Therapeutic decision based on molecular detection of resistance mechanism in an ALK-rearranged lung cancer patient: a case report

Elisa De Carlo,^1,* Monica Schiappacassi,^2,* Martina Urbani,³ Roberto Doliana,² Gustavo Baldassarre,² Valentina Da Ros,¹ Sandra Santarossa,¹ Emanuela Chimienti,¹ Eleonora Berto,¹ Lucia Fratino,¹ Alessandra Bearz<sup>1

1</sup>Clinical Oncology Department, IRCCS CRO Centro di Riferimento Oncologico Aviano, Aviano, Italy; ²Molecular Oncology Department, IRCCS CRO Centro di Riferimento Oncologico Aviano, Aviano, Italy; ³Radiology Department, IRCCS CRO Centro di Riferimento Oncologico Aviano, Aviano, Italy

*These authors contributed equally to this work

Background: The use of tyrosine kinase inhibitors (TKIs) of ALK is the therapy of choice for ALK-fusion patients. Unfortunately, all patients under this kind of treatment eventually develop acquired resistance through several well-known mechanisms, such as acquisition of a secondary mutation within the kinase domain, activation of a bypass signaling pathway, or a histological change like small-cell lung cancer transformation. At the time of progression, a tissue re-biopsy may give important molecular and morphological information regarding the mechanisms driving resistance to ALK TKIs. However, this procedure is not always feasible and it may not reflect the tumor heterogeneity, and therefore gives incomplete information. To overcome these drawbacks, the analysis of circulating tumor DNA (ctDNA) isolated from plasma, the so-called liquid biopsy, is emerging as a noninvasive and useful tool for detecting resistance mutations. Secondary resistance mutations are common in second-generation TKIs resistant patients and among these, Gly1202Arg (p.G1202R) emerged as the most frequent mutation.
Case presentation: We have treated an ALK-positive lung adenocarcinoma patient with a sequential strategy of ALK TKIs. Patient follow-up was performed combining clinical, radiological, and molecular profiling. ctDNA was isolated from plasma and by means of ultra-deep next generation sequencing; we searched for secondary ALK resistance mutations on exons 21–25. ALK mutation Gly1202Arg (G1202R) was detected. We have documented consistency between plasma levels of G1202R mutation and radiological progression or improvement.
Conclusion: Liquid biopsy appears to be a promising tool to anticipate progression and to drive the therapeutic strategy based upon ALK resistance mutations.

Keywords: non-small-cell lung cancer, EML4-ALK, ALK tyrosine kinase inhibitors, G1202R resistance mutation, liquid biopsy