Discussion

This study provides real-world evidence regarding the clinical utility of next-generation sequencing (NGS) in patients with advanced metastatic solid tumors in a low- and middle-income country (LMIC) setting. Our findings demonstrate that although 45% of patients had detectable genomic alterations, only 19% received NGS-directed treatment, and merely 9% achieved a progression-free survival (PFS) of six months or more.

The rate of actionable alterations (33%) in our study is consistent with previously published data. For example, the MOSCATO-01 trial reported actionable alterations in approximately 39% of advanced cancer patients, with 24% receiving matched targeted therapy and a 7% improvement in progression-free survival compared to prior therapy [7]. Similarly, the ProfiLER study showed 30% of patients had a targetable alteration, but treatment modification occurred in only 6% of cases, primarily due to logistical and economic limitations [8].

The discrepancy between the detection of actionable mutations and the actual delivery of genome-directed therapy remains a significant concern, especially in LMICs. In our cohort, 13 patients were unable to receive targeted treatment despite the availability of molecular options, owing to the unavailability of clinical trials in India and financial constraints. This highlights a persistent issue in precision oncology: access to therapy often lags behind diagnostic advances [9].

Furthermore, patients receiving NGS-matched therapy before the second-line setting seemed to have better outcomes, as observed in several cases with microsatellite instability (MSI-H) and high tumor mutational burden (TMB-H) responding to immune checkpoint inhibitors. These biomarkers are known to predict benefit from agents like pembrolizumab, which is FDA-approved for MSI-H and TMB-H tumors regardless of tissue origin [10,11]. However, broad implementation of such biomarkers in LMICs is challenged by cost, infrastructure, and drug availability [12].

The relatively low impact of NGS on therapeutic decision-making in our study is comparable to other real-world analyses. A study by Mateo et al. concluded that only 11% of patients in their cohort received matched therapy based on NGS results [4]. The ESCAT (ESMO Scale for Clinical Actionability of Molecular Targets) also emphasizes the need to prioritize alterations with high levels of evidence for clinical actionability [2]. Nonetheless, we excluded common targetable mutations with established standard-of-care therapies (e.g., EGFR, HER2, BRAF), which could explain our relatively lower PFS benefit rate.

An additional observation is that patients with gallbladder cancer constituted a notable proportion of those with actionable alterations and favorable responses. Although gallbladder cancer is relatively underrepresented in global genomic databases, emerging evidence suggests a role for HER2 amplification and MSI-H status as potential targets in this disease [13].

Overall, while the use of NGS in routine oncology practice in India is increasing, its full potential is yet to be realized. Financial barriers, lack of clinical trial access, and logistical issues in drug procurement continue to limit the real-world translation of genomic insights into clinical benefit [6].

Our study highlights the modest yet meaningful impact of NGS in guiding treatment for patients with advanced solid tumors in a resource-constrained setting. While genomic alterations were detected in nearly half of the patients, only a minority could access targeted therapies due to limited drug availability and cost issues. Nonetheless, a subset of patients receiving genome-driven therapy achieved durable responses.

To bridge the gap between molecular diagnostics and precision therapy in LMICs, there is a need for broader access to affordable targeted drugs, enrollment in international clinical trials, and policy frameworks that support precision oncology. Future studies should aim to integrate NGS with multidisciplinary decision-making and cost-effectiveness analyses to better define its utility in real-world oncology practice.

Limitation of the study

Non-availability of NGS at many superspecialty centers is the major setback right now in developing countries.