Translating Systems Medicine Into Clinical Practice: Examples From Pulmonary Medicine With Genetic Disorders, Infections, Inflammations, Cancer Genesis, and Treatment Implication of Molecular Alterations in Non-small-cell Lung Cancers and Personalized Medicine

Abstract

Non-small-cell lung cancers (NSCLC) represent 85% of all lung cancers, with adenocarcinoma as the most common subtype. Since the 2000's, the discovery of molecular alterations including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements together with the development of specific tyrosine kinase inhibitors (TKIs) has facilitated the development of personalized medicine in the management of this disease. This review focuses on the biology of molecular alterations in NSCLC as well as the diagnostic tools and therapeutic alternatives available for each targetable alteration. Rapid and sensitive methods are essential to detect gene alterations, using tumor tissue biopsies or liquid biopsies. Massive parallel sequencing or Next Generation Sequencing (NGS) allows to simultaneously analyze numerous genes from relatively low amounts of DNA. The detection of oncogenic fusions can be conducted using fluorescence in situ hybridization, reverse-transcription polymerase chain reaction, immunohistochemistry, or NGS. EGFR mutations, ALK and ROS1 rearrangements, MET (MET proto-oncogenereceptor tyrosine kinase), BRAF (B-Raf proto-oncogen serine/threonine kinase), NTRK (neurotrophic tropomyosin receptor kinase), and RET (ret proto-oncogene) alterations are described with their respective TKIs, either already authorized or still in development. We have herein paid particular attention to the mechanisms of resistance to EGFR and ALK-TKI. As a wealth of diagnostic tools and personalized treatments are currently under development, a close collaboration between molecular biologists, pathologists, and oncologists is crucial.

Next Generation Sequencing for Gene Fusion Analysis in Lung Cancer: A Literature Review

“…ALK rearrangements have a frequency of 2–7% among advanced lung ADC patients and five ALK inhibitors are currently available: the first generation crizotinib, the second generation alectinib, ceritinib and brigatinib and the third generation lorlatinib [ 4 ]. Different clinical trials demonstrated a better efficacy for the second generation drugs alectinib and brigatinib in comparison to crizotinib in the first line treatment of ALK -rearranged NSCLC [ 3 ].…”

“…The breakpoint site can occur in different exons, consequently forming various fusion variants associated with different TKI sensitivity [ 5 ]. ROS1 rearrangements have a frequency of 1–2% and crizotinib is currently the only approved TKI for the first line treatment [ 4 , 6 ]. However, in recent clinical trials it has been demonstrated that central nervous system activity of other TKIs targeting also ROS1 (ceritinib and entrectinib) is superior to crizotinib [ 3 ].…”

“…The RET gene is located on chromosome 10q1.2 and its rearrangements are detected in 1–2% of ADC with the most common fusion partner represented by the kinesin family member 5B ( KIF5B) . Over the years, different RET inhibitors have been developed and evaluated for the treatment of RET -rearranged tumors, including both multikinase inhibitors, like cabozantinib and vandetanib, and selective inhibitors, like pralsetinib and selpercatinib [ 4 , 10 , 11 ]. The multikinase inhibitors have shown an unsatisfying clinical efficacy with different off-target adverse events and a low overall response rate.…”

“…In many cases it is considered the gold standard and can discriminate rearrangements from polysomy and amplification, but it does not allow a determination of the exact fusion variant. Break apart probes can miss small intrachromosomal rearrangements and not all the identified DNA rearrangements produce an expressed fusion transcript [ 4 , 14 ]. IHC detects fusion proteins, besides the specific fusion variant: whenever an in-frame rearrangement occurs, the 3-prime (3′) region of the oncogene is juxtaposed with the 5-prime (5′) sequence of a fusion partner gene highly expressed in tumor cells, leading to an active and expressed oncoprotein [ 4 , 13 ].…”

“…Break apart probes can miss small intrachromosomal rearrangements and not all the identified DNA rearrangements produce an expressed fusion transcript [ 4 , 14 ]. IHC detects fusion proteins, besides the specific fusion variant: whenever an in-frame rearrangement occurs, the 3-prime (3′) region of the oncogene is juxtaposed with the 5-prime (5′) sequence of a fusion partner gene highly expressed in tumor cells, leading to an active and expressed oncoprotein [ 4 , 13 ]. IHC has a good sensitivity, almost all molecular pathology laboratories are familiar with this method, it is time saving and also easily automatable, cost-friendly, and different clinically validated antibodies are available [ 15 ].…”