A molecular-based approach to cancer therapies has revolutionized treatment. The discovery of molecular aberrations and recognizing them as major drivers of cancer initiation and progression, has resulted in a remarkable advance in molecular understanding but was followed by the emergence of precision medicine, sometimes referred to as personalized medicine.[1]

Precision medicine in the treatment of patients diagnosed with cancer has the aim of finding a selective targeted therapy for the specific tumoral molecular alterations found in each individual tumor. This approach, which has resulted in the capability to inhibit specific molecular targets and improved the clinical outcomes, has become the standard of care in several solid tumors, including breast cancer [2], lung cancer [3] colorectal cancers, and melanoma [4]. However, there are still limitations in this approach, including the intrinsic cancer heterogeneity [5], the complexity of the tumor microenvironment [6], and evolving molecular clonal dynamics [7] as mechanisms of treatment resistance.

Next-generation sequencing
Results from a recent study, published on September 7, 2021 in the British Journal of Cancer by Professor Andrés Cervantes, MD, Ph.D, Desamparados Roda Perez, MD, Ph.D, and colleagues in the Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, the University of Valencia in Valencia, Spain, shows the results of a molecular-based approach using an in-house customized next-generation sequencing (NGS) panel at a single academic institution.[8]

As part of the study, the researchers evaluated the improvement in clinical outcomes of applying this panel.

The molecular screening aimed to select the best potential therapeutic strategy for patients with advanced cancer to receive the treatment within the early clinical study program. Despite the small number of patients who presented actionable mutations, gene fusions, and other genomic alterations, the study team demonstrated that molecular profiling is feasible and effective. The results confirm a substantial benefit in the molecularly matched cohort receiving experimental targeted therapies.

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Study design
It was a single-center, retrospective analysis, where the study team investigated the feasibility and efficacy of comprehensive molecular profiling in patients with advanced solid tumors.

The first aim was to explore the benefit of a molecular profiling selection approach for candidates for early phase clinical studies in the context of targeted agents according to the evaluation of a molecular tumor board. Second, they investigated the impact of those targeted therapies compared to standard therapies of best investigators choice in subsequent treatment options for patients with advanced cancer. Third, by using a Bayesian model approach, they sought to define the primary predictive factors for potential treatment benefit.

All tumor samples were locally studied and analyzed for individual genomic target alterations by NGS, evaluating DNA. In those cases, in which the transcriptomic analysis could have helped in treatment options, an RNA analysis was also implemented. Genomic analysis was performed by a customized panel that included the evaluation of hotspot mutations in 83 genes plus 4 full genes analyzed. Transcriptomic protocol for fusion analysis was performed by RNA sequencing with ribosomic depletion. Data analysis was carried out by using an in-house-developed bioinformatics pipeline.

The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1).

The investigators molecularly screened 231 patients, of whom 87 were eligible for analysis. Each individual genomic report was reviewed and discussed weekly by a tumor board dedicated to precision medicine, attended by experts in medical oncology, molecular biology, pathology, clinical genetics and bioinformatics. Each result was discussed by taking into account the ESMO Scale for Clinical Actionability of molecular Targets. Additionally, they reviewed specific genomic results to debate common issues such as interpreting mutations with low allele frequency, the importance of tumor content or the potential role of other concomitant mutations. They stratified the patients into eligible or not for early phase clinical studies with targeted agents.

The most common tumor types were gynecological, lung, breast, digestive, and head and neck cancers. An actionable target was detected in 32 patients. An alteration of the DNA repair response pathway was detected in the highest percentage of patients, followed by PIK3CA mutations, FGFR2 mutations and FGFR gene fusion, MET activations, ERBB family pathway alterations and PTEN mutations. Patients were mostly included in specific protocols developing novel PIK3CA, AKT, FGFR, Check-1, MET, HER2 and PARP inhibitors.

Patients who received matched therapy had 6.47 months median PFS2 (95% confidence interval [CI] 2.24–14.43) compared to 2.76 months in those who received standard therapy (95% CI, 2.14–3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). The authors commented that the primary endpoint of increasing the PFS2/PFS1 ratio was reached and 33% of patients receiving molecular-matched therapies had a ratio ≥1.3, compared with only 7.9% of those who did not qualify for such therapies.

Moreover, disease control was seen in 68.7% of patients treated in the experimental arm, while it was only observed in 36.4% of those assigned to standard care. It is worth mentioning that 53% of patients treated in early phase clinical studies received post-progression treatment versus only 25% of those treated with standard therapies. Utilization of the window of opportunity with experimental targeted agents early on does not preclude receiving further lines of standard therapies. Early treatment to block molecular drivers contributes towards better disease control and avoids rapid clinical deterioration, facilitating further therapeutic interventions.

Clinical relevance and actionability
The study’s authors concluded that validation of true clinical relevance and actionability of each genomic alteration is critical and still far away from global standardization. This highlights a need to incorporate a multidisciplinary molecular tumor board in academic institutions to expand the use of precision oncology. They demonstrated the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies and improves disease control. However, prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.

This study was supported by grants from the Instituto de Salud Carlos III and others. The authors acknowledged the support of the INCLIVA BioBank, as part of the Valencian Biobanking Network and the Spanish National Biobanks Network.

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[8] Gambardella V, Lombardi P, Carbonell-Asins JA, et al. Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study. Br J Cancer; Published online 7 September 2021. DOI: https://doi.org/10.1038/s41416-021-01502-x [Article][PDF]

Featured image: Príncipe Felipe Science Museum, Valencia, Spain Photo Courtesey: © 2019 – 2021 Kit Suman on Unsplash. Used with permission

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