P. Pauwels MD, PhD

Contemporary biomarker testing for non-small-cell lung cancer

In recent years, the number of approved targeted therapies for patients with advanced non-small-cell lung cancer (NSCLC) has steadily increased, making an efficient and effective molecular profiling of paramount importance in the management of NSCLC patients. To ensure that patients receive the most appropriate treatment, broad upfront molecular testing including both established and new targetable alterations should nowadays be routine practice in the diagnostic work-up of newly diagnosed patients with advanced NSCLC. Specifically for Belgium, ComPerMed guidelines recommend to test the mutational status of EGFR, KRAS and BRAF, screen for MET exon 14 skipping mutations and look for the presence of genetic fusions/rearrangements involving ALK, ROS1, RET, and NTRK1-3. These biomarkers should be analyzed in all patients with non-squamous NSCLC and in selected NSCLC patients with a squamous histology (i.e., never smokers, very young patients). Given the multitude of biomarkers that need to be tested, multigene testing using next generation sequencing (NGS) has gradually replaced sequential single gene testing as the preferred molecular screening tool in NSCLC. In fact, combined DNA/RNA NGS is now considered to be the most reliable and efficient approach for comprehensive detection of all approved and emerging biomarkers in advanced NSCLC (excluding PD-L1 detection). Both tissue samples as cytology specimens can be used for these NGS analyses as long as they contain a sufficient percentage of neoplastic cells and are processed in a way that safeguards nucleic acid integrity. In Belgium, a program is in place offering reimbursed DNA/RNA NGS testing to NSCLC patients through a network of 10 reference centers.

Practical guidance for molecular testing in metastatic prostate cancer: A Belgian perspective

SUMMARY

The recent approval of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring pathogenic variants of BRCA2 or BRCA1 marks the start of molecularly guided precision medicine in prostate cancer. In parallel with this approval comes the need to embed molecular diagnostics in the clinical management of patients with mCRPC. To date, however, there are no established protocols in Belgium for the use of mutation testing in this setting. This article will therefore provide practical guidance for sample preparation and handling, pre-analytic processing, and pathogenic variant analysis in mCRPC. Across the different phases of this process, a multidisciplinary approach involving urologists, oncologists, radiologists, pathologists, molecular biologists, technicians, nurses, and geneticists will be key to safeguard adequate sample selection to perform molecular analyses at the time of metastatic disease. It will also facilitate high-quality molecular testing with a minimal failure rate. Only by optimising this process will physicians be able to adequately select mCRPC patients that are most likely to benefit from PARP inhibition, or other future targeted therapies, allowing to use these agents in the correct patient groups.

(BELG J MED ONCOL 2022;16(7):343–54)

Mazabraud’s Syndrome in association with other benign soft tissue tumours: A case report

SUMMARY

Mazabraud’s Syndrome is a rare benign disorder characterised by the association of two hallmark entities: fibrous dysplasia (FD) and intramuscular myxomas (IM). The aetiology of the disease is unclear, but molecular research of FD and IM points in the direction of post-zygotic mutations in the guanine nucleotide binding protein, alpha stimulating (GNAS) gene, which activates a trophic cascade leading to aberrant cellular proliferation. Although the diagnosis of Mazabraud’s Syndrome is rare, showing a prevalence lower than 1/1,000,000, it should be suspected in every patient presenting with FD and IM. These patients should get a bone scintigraphy and a magnetic resonance imaging (MRI) of the affected anatomical area. Other imaging techniques, such as positron emission tomography-computed tomography (PET-CT), may have additional value. Finally, the patients should perform a biopsy of the IM to confirm the diagnosis. The treatment includes bisphosphonates for FD, and surgery is reserved only for severe cases with persistent pain, deformity, fracture, or risk for a pathological fracture. Asymptomatic IM should be treated conservatively, but symptomatic lesions can be surgically excised. Follow-up is useful since malignant transformation of FD and recurrence of IM after excision are reported in the literature.

(BELG J MED ONCOL 2022;16(4):187–90)

PIK3CA in breast cancer: a Belgian practical testing guideline

SUMMARY

The PI3K/AKT pathway plays an important role in the oncogenesis of breast cancer. Activating mutations in PI3K, more specifically in the p110α catalytic unit of the class IA PI3K isoform (encoded by the PIK3CA gene), lead to an increased conversion of phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3) inducing a cell signalling cascade for cell proliferation and cell survival. PIK3CA mutations are found in 20–32% of all breast cancers (BC), particularly in hormone sensitive (HR+) BC. In breast cancer, activation of the PI3K pathway coexists with the activation of the oestrogen receptor pathway. Inhibition of one of these pathways may lead to compensatory activation of the other pathway. Therefore, mono-therapy with PI3K inhibitors has limited activity in HR+ BC. On the other hand, this explains the efficacy of a PI3K/ER dual blockade. This dual blockade is researched in the phase III SOLAR-1 trial. In the PIK3CA-mutated cohort of this study, there is an improved outcome for patients with advanced or metastatic HR+ HER2- BC, harbouring activating hotspot mutations in PIK3CA and previously treated with an aromatase inhibitor and no more than one line of endocrine therapy for MBC, who received fulvestrant (a selective oestrogen receptor degrader) and alpelisib (a p110α-isoform specific inhibitor) in comparison to the patients that received fulvestrant and placebo. Based on these results, a medical need program for alpelisib in a heavily pre-treated setting and an amendment were approved by the EMA and the Belgian FAMHP. Supporting this data, we propose the mutational analysis of PIK3CA, preferably by next generation sequencing on FFPE tumour material, in advanced or metastatic HR+ HER2- BC, previously treated with three lines of systemic therapy.

(BELG J MED ONCOL 2021;15(6):304-14)

Genetic and molecular biology in pancreatobiliary cancers: Testing for pancreatobiliary cancer in the context of the Belgian NGS convention

SUMMARY

Pancreatobiliary cancers (PBC) group pancreatic and biliary tract cancers and are among the cancers with the lowest survival rate. Emerging data suggest that novel biomarker-specific targeted therapies can be proposed for selected populations with survival benefit. This review summarises the scientific evidence to test for these biomarkers in order to optimise the management of pancreatobiliary cancers, within the context of the Belgian NGS convention.

(BELG J MED ONCOL 2021;15(4):170-6)

Guidelines for the detection of NTRK fusions. A report from the Belgian Molecular Pathology Working Group

(BELG J MED ONCOL 2021;15(3):112-6)

Optimisation of the liquid biopsy workflow: From research to clinical practice

SUMMARY

The general aim of this thesis was to determine the optimal workflow of circulating cell-free nucleic acid- (cfNA) based liquid biopsy for implementation in routine clinical practice. We started by evaluating several pre-analytical variables of the liquid biopsy workflow. We examined several cfDNA isolation kits, determined the optimal centrifugation protocol for both cfDNA and cfRNA, and determined the cfDNA stabilising efficiency of (specialised) blood collection tube (BCT). Next, we focused on the clinical applicability of liquid biopsy in non-small cell lung cancer (NSCLC). Based on this work, we specified recommendations regarding (pre-) analytical and biological variables to ensure successful liquid biopsy analysis.

(BELG J MED ONCOL 2021;15(1):48-50)