beta-blockers, magnesium sulphate for preeclampsia and rutaecarpine, as well as the possibilities using CGRP in gene therapy for prevention of vasospasm after subarachnoid haemorrage.

Review: circulating tumor cells in the practice of breast cancer oncology.

The primary cause of tumor-related death in breast cancer is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. Circulating tumor cells (CTCs) play a major role in the metastatic spread of breast cancer. Different analytical systems for CTCs isolation and detection have been developed and novel areas of research are directed towards developing assays for CTCs molecular characterization. This review describes the current state of art on CTCs detection techniques and the present and future clinical implications of CTCs enumeration and characterization.

SEOM clinical guideline for the management of cutaneous melanoma (2020)

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I–III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available (AU)

Running away from side effects: physical exercise as a complementary intervention for breast cancer patients.

The number of breast cancer survivors increases every year, thanks to the development of new treatments and screening techniques. However, patients present with numerous side effects that may affect their quality of life. Exercise has been demonstrated to reduce some of these side effects, but in spite of this, few breast cancer patients know and follow the exercise recommendations needed to remain healthy. In this review, we describe the different breast cancer treatments and the related side effects and implications of exercise in relation to these. We propose that exercise could be an integrative complementary intervention to improve physiological, physical and psychological factors that affect survival and quality of life of these patients. For that reason, the main objective of this review is to provide a general overview of exercise benefits in breast cancer patients and recommendations of how to design exercise interventions in patients with different side effects.