RESULTS OF LIQUID BIOPSY STUDIES BY NEXT
GENERATION SEQUENCING IN PATIENTS WITH
ADVANCED STAGE NON-SMALL CELL LUNG CANCER:
SINGLE CENTER EXPERIENCE FROM TURKEY
Buyuksimsek M1,*, Togun M2, Oguz Kara I1, Bisgin A3,4, Boga I4, Tohumcuoglu M1,
Ogul A1, Evren Yetisir A1, Sahin B1, Erdem Sumbul H5, Mirili C6
*Corresponding Author: Mahmut Buyuksimsek, M.D., Department of Oncology, Çukurova University
Faculty of Medicine, Sarican, Adana, Turkey. Tel: +90-536-862-20-26. Fax: +90-322-338-70-72.
E-mail: mahmutbuyuksimsek@gmail.com
page: 17
|
|
DISCUSSION
The treatment of NSCLC has become more successful
and individualized using targeted protocols according
to molecular subtypes. The earlier attempts with targeted
treatments involved unselected patients and did not result
in as good outcomes as anticipated. Regarding treatment
with the epidermal growth factor receptor tyrosine kinase
inhibitors (EGFR-TKIs) in unselected patients, while erlotinib
increased median survival by 2 months in previously
treated NSCLC patients [9], gefitinib did not improve
survival in a similar population [10].
However, targeted treatment in patients selected according
to molecular analyses resulted in unprecedented
outcomes. For instance, a prospective study in patients with
EGFR mutant LC, the response rate to targeted treatment
was over 60.0% [11]. Crizotinib resulted in a similar success
rate in LC patients with ALK rearrangements [12]. First line
treatment with dabrafenib/trametinib in NSCLC patients
carrying BRAF V600E mutations (seen in 2.0% of patients
with NSCLC) resulted in a response rate of 64.0% and 10
months of progression-free survival [13]. The identification
of the even rarer variants such as MET gene amplification
and ERBB2 mutations led to the discovery of new treatment
pathways. In 2014, the NCCN recommended utilization of
wider panels including BRAF, ERBB2 (HER2), MET, RET
and ROS1 in addition to EGFR and ALK. The reason for
their recommendation to widen the mutation panel was the
ever-increasing success with novel treatments targeted to
oncogenic driver mutations in comparison to cytotoxic and
immune checkpoint inhibitor therapies.
These tests were performed step by step, therefore
large tissue samples were inevitably needed [14]. Various
clinical studies indicate that attainment of ccfDNA
is an appropriate means of detecting mutations [15,16].
Recently, the advantages of plasma-based liquid biopsy
such as accessibility, practical use and reproducibility,
rendered it a good choice in patients with NSCLC. Tissue
biopsies usually bear the difficulty of access and may
provide insufficient samples for genetic testing due to the
tumor heterogeneity. Furthermore, the need for a repeat
biopsy after lack of response to treatment may be a cause of
significant morbidity. The ASSESS study reported a high
degree of concordance between plasma-based ccfDNA and
tissue or cytology samples in NSCLC [17].
We aimed to report our NGS results using liquid biopsy
samples in patients with metastatic NSCLC. The most
common mutation was regarding the EGFR gene. Some
of the patients had concomitant driver and resistance mutations.
The second most commonly detected gene was
KRAS. While the frequency of EGFR mutation in AC in
the western populations was 19.2%; it was seen in 47.9%
of Asian patients. The rates of KRAS mutations was 26.1%
in the western and 11.2% in Asian populations [18]. Turkey
lies between the western populations and Asia, and the frequencies
of EGFR and KRAS mutations in the present study
were 31.4% (17.4% activating) and 9.3%, respectively. The
other targets of individualized treatment protocols include
EML4-ALK fusion and variants of MET, ERBB2, BRAF,
PDGFRA and KIT. The most common variants detected in
patients with AC were in EGFR and KRAS genes. The two
most commonly detected variants were also seen in patients
with SCC in a diverse frequency according to their ethnic
origin [19]. In the present study, EGFR and MET variants
were also observed in patients with SCC. The activation of
the MET signaling pathway is suggested to cause resistance
to EGFR-TKI treatment. Crizotinib may provide successful
outcomes in patients with MET overexpression [20].
Therefore, target mutations should be sought using liquid
biopsy in patients with SCC. Despite the dramatic response
to molecular targeted treatments, nearly every medication
is associated with development of resistance. It is also important
to understand the molecular pathways of NSCLC in
order to understand mechanisms of resistance to medications
[21].The understanding of resistance mechanisms against
targeted treatments led to the development of second line
treatment options specific to EGFR and ALK mutations.
Moreover, the growing need for repeat biopsies in patients
with LC is associated with a substantial morbidity risk.
Furthermore, the paucity of centers for transthoracic biopsies
in many healthcare systems cause a logistics problem.
Therefore, the opportunity of following up patients with
LC using blood-based tests is an important topic of interest
in the technologically developing world [22,23].While the
most common mechanism of resistance against first and
second line EGFR-TKIs is the EGFR T790M mutation,
MET and ERBB2 amplification is responsible for a smaller
proportion of resistance [24]. In the present study, we also
aimed to investigate the causes of resistance in the eight
patients with progressive disease after the first treatment,
and found the following causes: new onset EGFR T790M
mutation, erased target mutation and a new onset BRAF gene
variant. The present study has some strong points as well as
limitations. New onset variants that are potential targets of
alternative treatment options and the disappearance of the
previous mutations showed the necessity of repeated liquid
biopsy studies. Liquid biopsy has a strong advantage in
NSCLC because of the difficulties of repeated interventional
procedures and accessibility problems. To the best of our
knowledge, this study is the first to report on the real-world
use of a comprehensive ccfDNA with clinical follow-ups
and NGS platforms in the molecular diagnosis of patients
with NSCLC in a Turkish population. The main limitation
of working with the circulating tumor cell as a liquid biopsy source is the fact that the sample obtained in patients with
early stage cancer may not contain sufficient amounts of
tumor-derived material and sometimes information from
tumor tissue may be difficult to separate information from
intact cells [25]. An example of this is PDGFRA c.236G>A
(G79D), KIT c.2362-77G>A variants, which are not compatible
with the diagnosis and clinical feature of a patient and
was evaluated as a polymorphism. The second liquid biopsy
sampling was performed only in a small number of cases
and this was the other limitation of this study.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
