Histological and Molecular Plasticity of ALK-positive Non-Small-Cell Lung Cancer under Targeted Therapy - a Case Report

Abstract

With medical progress in cancer therapy, tyrosine kinase inhibitors (TKIs) became a standard of care for many cancer types. But the broad range of possible targeted therapies was accompanied by a plethora of potential resistance mechanisms, of which many have still to be identified. Here, we present the case of a patient with an EML4-ALK translocated non-small-cell lung cancer treated with four different TKIs. His tumor developed not only a well-known ALK-TKI resistance mutation, but also underwent a histological transformation from adenocarcinoma to squamous cell carcinoma. To confirm a shared monoclonal origin of the phenotypically different tumors, a phylogenetic reconstruction was conducted: this revealed a cluster of mutations including NFE2L2, KMT2D and MLH1 which are possible triggering events for the transformation.

Biology and impact of lineage plasticity in ALK-positive NSCLC: a narrative review

“…While SCLC transformation was the first identified category of lineage transformation and is the most comprehensively described to date, squamous transformation (from adenocarcinoma, within the NSCLC spectrum) is also a recurrent finding at the time of acquired resistance to targeted therapies in lung cancer. Characterized by changes in morphology and immunohistochemical staining from adenocarcinoma-associated markers (e.g., napsin A and TTF-1) to squamous-associated markers (e.g., p40 and p63) ( 126 , 127 ), it has been reported in at least six cases of resistance to ALK TKIs ( 59 , 60 , 62 , 63 , 85 , 74 ) ( Table 2 and Table 3 ). Similar to SCLC transformation, squamous transformation is also a recurrent phenomenon in EGFR -mutant NSCLC ( 17 , 19 , 128 , 129 ) and squamous histology has also been rarely reported as a component of EGFR -mutant NSCLC histology at diagnosis ( 130 , 131 ).…”

“…Without any published prospective data or clinical trials specifically designed for this patient population, decisions regarding treatment at the time of squamous transformation still rely on anecdotal evidence and expert opinion. In reported cases of ALK-positive and EGFR -mutant tumors undergoing squamous transformation, systemic therapy at the time of transformation has been variable—ranging from continued TKI to chemotherapy and immune checkpoint inhibitors ( Table 2 ) ( 17 , 59 , 60 , 62 , 63 , 65 , 74 , 137 ). Unfortunately, the number of cases with reported clinical outcomes remains too few to inform prospective decision-making for patients currently on treatment.…”

Histologic transformation in lung cancer: when one door shuts, another opens

“…HTs to SqCC have also been reported after the use of ALK-TKIs in several cases. 55 – 60 Two reports have demonstrated the paired pre- and post-treatment genomic landscape of the transformed ALK -rearranged SqCC; however, much remains unknown about HTs in SqCC. 57 , 58 …”

“…[55][56][57][58][59][60] Two reports have demonstrated the paired pre-and post-treatment genomic landscape of the transformed ALK-rearranged SqCC; however, much remains unknown about HTs in SqCC. 57,58 Other molecular targeted agents for NSCLC HTs in patients with lung cancer are also caused by molecular targeted agents other than EGFR-and ALK-TKIs. For example, several reports have shown HTs after treatment with ROS1-TKIs or Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-inhibitors.…”

“…HTs to SqCC have also been reported after the use of ALK-TKIs in several cases. [55][56][57][58][59][60] Two reports have demonstrated the paired pre-and post-treatment genomic landscape of the transformed ALK-rearranged SqCC; however, much remains unknown about HTs in SqCC. 57,58 Other molecular targeted agents for NSCLC HTs in patients with lung cancer are also caused by molecular targeted agents other than EGFR-and ALK-TKIs.…”