Genomic Testing: The Key To Unlocking Targeted Cancer Therapies

We have certainly come a long way in cancer therapy, not only from 440 BC wherein the first breast tumour excision was recorded in the queen of Persia but also from days of chemotherapy to the current era of Precision oncology through targeted therapy. I would recommend reading “The Emperor of All Maladies: A Biography of Cancer” which won Siddhartha Mukherjee the Pulitzer Prize, it highlights advances made by physicians & pathologists in fields of surgery, radiation therapy, and chemotherapy, all of which remain major treatment modalities even today. However, there’s an integral member now in this multi-disciplinary team & that’s molecular genomics. 

Genomics supports all phases - identifying at-risk individuals, early detection, diagnosing specific types correctly, selecting best treatment options & evaluating response to treatment. 

Only 5 per cent to 10 per cent of cancers are caused by inherited genetic mutations e.g. BRCA while most are due to risk factors such as age, sun damage, tobacco use & unknown, however, no matter the reason for mutation, targeted therapy works the same hence relevance of testing & understanding underlying mutations in cancer patients whether germline (in the blood) or somatic (in tumour tissue). This is done through next-generation sequencing (NGS). 

Genomics has improved patients’ overall survival and the quality of life. E.g. trastuzumab pertuzumab for HER2 expressing breast cancer and osimertinib for EGFR mutated non-small cell lung cancer. The National Comprehensive Cancer Network (NCCN) guidelines are cancer-specific recommendations extensively used in clinical practice worldwide.

In current practice, as a standard process, when a patient is diagnosed as having cancer one wants to factor genomic tumour profiling in addition to grade & stage because it has a crucial role in selecting the right treatment based on prognostic & predictive biomarkers. Integrated oncology laboratories today support physicians in their decision-making, prevent inequalities in precision medicine and ensure patients benefit from available cancer management options by using expert morphologic assessment and molecular oncology technologies and platforms both in tissue and blood.

Guidelines play a crucial role in standardising cancer care and promoting equal access to adequate treatments, as well as guiding decisions about resource allocation. In recent years, clinical guidelines such as those of the NCCN have increasingly endorsed genomic testing in cancer care. In 2017 NCCN guidelines urged profiling for non-small cell lung cancer targeting ALK, ROS1, and EGFR alterations. In the 2023 review, endorsements spanned BRCA1/2, BRAF, FGFR, homologous recombination deficient, KIT, KRAS, MSI-H, dMMR, MET, NTRK, PALB2, PIK3CA, RET, and TMB and encompassed around 50 specific genomic alterations. Genetic profiling offers the potential to identify additional treatment possibilities, but the abundance of data requires a systematic approach to navigate the results.

Oncopathology reports look very different today than a decade or two ago incorporating genomic information in addition to patient and sample characteristics; data analysis; sample-specific assay performance; observed genomic alterations & implications for diagnosis, prognosis and therapy selection. We also include a summary statement in narrative form with the main findings of the NGS assay using visual aids and graphic solutions to facilitate comprehension of complex data. 

Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel–based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumour mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase (NTRK) fusions provide a rationale for genomic testing for all solid tumours. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and the expected efficacy of genomic biomarker–linked options relative to other approved or investigational treatments.

Liquid biopsies are also being used to detect circulating tumour cellular components in the bloodstream & have the potential to transform cancer by reducing health inequities in screening, diagnostics, and monitoring. In current medical practice though, liquid biopsy cfDNA is being used to guide treatment choices for patients & monitoring for recurrence with promising ongoing work in multi-cancer early detection. 

NGS report cannot replace the physician’s judgement for indicating a therapeutic strategy. Clinical decision-making should be driven by a patient-centric interpretation of the NGS assay results by treating physicians with support from a multidisciplinary team, in the context of results of other tests, as well as individual patients’ medical history. Communication between ordering physicians and professionals reporting genomic data is key to minimising uncertainties and optimising the impact of genomic tests in patient care. 

Dr Kirti Chadha

Guest Author The author is Head of Global Reference Laboratory, Metropolis Healthcare