Benefits of functional assays in personalized cancer medicine: more than just a proof-of-concept

Abstract

As complex and heterogeneous diseases, cancers require a more tailored therapeutic management than most pathologies. Recent advances in anticancer drug development, including the immuno-oncology revolution, have been too often plagued by unsatisfying patient response rates and survivals. In reaction to this, cancer care has fully transitioned to the “personalized medicine” concept. Numerous tools are now available tools to better adapt treatments to the profile of each patient. They encompass a large array of diagnostic assays, based on biomarkers relevant to targetable molecular pathways. As a subfamily of such so-called companion diagnostics, chemosensitivity and resistance assays represent an attractive, yet insufficiently understood, approach to individualize treatments. They rely on the assessment of a composite biomarker, the ex vivo functional response of cancer cells to drugs, to predict a patient's outcome. Systemic treatments, such as chemotherapies, as well as targeted treatments, whose efficacy cannot be fully predicted yet by other diagnostic tests, may be assessed through these means. The results can provide helpful information to assist clinicians in their decision-making process. We explore here the most advanced functional assays across oncology indications, with an emphasis on tests already displaying a convincing clinical demonstration. We then recapitulate the main technical obstacles faced by researchers and clinicians to produce more accurate, and thus more predictive, models and the recent advances that have been developed to circumvent them. Finally, we summarize the regulatory and quality frameworks surrounding functional assays to ensure their safe and performant clinical implementation. Functional assays are valuable in vitro diagnostic tools that already stand beyond the “proof-of-concept” stage. Clinical studies show they have a major role to play by themselves but also in conjunction with molecular diagnostics. They now need a final lift to fully integrate the common armament used against cancers, and thus make their way into the clinical routine.

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

“…We assessed the expression of ABC-transporters, MVP and YB-1 and analyzed their correlation with chemosensitivity of corresponding STS cells to the above-mentioned chemotherapeutic agents. Drug resistance was estimated using in vitro chemosensitivity assay proposed by Kurbacher et al [ 34 ], which, currently, are widely used in many modifications [ 35 , 36 , 37 , 38 ], based on different methods for estimation of cell viability [ 39 , 40 , 41 ].…”

Functional Drug Screening in the Era of Precision Medicine

“…Several commercial tests are available, including ChemoID and the Oncogramme. Chemosensitivity testing involves culturing a patient’s cells in monolayers, which fails to truly recapitulate the microenvironment in which the tumor grows and evolves, including the three-dimensional (3D) setting, immune system, signaling intermediates, heterogeneity, and architecture of the tumor ( 13 , 14 ). Likewise, cell morphology, proliferation, differentiation, and drug metabolism are significantly different in 2D versus 3D culture ( 15 ).…”

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin

“…Simultaneously, we analyzed drug resistance of STS cells by in vitro chemosensitivity/chemoresistance assay (CSRA). We used CSRA proposed by Kurbacher et al [ 15 ], which, at present, is used in many modifications [ 16 , 17 , 18 , 19 ], based on different methods for estimation of cell viability [ 20 , 21 , 22 ]. We then analyzed the association between chemoresistance and alterations in the genes of apoptosis pathways.…”