Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients: Potential Clinical Impact on Subsequent third-generation TKI Treatment

Daniela Iacono, Giorgia A. Osman, Maria R. Migliorino, Lucia Grillo, Daniele Remotti, Josè Nunnari, Serena Ricciardi, Antonio Rossi, Andrea Mancuso, Paolo Graziano, Angela Di Lorenzo, Monica Bronzini, Mauro Signora, Alvaro Leone

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. MATERIALS AND METHODS: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. RESULTS: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. CONCLUSIONS: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

Original languageEnglish
Pages (from-to)845-850
Number of pages6
JournalAmerican Journal of Clinical Oncology
Volume42
Issue number11
DOIs
Publication statusPublished - Nov 1 2019

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Protein-Tyrosine Kinases
Small Cell Lung Carcinoma
Mutation
Epidermal Growth Factor Receptor
Therapeutics
Biopsy
Non-Small Cell Lung Carcinoma
Adenocarcinoma
Gene Amplification
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients : Potential Clinical Impact on Subsequent third-generation TKI Treatment. / Iacono, Daniela; Osman, Giorgia A.; Migliorino, Maria R.; Grillo, Lucia; Remotti, Daniele; Nunnari, Josè; Ricciardi, Serena; Rossi, Antonio; Mancuso, Andrea; Graziano, Paolo; Di Lorenzo, Angela; Bronzini, Monica; Signora, Mauro; Leone, Alvaro.

In: American Journal of Clinical Oncology, Vol. 42, No. 11, 01.11.2019, p. 845-850.

Research output: Contribution to journalArticle

Iacono, Daniela ; Osman, Giorgia A. ; Migliorino, Maria R. ; Grillo, Lucia ; Remotti, Daniele ; Nunnari, Josè ; Ricciardi, Serena ; Rossi, Antonio ; Mancuso, Andrea ; Graziano, Paolo ; Di Lorenzo, Angela ; Bronzini, Monica ; Signora, Mauro ; Leone, Alvaro. / Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients : Potential Clinical Impact on Subsequent third-generation TKI Treatment. In: American Journal of Clinical Oncology. 2019 ; Vol. 42, No. 11. pp. 845-850.
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abstract = "OBJECTIVES: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. MATERIALS AND METHODS: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. RESULTS: The T790M mutation was found in 16 patients (59{\%}) whereas MET gene amplification was found in 2 (10.5{\%}) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11{\%}). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. CONCLUSIONS: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.",
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T1 - Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients

T2 - Potential Clinical Impact on Subsequent third-generation TKI Treatment

AU - Iacono, Daniela

AU - Osman, Giorgia A.

AU - Migliorino, Maria R.

AU - Grillo, Lucia

AU - Remotti, Daniele

AU - Nunnari, Josè

AU - Ricciardi, Serena

AU - Rossi, Antonio

AU - Mancuso, Andrea

AU - Graziano, Paolo

AU - Di Lorenzo, Angela

AU - Bronzini, Monica

AU - Signora, Mauro

AU - Leone, Alvaro

PY - 2019/11/1

Y1 - 2019/11/1

N2 - OBJECTIVES: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. MATERIALS AND METHODS: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. RESULTS: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. CONCLUSIONS: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

AB - OBJECTIVES: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. MATERIALS AND METHODS: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. RESULTS: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. CONCLUSIONS: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

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