ESMO Reviews Professor Feng Mingxiang: Baseline ctDNA is an independent predictor of postoperative recurrence and has broad clinical application scenarios!

Editor: Xiaoyuan

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The Annual Meeting of the European Society for Medical Oncology (ESMO) is the most prestigious and influential oncology conference
in Europe.
The 2022 ESMO Conference will be held offline (Paris, France) and online from September 9 to 13, 2022, covering basic research, translational research and the latest clinical research progress, and will provide a broad and excellent academic platform
for clinical practice and multidisciplinary discussion.
A number of blockbuster studies in the field of lung cancer will be presented at this year's ESMO conference
.

In an oral presentation, Professor Myung-Ju Ahn presented a study exploring longitudinal monitoring of ctDNA in patients with resectable stage IA-IIIA EGFR-mutated non-small cell lung cancer (NSCLC) in order to predict the prognosis
of these patients.
Yimaitong is honored to invite Professor Feng Mingxiang of Zhongshan Hospital affiliated to Fudan University to give an in-depth interpretation, the details are as follows:

Expert profiles

Professor Feng Mingxiang

Chief physician of the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, M.
D

In 2014, he was a visiting scholar at Barnes-Jewish Hospital at the University of Washington, under the tutelage of Professor Patterson and Professor Meyers, President of the American Society for Thoracic Surgery

Youth Committee Member of Thoracic Surgery Branch of Chinese Medical Association

The first place in the surgical skills competition held by the Chinese Medical Doctor Association in six provinces and one city in East China

Clinical research on minimally invasive thoracic surgery has been accepted by the European Annual Conference of Thoracic Surgery (ESTS), the American Annual Meeting of Thoracic Surgery (AATS), and the International Congress of Esophageal Diseases (ISDE).

Study Details:

Background:

For early-stage EGFR mutation-positive NSCLC, sequential adjuvant chemotherapy after radical surgery is one of
the standard treatment options.
Based on the ADAURA study, osimertinib has been approved as an adjuvant therapy
for the resection of stage IB-IIIA EGFR-sensitive mutation-positive NSCLC.
However, a one-size-fits-all treatment strategy and long-term treatment can lead to unwanted side effects and psychological burden
.
For adjuvant therapy strategies for individual patients, patient screening is a key part
of the benefits of adjuvant therapy with EGFR TKI.
Circulating tumor DNA (ctDNA) is a potential predictive biomarker for detecting minimal residual disease (MRD) and recurrence
.
This study followed patients with early EGFR mutation-positive NSCLC using ctDNA longitudinal monitoring
.

Method:

Between August 2015 and October 2017, 278 patients
with resected stage IA-IIIA EGFR mutation-positive NSCLC were included in the study.
From baseline, along with radiological monitoring, ctDNA is monitored longitudinally using droplet digital PCR for 5 years or until relapse
.

Study design

Outcome:

As of the data cut-off on April 12, 2022, the median follow-up was 62.
0 months, and among the 278 patients, stage IIA, IB, IIA, IIB, and IIIA patients accounted for 60.
1%, 18.
3%, 10.
1%, 2.
2%, and 9.
4%, respectively
.
EGFR exon 19 deletions and L858R point mutations accounted for 60.
1% and 39.
9%, respectively
.

Patient baseline characteristics

The 3-year DFS rates in patients at each stage were 95%, 78%, 58%, 50%, and 32%, respectively
.
Among the 278 patients, 67 (24.
1%) had baseline ctDNA tested, of which 23.
4% (stage IA), 17.
6% (stage IB), 17.
9% (stage IIA), 50.
0% (stage IIB), and 42.
3% (stage IIIA) (P=0.
06)
were respectively.
As the stage increases, so does the ctDNA copy number (P<0.
0001).
<b12>

Key result 1

76.
1% of patients with baseline ctDNA (51/67) had a negative ctDNA test 4 weeks after surgery
.
Patients were classified into three groups based on ctDNA: group A, baseline ctDNA negative (n=211); Group B: baseline ctDNA positive but MRD negative (n=51); Group C: baseline ctDNA positive, MRD positive (n=16).

There was a significant difference in 3-year DFS rates between the three groups: Group A, 83.
3%; Group B, 78%; Group C, 50% (P = 0.
02).

After adjusting for clinicopathological variables, ctDNA (HR=1.
27, 95% CI 1.
03-1.
57, P=0.
03) remained an independent risk factor
.

Key result 2

Conclusion:

76.
1% of patients showed that ctDNA was negative 4 weeks after surgery
.

Multivariate analysis showed that ctDNA was an independent predictor
of postoperative risk of recurrence, regardless of stage.

Based on ctDNA status, the DFS of the three groups differed
significantly.

