Guest Editorial
Over the past few decades, genomics has emerged as a driving force to improve clinical and public health globally. The advent of genomic technologies has impacted cancer care and treatment to a remarkable extent. Of late, there has been an upsurge in the discovery of novel molecular targets, leading to the development of new sensitive diagnostics and effective therapeutic strategies. Further, high throughput genomics studies have led to the creation of innovative computational avenues to decode big data, which vastly improved our understanding of the molecular complexities of cancer. Lately, precision oncology has received more attention and acceptability due to an increase in the ‘omics’ data generated from patient-derived bio-specimens. However, the field of precision medicine in oncology is still in its infancy in India. One of the major roadblocks to precision medicine is establishing methodically well-furnished biorepositories and state-of-the-art technologies at healthcare institutions. Despite the increasing number of deaths in low- and middle-income countries, simple diagnostic methods such as pathological evaluation are often delayed and, at times, underperformed, leading to ill-conceived treatment strategies resulting in poor cancer prognosis and high mortality. The pathological assessment of tumour tissues is crucial for defining the therapy regime. For instance, in breast cancer cases, endocrine therapy with Tamoxifen, an affordable non-steroidal antiestrogen, depends on the histopathology evaluation of the tumour size and grade, lymph nodes, the status of estrogen receptor and progesterone receptor, which thus requires timely and precise diagnoses for effective therapeutic intervention. Like-wise, Trastuzumab (Herceptin) is a widely accepted targeted therapy that offers considerable clinical advantage, specifically in breast cancer patients with HER2-overexpression.
In addition to well-managed cancer biorepositories, the constitution of multidisciplinary tumour boards at tertiary cancer centres could be a game-changer. For instance, the results of molecular diagnostic tests could be reviewed thoroughly by such committees, and the clinical decision can be integrated into cancer treatment practices. Introduction of artificial intelligence (AI)-driven computational pathology would be a powerful potential technology to preclude inter-observer variability that exists in conventional pathological examinations. Digital pathology is thus emerging as a dynamic diagnostic tool, and its integration with AI would offer several advantages, such as highly sensitive detection of tumour infiltration and identification of different cell types in the tumour microenvironment.
Asia contributes to about ~40% of the cancer burden of the world, but the representation of cancer patients from India is minuscule in clinical trial-related studies globally. More so, most of the approved companion diagnostics are based on discoveries of the -omics studies derived from the Caucasian population. This biased representation often leads to racial disparities in cancer treatment outcomes, mainly due to population-specific variants and the presence of definitive somatic or germline mutations.
The Indian Council of Medical Research, highlighted about ~27% of cancer burden due to tobacco consumption in 2020, accounting for one-third of the global cancer burden. In the National Global Adult Tobacco Survey, data based on the tobacco usage prevalence and relative risks of all-cause tobacco-associated mortality estimated an economic burden of more than 1% of India’s GDP (Nicotine Tob. Res., 2021, 23(2), 294–301). Additionally, the treatment cost for cancer is skyrocketing globally; thus, more efforts should be focused on prevention and screening programmes. These could be prioritized under the non-communicable disease eradication programme by implementing a robust surveillance system, particularly for high-risk individuals. Such initiatives would assist in the early detection of cancers, such as gingivobuccal, oral or tongue cancer. Simple visual investigation focusing on the detection of oral submucous fibrosis, leukoplakia and erythroplakia, could reduce the overall oral cancer-associated deaths as well as the financial burden incurred by high-risk individuals. Other factors, such as changes in the population dynamics and its expansion, also contribute to an increase in cancer incidence. For instance, the elderly population (>60 years) is expected to rise in India. This fraction of the population is at a higher risk of developing age-associated malignancies, e.g. breast, pancreatic, lung, bladder and prostate cancers. Thus, a defined framework for routine cancer screening with guidelines to prevent over-diagnosis should be introduced.
The completion of the Human Genome Project in 2003 revolutionized biomedical and cancer research by generating next-generation sequencing tools for genomic profiling and molecular subtyping of various cancer types. The genetic, epigenetic and transcriptomic insights of specific cancer type(s) catapulted individualized diagnosis and prognostics, as well as design of evidence-based drug modules and treatment regimens.
