Blood- and tumor-based analyses for improved prognostics in lung cancer
Författare
Summary, in English
Lung cancer is a common cancer type associated with poor prognosis. Even in the group of patients with earlystage tumors, for which curative treatment is possible, lung cancer recurrence is frequent. The aim of this thesis was to investigate the potential prognostic role of mutations in tumor specimens, blood-based proteins and circulating tumor DNA.
In study I, we performed EGFR mutation detection by immunohistochemical (IHC) staining in 350 tumors (two cohorts; 298 tumors and 52 tumors, respectively). Mutation detection by IHC staining was not reliable, the antibodies used for EGFR mutation-specific staining was sometimes unspecific, and the optimal dilution of the antibodies was not clear. Thirteen of 17 mutations detected by IHC staining could be verified with PCR or Sanger sequencing in the larger cohort.
Mutational spectra was further investigated in study II, where mutational profiling was based on next generation sequencing (NGS) with a panel of 26 solid tumor-related genes. NGS was implemented as part of clinical routine in an autonomous health care region in southern Sweden (Region Skåne) in 2015 and we present the first 1.5-year of clinical NGS-based mutational profiling and its clinical impact. The most frequently mutated genes in this panel were TP53 and KRAS. Mutations in these genes were not associated with progression-free survival (PFS) or overall survival (OS) in patients with advanced lung cancer treated with platinum-based chemotherapy. Targetable alterations in driver oncogenes (for example EGFR) were detected in 16% of all tumors and in 59% of tumors from never-smokers.
In study III and IV, we investigated tumor markers in serum and cell-free circulating tumor DNA (ctDNA) in plasma obtained pre-operatively from early stage lung cancer patients treated with curatively intended surgery and studied their relation to lung cancer recurrence. In study III, analysis of five tumor markers, implemented in the monitoring of other solid tumors, revealed a tendency of correlation between tumor markers and lung cancer recurrence in a cohort of 107 lung adenocarcinomas. The two most interesting markers were CA 19-9 and CA 125 which were further analyzed in study IV, comprising 58 lung adenocarcinomas, in which we also analyzed pre-operative plasma for ctDNA. With limited amount of plasma, we still detected seven cases with positive ctDNA in preoperative plasma. Both ctDNA and the combination of ctDNA and tumor markers were associated with worse outcome but also more frequent in higher stage. Thus, larger studies are necessary to study the prognostic potential of these blood-based markers.
In summary, this thesis evaluates treatment-predictive molecular methods and investigates their potential prognostic impact. It presents the mutational spectra in a population-based lung cancer cohort with clinically wellcharacterized follow up, and suggests a possible role for blood-based prognostication in lung cancer.
In study I, we performed EGFR mutation detection by immunohistochemical (IHC) staining in 350 tumors (two cohorts; 298 tumors and 52 tumors, respectively). Mutation detection by IHC staining was not reliable, the antibodies used for EGFR mutation-specific staining was sometimes unspecific, and the optimal dilution of the antibodies was not clear. Thirteen of 17 mutations detected by IHC staining could be verified with PCR or Sanger sequencing in the larger cohort.
Mutational spectra was further investigated in study II, where mutational profiling was based on next generation sequencing (NGS) with a panel of 26 solid tumor-related genes. NGS was implemented as part of clinical routine in an autonomous health care region in southern Sweden (Region Skåne) in 2015 and we present the first 1.5-year of clinical NGS-based mutational profiling and its clinical impact. The most frequently mutated genes in this panel were TP53 and KRAS. Mutations in these genes were not associated with progression-free survival (PFS) or overall survival (OS) in patients with advanced lung cancer treated with platinum-based chemotherapy. Targetable alterations in driver oncogenes (for example EGFR) were detected in 16% of all tumors and in 59% of tumors from never-smokers.
In study III and IV, we investigated tumor markers in serum and cell-free circulating tumor DNA (ctDNA) in plasma obtained pre-operatively from early stage lung cancer patients treated with curatively intended surgery and studied their relation to lung cancer recurrence. In study III, analysis of five tumor markers, implemented in the monitoring of other solid tumors, revealed a tendency of correlation between tumor markers and lung cancer recurrence in a cohort of 107 lung adenocarcinomas. The two most interesting markers were CA 19-9 and CA 125 which were further analyzed in study IV, comprising 58 lung adenocarcinomas, in which we also analyzed pre-operative plasma for ctDNA. With limited amount of plasma, we still detected seven cases with positive ctDNA in preoperative plasma. Both ctDNA and the combination of ctDNA and tumor markers were associated with worse outcome but also more frequent in higher stage. Thus, larger studies are necessary to study the prognostic potential of these blood-based markers.
In summary, this thesis evaluates treatment-predictive molecular methods and investigates their potential prognostic impact. It presents the mutational spectra in a population-based lung cancer cohort with clinically wellcharacterized follow up, and suggests a possible role for blood-based prognostication in lung cancer.
Avdelning/ar
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Bröstcancer-genetik
- Institutionen för kliniska vetenskaper, Lund
Publiceringsår
2019-04
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Volym
2019
Issue
52
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Cancer and Oncology
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-7619-781-3
Försvarsdatum
23 maj 2019
Försvarstid
09:00
Försvarsplats
LUX, B152, Helgonavägen 3, Lund
Opponent
- Tom Dønnem (professor)