Baseline ctDNA positivity or MRD positivity is associated with
poorer DFS in patients with radical resection of stage IA-IIIA EGFR mutation-positive NSCLC.

Professor Fung Mingxiang commented:

Preoperative baseline ctDNA, or MRD, is valuable and accurate in predicting prognosis

At present, the treatment evaluation and postoperative follow-up of lung cancer mainly rely on imaging testing, but imaging technology cannot identify tumor recurrence and metastasis
early.
In recent years, a number of studies have shown that ctDNA may be a reliable tool for tracking and evaluating tumor dynamics in real time, and can be used to predict response and efficacy
after tumor treatment 。 At this year's ESMO conference, Professor Myung-Ju Ahn from Sungkyunkwan University School of Medicine, South Korea, shared the application and value of ctDNA-MRD longitudinal monitoring in the postoperative recurrence risk and prognosis assessment of patients with EGFR-sensitive mutation-positive NSCLC in IA-IIIA stage (7th TNM stage), further verifying the application value and accuracy advantages
of ctDNA or ctDNA-MRD.
The study was conducted in a prospective design with a follow-up of five years and an observation endpoint of postoperative recurrence
.
The study eventually included 278 patients, divided into 3 groups according to the different states of ctDNA-MRD, and the results showed that preoperative baseline ctDNA or MRD positivity was significantly associated
with poor postoperative prognosis of patients.

ctDNA is a free fragment of DNA secreted and released by tumor cells after necrosis and apoptosis, and theoretically, ctDNA and tumor burden can show a good positive correlation
.
MRD, on the other hand, is an indicator
calculated from ctDNA to assess the residual state of tumor lesions.
Prior to this, LUNGCA and DYNAMIC studies led by Chinese experts have been fully explored in the use of ctDNA-MRD in predicting the residual state of lung cancer after surgery and assessing the risk of postoperative recurrence, and have also achieved good results
.
In the results presented by Professor Myung-Ju Ahn at this year's ESMO conference, we also see the value and accuracy
of preoperative baseline ctDNA or MRD in predicting the tumor burden of patients and predicting the risk of recurrence after surgery.

Thinking and challenging

At the same time, this study also gives us some food for thought
.
First of all, in the included population, we can see that about 40% of patients in stage IB-IIIA in this study, and less than 20% of patients received postoperative adjuvant chemotherapy, and the data on patients receiving postoperative targeted therapy were not mentioned
.
Because adjuvant therapy has a very important impact on the recurrence and prognosis of patients after surgery, the correspondence and detailed analysis of this part of the data, as well as the dynamic change data of ctDNA-MRD in the process of adjuvant therapy, are actually the results
we are very concerned about and expect.

Secondly, in the surgical method, we can see that 77.
3% of patients received lobectomy, 22.
6% of patients received lung segment or wedge resection, in the preoperative baseline ctDNA positive 67 patients, 76.
1% turned ctDNA negative after surgery, here 76.
1% of patients can be understood as molecular sense of "R0 resection", but for the remaining 23.
9% of patients who did not reach molecular significance "R0" resection, whether it was caused by the lack of surgical method, that is, treatment intensity This point is also a question
worth thinking about by surgeons.
Because what surgeons usually think of as R0 removal is actually a very macroscopic, naked eye standard
.
But in fact, many patients with even early-stage lung cancer solid tumors have a significant number of relapses after R0 resection
.
ctDNA and ctDNA-MRD can demonstrate their role and value in this regard, and can be used as a good molecular marker to help us predict and evaluate the risk and status
of tumor recurrence in patients.
Finally, in terms of sample size, the study brought by Professor Myung-Ju Ahn this time is still a single-center small sample study, so there may be some shortcomings in some data, such as the postoperative ctDNA negative results of patients in different stages, and some effects
due to insufficient sample size can be seen on some survival curves.
Therefore, for the results of this study, we still hope to see further validation from more centers and larger samples
.
This is also worth looking forward to
.

Finally, it should be pointed out that although many research institutions at home and abroad, including our center, have done a lot of research on the molecular diagnosis of lung cancer recurrence and metastasis, so far there is still no molecular marker that can effectively predict and evaluate the risk and status of postoperative recurrence in patients, which is also an important topic
facing clinical management at present.
The results of the results of this conference on ctDNA-MRD make us look forward
to the role of ctDNA-MRD detection in predicting the risk of recurrence in patients after lung cancer surgery.
It is hoped that in the future, ctDNA-MRD detection can truly change the current clinical diagnosis and treatment mode of lung cancer and truly achieve individualized treatment
based on the molecular detection status of patients.

References:

933MO-Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage IA-IIIA EGFR mutant non-small cell lung cancer.
2022 ESMO.