The Indian population, known for its rich genetic diversity, comprises 17% of the world’s population; regardless, the Indian genome is still inadequately represented in the genomic sequencing datasets available globally. It took almost 15 years for India to realize the need to undertake a comprehensive genomic study of our population, and finally, the Council of Scientific and Industrial Research-funded IndiGen sequencing project was initiated. The whole genome sequencing results of 1029 healthy Indians belonging to diverse ethnic groups were announced in 2019 (Nucleic Acids Res., 2021, 49(D1), D1225–D1232). The overarching goal was to accelerate genetic epidemiological studies, classify variants involved in Mendelian disorders, improve precision medicine and create effective public health policies catering to the Indian population. Considering the rich genetic diversity of the Indian population, ~32% of the genetic variants were found to be unique to India, reaf-firming the necessity for an India-centric genome programme. Recently, the Department of Biotechnology formed a consortium involving 20 national institutes to perform whole genome sequencing of 10,000 representative individuals across India to identify genetic variations and generate a reference haplotype for the Indian population. Earlier in 2008, India participated in the International Cancer Genome Consortium (ICGC), a forum that coordinated large-scale cancer genome studies using major cancer types and/or sub-types across the globe. Under ICGC, the National Institute of Biomedical Genomics, India generated genomic data on gingivobuccal oral cancer, and systematically identified its variants. These efforts resulted in the formation of GENomic Variants of Oral Cancer (dbGENVOC), an open-access web portal that permits data mining for cancer variants specific to Indian oral cancer patients (Database, 2021, 2021, baab034). Such initiatives would go a long way in identifying population-specific actionable targets for approved drugs against oral cancer.
Likewise, chronic myeloid leukaemia (CML) characterized by the t(9; 22) reciprocal translocation serves as an excellent model, where tyrosine kinase inhibitors (TKIs) are successful at managing CML. Besides cytogenetics-based diagnostics, the quantitative RT-PCR-based detection of the BCR-ABL1 fusion transcript is a widely accepted sensitive method for testing disease burden after treatment with TKI. The majority of CML patients have a decent life span on TKI therapies. However, some patients may develop resistance due to poor primary response or acquired resistance to TKI therapy, necessitating investigation of the immune-modulatory response in these patients. The Chimeric Antigen Receptor T cell (CAR-T) therapy has emerged as a revolutionary therapy in the management of cancer, especially for relapsed or refractory B-cell malignancies. ImmunoACT, an IIT Bombay incubated company, holds a promise to provide indigenous NexCAR19, a technology that put together the antigen-binding properties of monoclonal antibodies with self-renewal and lytic abilities of the T-cells. This technology was recently approved by the Central Drugs Standard Control Organization, with the promise to offer indigenous CAR-T cell therapy at an affordable price for hematological malignancies, which is an excellent example of Self-reliant India.
Recently, 4basecare Onco-Solutions, a private Indian precision oncology company, carried out whole-exome sequencing of Indian cancer patients spanning 30 different cancer types, and calculated the tumour mutation burden (TMB) for the stratification of patients for immune checkpoint inhibitor therapy (JCO Glob. Oncol., 2023, 9, e2300047). The TMB serves as a predictive biomarker for immunotherapy and has gained acceptance for administering pembrolizumab, an FDA-approved humanized antibody that targets the programmed cell death protein 1 (PD-1) receptor. This study reveals a wide disparity in the TMB scores across different cancer types, highlighting its importance in patient selection criteria for targeted immunotherapy.
Unfortunately, access to genome sequencing or targeted therapies in India is limited to a handful of patients due to its prohibitive cost and poor accessibility. Many cancer types still lack promising drug targets and available targeted therapies. Thus, research on discovering new cancer biomarkers and therapeutic targets is essential to expand the scope of tailored treatments for diverse cancer patients across the socio-economic spectrum. There is an urgent need to encourage collaboration between academic and industrial oncology research in the country, as much of the bench-side research fails to scale up to advanced technology readiness. A framework for facilitating an effective partnership between government stakeholders, players in the private sector, and NGOs with a focus on improving academia–industry–public collaboration for the benefit of cancer patients is necessary. For example, the Indian Cancer Genome Atlas (ICGA), a national consortium working to generate an indigenously developed, open-source, comprehensive database of molecular profiles of all cancer types predominant in India. Taking into account the high mortality rate associated with triple-negative breast cancers in Indian women, the ICGA initiated its first pilot project for a large-scale multi-omics profiling of Indian breast cancers, which will fill the gaps in treatment and management of breast cancer. We are also optimistic about the recently launched National One Health Mission, which will coordinate, support and integrate all the existing healthcare activities and bridge the gap where it is needed.