From icing to slicing the cake: the new hope of precision medicine for lung cancer

“Έτσι, δεν γνωρίζω” is the famous Socratic motto which stands for “I know, that I do not know”. It was more than a humble outing, actually an open and virtuous learning method by a Greek philosopher of the fifth century. It should still be more than a feeling towards the progress made, particularly during the last decade, in the diagnosis and treatment of lung cancer. Over 30 years, we stepped forward to a genetic or genomic grounded medicine (namely, the precision-medicine) from previous tumour organ- and then morphology-based transitions. In the nineties, a diagnosis of lung cancer was enough to offer each patient a systemic treatment. From the twenties to twenty-tents, we offered different and more active treatments based on histological subtypes. There was an attitude to combine and escalate treatments based on their mechanisms of action in these two eras as the knowledge of tumour determinants was still poor. From the first decades of 2000, the progressive identification of gene alterations driving tumour progression alongside the discovery of effective targeted treatments has offered a new horizon for treating lung cancer based on a new translational approach (1). It entails further progress in lung cancer treatment are dependent on the genomic characterization for the hallmarks of the tumour at baseline and molecular dynamic monitoring for mechanisms of primary and secondary resistance to targeted therapies (2). After about a decade from the dawn of precision medicine, currently, about one every four patients with non-small cell lung cancer (NSCLC) can receive today a targeted agent addressing gene alterations in 8 different pathways of lung cancer progression (EGFR, ALK, ROS1, BRAF, KRASG12C, MET, NTRK, RET) (3-5). Targeted agents are more active and usually less toxic, and more convenient than chemotherapy. Moreover, some of those gene alterations might be drivers and actionable across different tumour subtypes (i.e., BRAF, NTRK, RET) and led to agnostic approval of anticancer agents based on new trial designs (like “basket” trials) (6). Besides genomic alterations, a high tumor cell expression of programmed cell death-ligand 1 (PD-L1) and/or tumour mutational burden (TMB) can be used to select patients with NSCLC for immunotherapy (7,8). At the same time, we have to face new complex diagnostic and therapeutic challenges. Despite these novel treatments and their transition to earlier disease stages, lung cancer remains incurable for most patients (9). We are still unable to detect or target tumour molecular drivers or deal with primary or acquired resistant mechanisms to targeted agents and immunotherapy (10,11). There is a need to harmonize diagnostic assays and make them widely available for molecular profiling and monitoring (12). These are the topics of this special series on precision medicine in thoracic oncology.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Precision Cancer Medicine for the series “Non-Small Cell Lung Cancer”. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://pcm.amegroups.com/article/view/10.21037/pcm-21-39/coif). The series “Non-Small Cell Lung Cancer” was commissioned by the editorial office without any funding or sponsorship. AA and GLB served as the unpaid Guest Editors of the series. AA serves as an unpaid Associate Editor-in-Chief of Precision Cancer Medicine from December 2019 to November 2021. GLB reports consulting fee from AstraZeneca, Roche and Astellas, support for attending meetings and/or travel from AstraZeneca and Ipsen. AA reports personal fees from AstraZeneca, Pfizer, Takeda, Roche, Takeda, MSB, and BMS, as well as grants and personal fees from Boehringer-Ingelheim, outside the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Giuseppe L. Banna

Alfredo Addeo