bims-preonc 2024-09-01 papers

Issue of 2024–09–01
six papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Curr Oncol. 2024 Aug 06. 31(8): 4519-4530

Equitable Access to Genomic Molecular Testing for Australian Cancer Patients: Insights from the Victorian Precision Oncology Summit.

Genevieve Dall, Karen Harris, Nonie Chan, Stephen J Luen, Sophia Frentzas, Daphne Day, Michelle Barrett, Anna Kilgour, Mark Buzza.

The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.

Keywords: cancer; comprehensive genomic profiling; equitable access; genomic testing; precision oncology

DOI: https://doi.org/10.3390/curroncol31080337

Ann Oncol. 2024 Aug 24. pii: S0923-7534(24)01519-9. [Epub ahead of print]

The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive.
METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised.
RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development.
CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Keywords: biomarkers; classification; drug development; molecular targeted therapy; tumour-agnostic

DOI: https://doi.org/10.1016/j.annonc.2024.07.730

Adv Clin Chem. 2024 ;pii: S0065-2423(24)00094-5. [Epub ahead of print]123 179-219

RNA biomarkers in cancer therapeutics: The promise of personalized oncology.

Hector Katifelis, Maria Gazouli.

Cancer therapy is a rapidly evolving and constantly expanding field. Current approaches include surgery, conventional chemotherapy and novel biologic agents as in immunotherapy, that together compose a wide armamentarium. The plethora of choices can, however, be clinically challenging in prescribing the most suitable treatment for any given patient. Fortunately, biomarkers can greatly facilitate the most appropriate selection. In recent years, RNA-based biomarkers have proven most promising. These molecules that range from small noncoding RNAs to protein coding gene transcripts can be valuable in cancer management and especially in cancer therapeutics. Compared to their DNA counterparts which are stable throughout treatment, RNA-biomarkers are dynamic. This allows prediction of success prior to treatment start and can identify alterations in expression that could reflect response. Moreover, improved nucleic acid technology allows RNA to be extracted from practically every biofluid/matrix and evaluated with exceedingly high analytic sensitivity. In addition, samples are largely obtained by minimally invasive procedures and as such can be used serially to assess treatment response real-time. This chapter provides the reader insight on currently known RNA biomarkers, the latest research employing Artificial Intelligence in the identification of such molecules and in clinical decisions driving forward the era of personalized oncology.

Keywords: Immunotherapy biomarkers; Personalized oncology; RNA biomarkers; Radiosensitivity biomarkers; Toxicity biomarkers

DOI: https://doi.org/10.1016/bs.acc.2024.06.003

Int J Mol Sci. 2024 Aug 06. pii: 8594. [Epub ahead of print]25(16):

Liquid Biopsy in the Clinical Management of Cancers.

Ho-Yin Ho, Kei-See Kasey Chung, Chau-Ming Kan, Sze-Chuen Cesar Wong.

Liquid biopsy, a noninvasive diagnosis that examines circulating tumor components in body fluids, is increasingly used in cancer management. An overview of relevant literature emphasizes the current state of liquid biopsy applications in cancer care. Biomarkers in liquid biopsy, particularly circulating tumor DNA (ctDNA), circulating tumor RNAs (ctRNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and other components, offer promising opportunities for early cancer diagnosis, treatment selection, monitoring, and disease assessment. The implementation of liquid biopsy in precision medicine has shown significant potential in various cancer types, including lung cancer, colorectal cancer, breast cancer, and prostate cancer. Advances in genomic and molecular technologies such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR) have expanded the utility of liquid biopsy, enabling the detection of somatic variants and actionable genomic alterations in tumors. Liquid biopsy has also demonstrated utility in predicting treatment responses, monitoring minimal residual disease (MRD), and assessing tumor heterogeneity. Nevertheless, standardizing liquid biopsy techniques, interpreting results, and integrating them into the clinical routine remain as challenges. Despite these challenges, liquid biopsy has significant clinical implications in cancer management, offering a dynamic and noninvasive approach to understanding tumor biology and guiding personalized treatment strategies.

Keywords: cancers; clinical management; liquid biopsy

DOI: https://doi.org/10.3390/ijms25168594

Klin Onkol. 2024 ;38(1): 40-49

Analysis of the effect of baseline detection and early clearance of ct-DNA, on survival outcomes among patients with advanced EGFR-mutant non-small cell lung cancer.

A Joel, R Abarna, R T Chacko, A Singh, J T Georgy, A O John, D B Thumaty, S Balukrishna, R Isiah, S Paavamani, T A Kodiatte, S Rima, G Rebekah, R Pai.

BACKGROUND: To determine if circulating tumor DNA (ct-DNA) dynamics of epidermal growth factor receptor (EGFR) mutation in plasma can identify a subset of patients with EGFR-mutant (EGFR- m) non-small cell lung cancer (NSCLC) with inferior survival outcomes, we analyzed and compared survival outcomes among patients with and without baseline presence and early clearance of EGFR ct-DNA in plasma.
MATERIAL AND METHODS: For 66 patients newly dia-gnosed with EGFR- m NSCLC, plasma samples were collected at baseline and 1st response assessment at 12-24 weeks for extraction of ct-DNA. Estimation of ct-DNA (EGFR exons 18, 19, 20 and 21) was done using droplet digital polymerase chain reaction (dd-PCR) on the QX200 ddPCR system (BioRad, USA). Patients with detectable EGFR ct-DNA at baseline (sample 1), with either undetectable or persistent detectable ct-DNA in sample 2 were classified as clearers and non-clearers, respectively.
RESULTS: Fifty-three patients received 1st/ 2nd generation EGFR tyrosine kinase inhibitors (TKIs) and 13 received either 3rd generation TKI (osimertinib) or chemotherapy plus gefitinib. The baseline ct-DNA-positive group had more patients with extra thoracic disease (60.4 vs. 48.5%). For the entire cohort, there was no difference in median progression-free survival (PFS) among baseline ct-DNA-negative (13.57 months) vs. ct-DNA-positive patients (12.32 months) (HR 0.74). There was a significant improvement of PFS among early ct-DNA clearers vs. non-clearers (12.32 vs. 9.92 months; HR 0.57). For those treated with 1st/ 2nd generation EGFR TKIs, this improvement in median PFS among early ct-DNA clearers vs. non-clearers was more apparent (11.76 vs. 6.8 months; HR 0.34).
CONCLUSIONS: Baseline detection of the presence of ct-DNA of EGFR mutation in plasma was not predictive of first-line PFS, but is associated with extra thoracic disease. Patients with EGFR mutation and persistence of ct-DNA at first follow-up have worse PFS and overall survival (OS) in comparison to those clearing the same in plasma, especially among those treated with 1st/ 2nd generation EGFR TKIs.

Keywords: EGFR mutation; EGFR mutations; EGFR tyrosine kinase inhibitors; advanced non-small cell lung cancer; ct-DNA; mutant allele frequency

DOI: https://doi.org/10.48095/ccko202440