Targeted gene panel sequencing of liquid and tissue biopsies reveals actionable genomic alterations in Ghanaian metastatic breast cancer cases.

PURPOSE: Breast cancer is a major cause of cancer-related mortality among African women. The adoption of molecular genomic technologies in the management of cancer cases is limited in Africa. To provide much-needed insights on the feasibility and utility of such precision medicine paradigms in Africa, we conducted a prospective, non-interventional study involving combined tissue and plasma Next-generation sequencing (NGS)-based testing in cancer patients in Ghana. METHODS: We recruited 20 newly diagnosed, histologically confirmed, treatment-naïve women with metastatic breast cancer at the Cape Coast Teaching Hospital in Ghana. Tissue (NGS) and cell-free DNA (cfDNA) liquid biopsy analysis were ordered on all 20 patients. RESULTS: All 20/20 (100 %) liquid biopsy samples were acceptable for analysis, whereas only 6/20 (30 %) passed quality control for tissue NGS testing. Liquid biopsy detected 42 cfDNA mutations in 17/20 patients. Of the 17 patients, 3 (17.6 %) had mutations previously associated with African ancestry, including BRCA1 p.K719E, ARAF p.S262I and GATA3 p.G125dup. Eight potentially actionable alterations specific to breast cancer were found in 6/17 (35.3 %) liquid biopsy samples, while potentially actionable mutations non-specific to breast cancer were detected in 12/17 (70.6 %). Tissue biopsy analysis detected mutations in all 6 patients tested, with 3/6 (50 %) patients presenting potentially actionable mutations relevant to breast cancer. CONCLUSION: Liquid biopsy detected multiple additional actionable variants in Ghanaian women with breast cancer. Plasma cfDNA analysis featured fewer variations in sample preparation which is a key consideration in resource-limited settings. Liquid biopsy presents a great opportunity to improve cancer care in Africa.

Androgen Receptor Splice Variant 7 in Asian Patients With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes. METHODS: Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients. CONCLUSION: In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.

Machine learning unveils an immune-related DNA methylation profile in germline DNA from breast cancer patients.

BACKGROUND: There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer. METHODS: DNA methylation profiling was performed for 524 Asian Chinese individuals, comprising 256 breast cancer patients and 268 age-matched healthy controls, using the Infinium MethylationEPIC array. Feature selection was applied to 649,688 CpG sites in the training set. Predictive models were built by training three machine learning models, with performance evaluated on an independent test set. Enrichment analysis to identify transcription factors binding to regions associated with the selected CpG sites and pathway analysis for genes located nearby were conducted. RESULTS: A methylation profile comprising 51 CpGs was identified that effectively distinguishes breast cancer patients from healthy controls achieving an AUC of 0.823 on an independent test set. Notably, it outperformed all four previously reported breast cancer-associated methylation profiles. Enrichment analysis revealed enrichment of genomic loci associated with the binding of immune modulating AP-1 transcription factors, while pathway analysis of nearby genes showed an overrepresentation of immune-related pathways. CONCLUSION: This study has identified a breast cancer-associated methylation profile that is immune-related to potential for early cancer detection.

An approach to genetic testing in patients with metastatic castration-resistant prostate cancer in Singapore.

Introduction: There has been a rapid evolution in the treatment strategies for metastatic castration-resistant prostate cancer (mCRPC) following the identification of targetable mutations, making genetic testing essential for patient selection. Although several international guidelines recommend genetic testing for patients with mCRPC, there is a lack of locally endorsed clinical practice guidelines in Singapore. Method: A multidisciplinary specialist panel with representation from medical and radiation oncology, urology, pathology, interventional radiology, and medical genetics discussed the challenges associated with patient selection, genetic counselling and sample processing in mCRPC. Results: A clinical model for incorporating genetic testing into routine clinical practice in Singapore was formulated. Tumour testing with an assay that is able to detect both somatic and germline mutations should be utilised. The panel also recommended the "mainstreaming" approach for genetic counselling in which pre-test counselling is conducted by the managing clinician and post-test discussion with a genetic counsellor, to alleviate the bottlenecks at genetic counselling stage in Singapore. The need for training of clinicians to provide pre-test genetic counselling and educating the laboratory personnel for appropriate sample processing that facilitates downstream genetic testing was recognised. Molecular tumour boards and multidisciplinary discussions are recommended to guide therapeutic decisions in mCRPC. The panel also highlighted the issue of reimbursement for genetic testing to reduce patient-borne costs and increase the reach of genetic testing among this patient population. Conclusion: This article aims to provide strategic and implementable recommendations to overcome the challenges in genetic testing for patients with mCRPC in Singapore.