A genome-wide cell-free DNA methylation analysis identifies an episignature associated with metastatic luminal B breast cancer.

Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array in a cohort of 14 women, including metastatic LBBC patients and nontumor controls. The methylation levels of cfDNA and tissue samples were validated with droplet digital PCR. The methylation and gene expression data of 582 primary luminal breast tumors and 79 nontumor tissues were obtained from The Cancer Genome Atlas (TCGA). We found an episignature of 1,467 differentially methylated CpGs that clearly identified patients with LBBC. Among the genes identified, the promoter hypermethylation of WNT1 was validated in cfDNA, showing an area under the ROC curve (AUC) of 0.86 for the noninvasive detection of metastatic LBBC. Both paired cfDNA and primary/metastatic breast tumor samples showed hypermethylation of WNT1. TCGA analysis revealed significant WNT1 hypermethylation in the primary tumors of luminal breast cancer patients, with a negative association between WNT1 methylation and gene expression. In this proof-of-principle study, we discovered an episignature associated with metastatic LBBC using a genome-wide cfDNA methylation approach. We also identified the promoter hypermethylation of WNT1 in cfDNA as a potential noninvasive biomarker for luminal breast cancer. Our results support the use of EPIC arrays to identify new epigenetic noninvasive biomarkers in breast cancer.

Follow-up of primary melanoma patients with high risk of recurrence: recommendations based on evidence and consensus

In spite of the good prognosis of patients with early-stage melanoma, there is a substantial proportion of them that develop local or distant relapses. With the introduction of targeted and immune therapies for advanced melanoma, including at the adjuvant setting, early detection of recurrent melanoma and/or second primary lesions is crucial to improve clinical outcomes. However, there is a lack of universal guidelines regarding both frequency of surveillance visits and diagnostic imaging and/or laboratory evaluations. In this article, a multidisciplinary expert panel recommends, after careful review of relevant data in the field, a consensus- and experience-based follow-up strategy for melanoma patients, taking into account prognostic factors and biomarkers and the high-risk periods and patterns of recurrence in each (sub) stage of the disease. Apart from the surveillance intensity, healthcare professionals should focus on patients’ education to perform regular self-examinations of the skin and palpation of lymph nodes. (AU)

Follow-up of primary melanoma patients with high risk of recurrence: recommendations based on evidence and consensus.

In spite of the good prognosis of patients with early-stage melanoma, there is a substantial proportion of them that develop local or distant relapses. With the introduction of targeted and immune therapies for advanced melanoma, including at the adjuvant setting, early detection of recurrent melanoma and/or second primary lesions is crucial to improve clinical outcomes. However, there is a lack of universal guidelines regarding both frequency of surveillance visits and diagnostic imaging and/or laboratory evaluations. In this article, a multidisciplinary expert panel recommends, after careful review of relevant data in the field, a consensus- and experience-based follow-up strategy for melanoma patients, taking into account prognostic factors and biomarkers and the high-risk periods and patterns of recurrence in each (sub) stage of the disease. Apart from the surveillance intensity, healthcare professionals should focus on patients' education to perform regular self-examinations of the skin and palpation of lymph nodes.

Clinical Relevance and Therapeutic Application of CTCs in Advanced Breast Cancer.

Precision medicine through liquid biopsy represents an emerging approach in the management of cancer. The CTC count in blood samples from patients with advanced breast cancer is a powerful prognostic factor for both progression free and overall survival. Moreover, high levels of CTCs at any time during the treatment can reliably predict progression before imaging studies and/or tumor markers. Furthermore, there are works on the molecular characterization of the CTCs and their potential ability to guide the treatment in a dynamic way. However, their role remains controversial. Detection and enumeration of CTCs is variable among different tumors and is subjected to biases related mainly to their methodology, which is not completely standardized. In addition, they must demonstrate their clinical value to guide the treatment and a translation on patient's survival.

Detection of MET Alterations Using Cell Free DNA and Circulating Tumor Cells from Cancer Patients.

MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p <10-10) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch® and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05; HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapy.

Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies.

Skin localization occurs in about 25% of women with metastatic breast cancer and represents a major therapeutic challenge. Although clinical literature on response of cutaneous metastases to chemotherapy is scarce, good response to eribulin has been reported. Herein, the clinical courses of three women with skin lesions secondary to metastatic breast cancer are described. The first patient achieved a complete clinical response in skin metastases with good tolerability to fourth-line eribulin (progression-free survival [PFS]: 8.5 months). In the second case, eribulin administered as fifth-line chemotherapy produced an objective response and PFS of 6 months with good tolerability. The third patient also received eribulin in the fifth line and had a visible skin response from the first administration (PFS: 5 months).