Major Partner: Australian Clinical Labs MAJOR PARTNER
Update on Genetic Testing in Cancer and Targeted Therapy
BACK TO CONTENTS
About the author
Assoc. Prof. Mirette Saad
Speciality: Chemical pathology and molecular genetics Areas Of Interest: Cancer genetics, antenatal genetic screening and fertility, medical research and teaching Phone: (03) 9538 6777 Email: mirette.saad@clinicallabs.com.au
MBBS (Hons), MD, MAACB, FRCPA, PhD Lab: Clayton VIC
Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Clinical Director of Molecular Genetic Pathology at Australian Clinical Labs. At Clinical Labs, A/Prof Mirette Saad leads the Molecular Genetic testing for Non-Invasive Prenatal Testing (NIPT), genetic carrier screening, personalised drug therapy and cancer. She is a Chair of the RCPA Chemical Pathology Advisory Committee, Member of the RCPA Genetic Advisory Committee and a Chair of the Precision Medicine Services at Australian Clinical Labs.
Cancer, a leading cause of mortality, is associated with aberrant genes. The world of molecular profiling in cancer has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumours. New agents have been approved based on molecular testing instead of tumour site of origin. Driver Mutations Guide Treatment Decisions The introduction of targeted therapies in lung, colon, melanoma and breast cancer have contributed to a significant increase in overall survival (OS) related to these diseases. Genetic variants identified in cancer are known to be associated with increased or decreased sensitivity to targeted therapy. For example, while PIK3CA and EGFR mutations are sensitive to tyrosine kinase inhibitors (TKIs), RAS and BRAF are known to be resistant. Crizotinib is an ALK/ROS1/MET inhibitor that is already FDA approved in ALK-positive or ROS1-positive NSCLC but also has proven clinical activity in cases of MET exon 14 alterations and MET amplification. PD-L1 expression in metastatic NSCLC can benefit from FDA approved pembrolizumab monotherapy under specific criteria. Recently, a third-generation EGFR TKI, which is effective in tumours harbouring the p.T790M EGFR mutation was approved in Australia for patients with NSCLC following progression on an EGFR TKI. In breast cancer, mutated PIK3CA has become an attractive therapeutic target. While anti-BRAF inhibitors (BRAFi) remains the first-line treatment for melanoma tumours that harbour a BRAF mutation, particularly in Australia, other oncogenic driver mutations such as cKIT mutations may guide the selection of KIT TKIs (imatinib and sunitinib) for the melanoma treatment. New Guidelines; Broadening Molecular Profiling Boundaries Recent NCCN guidelines recommended additional genetic biomarkers for different types of cancer tissues. In lung cancer, the new NCCN guidelines recommend testing for EGFR, ALK, ROS1, BRAF, and PD-L1 for all patients with NSCLC at baseline before treatment. Universal Microsatellite instability (MSI)/DNA mismatch repair (MMR) testing at the time of initial diagnosis for all stages of colorectal tumours is now recommended to determine whether patients have a germline
mutation indicative of Lynch syndrome. For additional treatment options, testing for KRAS/NRAS/BRAF in un-resectable left-sided stage IV metastatic colorectal cancer (mCRC) tumours is also recommended. In addition to breast and ovarian cancers, germline mutations, mainly BRCA1/2, along with somatic mutation testing are recently recommended by NCCN guidelines for both pancreatic and prostate cancers. In prostate cancer, BRCA1/BRCA2 can occur in 20-25% of all advanced prostate cancer. Although ATM testing is not yet recommended by the NCCN as a predictive measure, Na et al., showed that germline BRCA2 and ATM mutations distinguish lethal from indolent prostate cancers and are associated with shorter survival times and earlier age at death. While tumour mutation burden (TMB) is certainly an interesting emerging biomarker, evidence of its importance is growing.
ctDNA identified the emergence of polyclonal and heterogeneous patterns of mutation in KRAS, NRAS, BRAF, or EGFR with mutations found in 96% of panitumumab- or cetuximab refractory patients. Subsequently, Misale et al., were able to illustrate a way to use this information to overcome treatment resistance. Furthermore, studies demonstrate better outcomes when no tumour-derived DNA is found in patients following surgery or chemotherapy in colorectal cancer patients, whereas those with whom tumour DNA is still present do better with the addition of more aggressive targeted treatment or chemotherapy. In melanoma, several studies showed the utility of ctDNA as a diagnostic, predictive and prognostic biomarker for patients on anti-BRAF treatment.
Liquid Biopsy: Circulating Tumour DNA (ctDNA) Testing The variety of validated technologies emerging enables more precise and robust analysis of circulating tumour-derived DNA (ctDNA) extracted from blood with sufficient sensitivity and specificity to accurately detect cancer biomarkers.
Moreover, ctDNA can also ease the decision in the daily clinical practice when radiological evaluation is problematic especially for patients receiving PD-1 inhibitor immunotherapy. In this context, an important advantage of ctDNA is the possibility of non-invasive serial testing for monitoring treatment response and resistance to therapy.
It is clear today that a single biopsy from a single metastatic site does not seem to be representative of the metastatic cancer. The advent of molecular profiling overcame the limitations of traditional solid tumour classification methods, which relied on the morphology of tumour cells and the surrounding tissue.
Finally, precision medicine in cancer is moving that quickly specially in the malignant heme space and is now a part of our standard practice. While with new challenges, it will continue to move forward with more discoveries to come. References on request
While considered the gold standard, tissue biopsy-based tumour diagnosis has many limitations. For instance, tumour heterogeneity, the detection of early-stage tumour or residual lesions is unsatisfactory, and its application in the evaluation of treatment efficacy, resistance, relapse and prognosis is also limited. The use of liquid biopsy profiling has proven useful in selected clinical scenarios. The first ctDNA liquid biopsy approved for use in clinical settings was in lung cancer patients for the identification of EGFR mutations for first line therapy or identifying resistance mutations that will allow for treatment with third generation EGFR inhibitors. In colorectal cancer, ctDNA could also be used to track clonal evolution and targeted drug responses. In patients with metastatic colorectal cancer who developed resistance to EGFR antibodies, analysis of
Building better health partnerships MEDICAL FORUM | INNOVATION & TRENDS ISSUE
Contact a local pathologist near you
Dr Shona Hendry MBBS (Hons), FRCPA Lab: Subiaco Speciality: Anatomical pathology Areas Of Interest: Molecular pathology, Gastrointestinal pathology, cytology, bone and soft tissue and urology. Phone: (08) 9213 2173 Email: shona.hendry@clinicallabs.com.au Dr Hendry is an Anatomical Pathologist with special interests in molecular pathology, gastrointestinal pathology, cytology, bone and soft tissue and urology. She is an Honours graduate of the University of Western Australia medical school who completed much of her pathology registrar training in Perth, gaining her FRCPA in 2016.
1300 367 674 | clinicallabs.com.au FEBRUARY 2020 | 5
