"Nature" sub-published strong evidence: postoperative ctDNA-MRD analysis can predict the benefit of adjuvant chemotherapy in NSCLC!

Detection of ctDNA-MRD can better predict the risk of disease recurrence and help guide adjuvant chemotherapy decisions

Lung cancer is one of the most common malignancies and the leading cause of cancer-related death worldwide

Recent studies have shown that the presence of ctDNA predates recurrence on imaging, and ctDNA-based MRD assessment (ctDNA-MRD) has the potential to change the treatment pattern of NSCLC

Based on the data published to date, we can find that ctDNA-MRD is a reliable prognostic biomarker in NSCLC,1,2 but data supporting ctDNA-MRD as a predictive biomarker are lacking

Here, we first insert a topic, that is, how to distinguish between prognostic biomarkers and predictive biomarkers?

In 1998, the National Institutes of Health (NIH) Biomarker Definition Working Group defined a biomarker as “a characteristic that is objectively measured and assessed as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to therapeutic interventions.

In other words, in NSCLC, ctDNA-MRD analysis is a prognostic biomarker that reliably predicts disease recurrence, but data supporting ctDNA-MRD as a predictive biomarker for adjuvant therapy response are lacking

On November 19, 2021, "Nature Communications", a subsidiary of "Nature", published the results of a ctDNA-MRD study jointly completed by Nanjing Shihe Gene and the Cancer Hospital of the Chinese Academy of Medical Sciences.

▲Using ctDNA to predict postoperative dynamic recurrence risk and benefit of adjuvant chemotherapy in NSCLC

A total of 116 patients with NSCLC who underwent surgical resection were included in this prospective study, 13 of whom discontinued treatment for various reasons and were therefore excluded from subsequent analyses, culminating in targeted NGS on tumor tissue and plasma samples from 103 patients detection

71 of 103 patients (68.

technical analysis

MRD detection strategy: tumor-informed assay, fixed panel;

Detection panel: The lung cancer tracking panel is pre-designed according to TCGA and other databases, including 139 important lung cancer-related genes, and the panel size is 0.

Test samples: tumor tissue samples, plasma ctDNA samples;

Sample input amount: 1~2ug for gDNA; 50ng for ctDNA;

Library construction method: probe hybridization capture method (IDT);

Sequencing platform: Illumina Hiseq4000;

Sequencing depth: The average sequencing depth of tumor tissue samples is 850X, the average sequencing depth of plasma ctDNA samples is 30,000X (ATG-seq), and the average sequencing depth of white blood cell controls is 300X;

LoD: LoD of variant allele frequency (VAF) is 0.

ctDNA-MRD positive: presence of one or more plasma ctDNA mutations matching the tumor tissue sample;

Sample collection for ctDNA-MRD testing: tumor tissue samples were collected during surgery and pre-treatment peripheral blood samples collected before surgery were used for pre-operative mutation analysis

Somatic mutations were detected in 91 of 103 patient tumor specimens, with a median of 2 mutations per patient (range: 1–8 mutations)

ctDNA shedding was associated with pTMN stage, with ctDNA detection rates of 61.

Of the 85 patients for whom post-operative plasma samples were obtained, 18 (21.

The main findings of the study are:

1) ctDNA-MRD positivity was significantly associated with worse recurrence-free survival (RFS) after surgery and after adjuvant chemotherapy (ACT)

2) Among the postoperative ctDNA-MRD-positive stage II-III patients, patients who received ACT had better RFS than those who did not; while postoperative ctDNA-MRD-negative patients did not seem to need ACT treatment, Because they had a similarly low risk of recurrence with or without ACT
.

3) Longitudinal ctDNA analysis, patients with positive ctDNA-MRD detected at any time point during post-treatment monitoring had significantly lower RFS than patients with consistently negative ctDNA-MRD postoperatively
.
In addition, the median lead time from positive detection of ctDNA-MRD to radiographic prediction of recurrence was 88 days
.

4) Combined modeling using ctDNA longitudinal monitoring and recurrence time data can accurately predict the recurrence status of patients at 12 and 15 months after surgery
.

Overall, this study demonstrates ctDNA-MRD as a reliable biomarker for postoperative and post-ACT risk stratification in NSCLC and early detection of recurrence
.
In addition, our data further suggest that postoperative ctDNA-MRD analysis can guide ACT treatment decisions and avoid overtreatment of patients who are unlikely to benefit from ACT therapy
.

References: 

1.
Chaudhuri AA, Chabon JJ, Lovejoy AF, et al.
Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.
Cancer Discov.
2017;7(12):1394-1403.
 

2.
Abbosh C, Birkbak NJ, Wilson GA, et al.
Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.
Nature.
2017;545(7655):446-451.
 

3.
Atkinson, AJ, Colburn, WA, DeGruttola, VG, DeMets, DL, Downing, GJ, Hoth, DF, Oates, JA, Peck, CC, Schooley, RT, Spilker, BA, Woodcock, J.
, & Zeger, SL (2001).
Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework.
Clinical pharmacology and therapeutics, 69(3), 89-95.
 

4.
Qiu, B.
, Guo, W.
, Zhang, F.
et al.
Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC.
Nat Commun 12, 6770 (2021).