The complete treatment and management of brain metastases in a patient with limited-stage small cell lung cancer under molecular residual disease (MRD) monitoring: a case report
Highlight box
Key findings
• This case report describes the complete treatment course of a patient with limited-stage small cell lung cancer (LS-SCLC) under serial molecular residual disease (MRD) monitoring.
• Dynamic changes in MRD status were closely associated with treatment response and systemic disease progression.
• MRD positivity re-emerged after brain metastases developed, highlighting both the potential value and limitations of MRD monitoring in LS-SCLC.
What is known and what is new?
• MRD detection using circulating tumor DNA (ctDNA) has shown strong prognostic value in several solid tumors, particularly in non-small cell lung cancer, but evidence in SCLC—especially LS-SCLC—remains limited.
• This report provides real-world evidence that MRD monitoring may aid in evaluating treatment efficacy and recurrence risk in LS-SCLC. Notably, MRD monitoring failed to provide an early warning before the development of brain metastases, underscoring a potential sensitivity limitation related to central nervous system involvement.
What is the implication, and what should change now?
• MRD monitoring may serve as a useful adjunct for assessing systemic disease control and guiding treatment decisions in LS-SCLC.
• Optimize surveillance strategies: Conduct quarterly MRD testing during the 2-year high-recurrence period post-surgery, combined with brain magnetic resonance imaging (MRI) every 3–6 months—MRD cannot replace MRI for intracranial lesion screening.
Introduction
Small cell lung cancer (SCLC) is a very invasive and highly metastatic tumor that accounts for approximately 13–17% of all lung cancers (1). The current standard treatment for limited-stage SCLC (LS-SCLC) is concurrent chemoradiotherapy. Although most patients seek to be cured and respond well to initial treatment, LS-SCLC is known for its high degree of malignancy and proclivity toward recurrence and metastasis, especially brain metastasis, and patients demonstrate a median overall survival (OS) of 25–30 months and a 5-year OS rate of 31–34% (2,3).
Molecular residual disease (MRD) refers to tumor-derived molecular abnormalities detectable in liquid biopsy after treatment but undetectable by conventional imaging. The detection of MRD has demonstrated good clinical performance in recurrence prediction, prognosis evaluation, and efficacy monitoring for a variety of solid tumors, such as non-small cell lung cancer (NSCLC), colon cancer, and breast cancer. As a supplement to existing recurrence/prognosis evaluation systems, the detection of MRD can provide multidimensional information for informing subsequent treatment decisions (4,5). The LUNGCA-1 study revealed that the recurrence rate of MRD-positive patients within one month after surgery is 80.8%, suggesting that the identification of MRD can effectively predict postoperative recurrence in patients with NSCLC. Adjuvant therapy for MRD-positive patients can significantly improve relapse-free survival [hazard ratio (HR) 0.3; 95% confidence interval (CI): 0.10–0.80; P=0.008], suggesting that it is very important to consider the circulating tumor DNA (ctDNA)-MRD status in treatment decision-making (6). The GALAXY study evaluated the role of ctDNA in recurrence prediction and in administering adjuvant chemotherapy for patients with resectable colorectal cancer (CRC). The results revealed that the disease-free survival of ctDNA-positive patients at the surveillance window was significantly worse than that of ctDNA-negative patients (HR 33.56, 95% CI: 26.07–43.20; P<0.0001) (7). The DYNAMIC study revealed that ctDNA-positive stage II colon cancer patients could benefit from chemotherapy, but the risk of recurrence was greater than 80% in patients who were not receiving chemotherapy. In the ctDNA-guided treatment of stage II CRC patients, the use of adjuvant chemotherapy was reduced without affecting the survival benefit of the overall population (8). Although ctDNA-guided strategies have shown clinical value in other malignancies, these findings cannot be directly extrapolated to SCLC due to its distinct biological behavior and ctDNA dynamics.
Compared with NSCLC, evidence supporting the clinical application of MRD monitoring in SCLC remains extremely limited. In particular, the role of MRD in predicting recurrence patterns and brain metastases in LS-SCLC has not been well described. SCLC differs significantly from other types of cancer in terms of molecular characteristics and tumor DNA concentration in the blood, both of which may affect the sensitivity and specificity of MRD detection. In SCLC, the ctDNA molecular response can be detected on average 4 weeks earlier than with traditional imaging [including positron emission tomography (PET)/computed tomography (CT)] (9). The incidence of brain metastases at the time of SCLC diagnosis is 10–18%, but nearly 30% of patients have no corresponding symptoms. Fluorodeoxyglucose (FDG)-PET/CT has good performance in the staging and diagnosis of SCLC, but it is expensive, and its sensitivity is not as high as that of magnetic resonance imaging (MRI) in the detection of brain metastases. Therefore, early detection and management of brain metastases are challenging because of their occult and often asymptomatic features (10). This case provides real-world longitudinal evidence illustrating both the potential utility and limitations of MRD monitoring in LS-SCLC, thereby contributing incremental knowledge beyond existing reports.
This case report aimed to describe the full course of treatment for a LS-SCLC patient under MRD monitoring with a focus on the effectiveness of MRD monitoring in predicting brain metastases and its potential in identifying the risk of recurrence. Through this case report, we hope to explore the current limitations and potential value of the detection of MRD in optimizing the management of patients and improving their outcomes. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0003/rc).
