The emerging clinical relevance of genomics in cancer medicine

Abstract

The combination of next-generation sequencing and advanced computational data analysis approaches has revolutionized our understanding of the genomic underpinnings of cancer development and progression. The coincident development of targeted small molecule and antibody-based therapies that target a cancer's genomic dependencies has fuelled the transition of genomic assays into clinical use in patients with cancer. Beyond the identification of individual targetable alterations, genomic methods can gauge mutational load, which might predict a therapeutic response to immune-checkpoint inhibitors or identify cancer-specific proteins that inform the design of personalized anticancer vaccines. Emerging clinical applications of cancer genomics include monitoring treatment responses and characterizing mechanisms of resistance. The increasing relevance of genomics to clinical cancer care also highlights several considerable challenges, including the need to promote equal access to genomic testing.

Fig. 1. Clinical utility of genomic assays in cancer care.

Following the introduction of next-generation sequencing (NGS)-based assays, and reflecting rapid progress in cancer biology and therapeutics, clinical NGS-based diagnostic assays have achieved clinical utility owing to the ability of their results to direct therapeutic decision-making. BRCA, breast cancer susceptibility protein; HRD, homologous recombination deficiency; PARP, poly(ADP-ribose) polymerase; Pol E, DNA polymerase-ε. ^aCan be germ line or somatic alterations and have the same treatment indication regardless of the origins of the alteration.

Fig. 2. Clinical trial designs invoking cancer genomics assays.

Two basic clinical trial designs for the testing of genomically targeted cancer therapies have emerged. a | Basket trials place all patients with tumours expressing the same genomic target into the same ‘basket, enabling patients to receive a matched targeted therapy. b | Umbrella trials involve the investigation of multiple targeted therapies and the enrolment of specific groups of patients into different trials according to their tumour genotype. In both types of trials, a next-generation sequencing assay that enables the detection of many targetable alterations can provide information enabling patients to be included into one of multiple trial cohorts available within a cancer centre. Figure adapted from REF, NRC Research Press, CC-BY-4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 3. NGS-based neoantigen discovery.

Neoantigen discovery is pursued using next-generation sequencing (NGS) data from comparisons of tumour DNA with nontumour genomic DNA obtained from the same patient to identify the presence of somatic variants with the potential to alter amino acid sequences in the resulting protein. As illustrated in step 1, tumour and nontumour hybrid-capture exome NGS data are generated, as are RNA sequencing data from the tumour isolate. In step 2, computational predictions of the presence of somatic variants are made using the appropriate algorithms, and these predictions are parsed into the resulting novel peptides, along with the calculated HLA haplotypes, and then evaluated by a neoantigen predictor (step 3). These processes are followed by sequence integration (step 4), which culls the potential neoantigen list using cross-comparisons with RNA sequencing data, including evidence of expression, and finally, quality filtering steps (step 5) eliminate known false positive results (such as hypothetical proteins) to produce a final neoantigen prediction list. Neoantigens can be validated using enzyme-linked immunospot (ELISPOT) assays or other approaches (step 6), although this validation step is not always pursued, especially when few candidates exist or a short turnaround time is essential. The design of antitumour vaccines can involve many different approaches, including long (~20 mer) or short (8–11 mer) peptides, RNA-based or DNA-based vaccines, or dendritic cell vaccines. MHC, major histocompatibility complex; TCR, T cell receptor. Figure is adapted from images courtesy of J. Hundal, Washington University School of Medicine in St Louis, MO, USA, and K Campbell, Washington University in St Louis, MO, USA.

Fig. 4. Liquid biopsy assays enable the monitoring of genomic alterations present in circulating tumour DNA.

The findings of genomic characterizations comparing tumour and nontumour DNA can inform the design and use of liquid biopsy-based approaches. These directed assays enable the detection and comparison of somatic mutations present in circulating tumour DNA (ctDNA) during treatment and over time, in comparison with a baseline tumour DNA sample taken after diagnosis and before tumour resection. Liquid biopsy results can then be compared to those obtained using conventional imaging-based approaches to disease monitoring for the potential to detect recurrent disease or emerging therapy resistance (only when specific resistance-conferring genotypes are known). NGS, next-generation sequencing. Figure is adapted from image courtesy of N. Rosenfeld, Cancer Research UK Cambridge Institute, UK, and D. Tsui, Memorial Sloan Kettering Cancer Center, NY, USA.