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

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Abstract

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.

Original languageEnglish
Pages (from-to)8945-8950
Number of pages6
JournalOncoTargets and Therapy
Volume11
DOIs
Publication statusPublished - Jan 1 2018

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Lung Neoplasms
Mutation
Protein-Tyrosine Kinases
Therapeutics
Biopsy
Neoplasms
DNA
Small Cell Lung Carcinoma
Exons
Phosphotransferases

Keywords

  • Alk tyrosine kinase inhibitors
  • EML4-ALK
  • G1202R resistance mutation
  • Liquid biopsy
  • Non-small-cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

Cite this

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title = "Therapeutic decision based on molecular detection of resistance mechanism in an ALK-rearranged lung cancer patient: A case report",
abstract = "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 = "Alk tyrosine kinase inhibitors, EML4-ALK, G1202R resistance mutation, Liquid biopsy, Non-small-cell lung cancer",
author = "{De Carlo}, Elisa and Monica Schiappacassi and Martina Urbani and Roberto Doliana and Gustavo Baldassarre and {Da Ros}, Valentina and Sandra Santarossa and Emanuela Chimienti and Eleonora Berto and Lucia Fratino and Alessandra Bearz",
year = "2018",
month = "1",
day = "1",
doi = "10.2147/OTT.S184745",
language = "English",
volume = "11",
pages = "8945--8950",
journal = "OncoTargets and Therapy",
issn = "1178-6930",
publisher = "Dove Medical Press Ltd.",

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TY - JOUR

T1 - Therapeutic decision based on molecular detection of resistance mechanism in an ALK-rearranged lung cancer patient

T2 - A case report

AU - De Carlo, Elisa

AU - Schiappacassi, Monica

AU - Urbani, Martina

AU - Doliana, Roberto

AU - Baldassarre, Gustavo

AU - Da Ros, Valentina

AU - Santarossa, Sandra

AU - Chimienti, Emanuela

AU - Berto, Eleonora

AU - Fratino, Lucia

AU - Bearz, Alessandra

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Alk tyrosine kinase inhibitors

KW - EML4-ALK

KW - G1202R resistance mutation

KW - Liquid biopsy

KW - Non-small-cell lung cancer

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U2 - 10.2147/OTT.S184745

DO - 10.2147/OTT.S184745

M3 - Article

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VL - 11

SP - 8945

EP - 8950

JO - OncoTargets and Therapy

JF - OncoTargets and Therapy

SN - 1178-6930

ER -