Case presentation
The patient was 49 years old at the time of medical treatment. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Guizhou Provincial People’s Hospital [approval No. (2024)004]. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. A chest CT scan on November 21, 2022 revealed a tumor at the porta of the right lower lobe of the lung, approximately 4.2 cm × 1.8 cm in size. On November 24, 2022, lymph node biopsy revealed SCLC in the right lower lung, with a clinical stage of cT2aN1M0 IIB (Figure 1). A next-generation sequencing (NGS)-DNA panel of 769 genes in the biopsy tissue (Table 1) revealed low expression levels of programmed death ligand 1 (PD-L1) [tumor proportion score (TPS): <1%, combined positive score (CPS): <1], microsatellite stability (MSS), and high tumor mutational burden (TMB-H, 11.69 mut/Mb).
Table 1
| Gene | Transcript | Genome | Mutation protein | Nucleotide variation | NGS-DNA panel | MRD | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Biopsy tissue (2022-11-22) | Surgical tissue (2023-02-10) | Paraffin section (2023-02-10) | Blood first (2023-03-02) | Blood second (2023-05-09) | Blood third (2023-08-07) | Blood fourth (2024-03-02) | ||||||
| AKT2 | NM_001626 | chr19:g.40741933G>A | p.R347C | c.1039C>T | 38.51% | 21.16% | 21.16% | 0.03% | – | – | 3.38% | |
| ALOX12B | NM_001139 | chr17:g.7984154C>G | – | c.527+48G>C | – | – | 20.30% | – | – | – | 3.15% | |
| AXIN1 | NM_003502 | chr16:g.396684C>A | p.L114F | c.342G>T | 42.18% | 21.27% | 21.27% | – | – | – | 3.93% | |
| EPHA5 | NM_004439 | chr4:g.66197291A>G | – | c.3008+400T>C | – | – | 17.43% | – | – | 0.03% | 2.55% | |
| GRIN2A | NM_001134407 | chr16:g.9943631C>T | p.R437Q | c.1310G>A | 42.33% | 20.57% | 20.57% | – | – | – | 4.17% | |
| GRIN2A | NM_001134407 | chr16:g.9857026T>A | p.S1459C | c.4375A>T | 39.54% | 17.64% | 17.64% | – | – | 0.03% | 2.73% | |
| GRIN2A | NM_001134407 | chr16:g.9857150C>T | p.R1417R | c.4251G>A | – | – | 23.81% | – | – | – | 3.23% | |
| HMCN1 | NM_031935 | chr1:g.186086779A>G | – | c.11848+24A>G | – | – | 16.09% | – | – | – | 3.24% | |
| HMCN1 | NM_031935 | chr1:g.186114887G>A | p.D4814N | c.14440G>A | 37.83% | 18.32% | 18.32% | – | – | – | 3.13% | |
| INPP4A | NM_001134224 | chr2:g.99181238G>C | – | c.2167+12G>C | – | – | 19.03% | – | – | – | 2.35% | |
| JAK2 | NM_004972 | chr9:g.5072522A>G | p.K558F | c.1672A>C | 36.79% | 15.51% | 15.51% | – | – | – | 2.90% | |
| KDR | NM_002253 | chr4:g.55968162G>T | p.T723N | c.2168C>A | 46.82% | 18.54% | 18.54% | – | – | – | 1.96% | |
| KDR | NM_002253 | chr4:g.55970871G>T | p.C642* | c.1926C>A | 43.10% | 20.80% | 20.80% | – | – | – | 1.85% | |
| PDCD1LG2 | NM_025239 | chr9:g.5534756G>C | p.V23L | c.67G>C | 38.59% | 14.40% | 14.40% | – | – | – | 4.36% | |
| POLE | NM_006231 | chr12:g.133238073C>T | – | c.2864+40G>A | – | – | 22.07% | – | – | – | 2.42% | |
| PTEN | NM_000314 | chr10:g.89692851dupT | p.S113Kfs*2 | c.335dupT | 45.08% | – | 14.56% | 0.01% | – | – | 3.36% | |
| PTPRD | NM_002839 | chr9:g.8319933C>G | p.T1856T | c.5568G>C | – | – | 18.65% | – | – | – | 3.78% | |
| PTPRT | NM_133170 | chr20:g.40864811C>G | – | c.2399+58G>C | – | – | 21.31% | – | – | – | 2.88% | |
| RET | NM_020975 | chr10:g.43597889A>G | p.Y146C | c.437A>G | 41.46% | 20.41% | 20.41% | – | – | – | 4.05% | |
| SLX4 | NM_032444 | chr16:g.3642906G>C | – | c.2161-40C>G | – | – | 18.35% | – | – | – | 3.60% | |
| TP53 | NM_000546 | chr17:g.7578300T>A | – | c.560-11A>T | – | – | 26.95% | 0.03% | – | – | 3.02% | |
| TP53 | NM_000546 | chr17:g.7578536T>C | p.K132E | c.394A>G | 71.21% | 25.04% | 25.04% | – | – | 0.02% | 3.95% | |
| TRAF7 | NM_032271 | chr16:g.2226430G>A | – | c.1998+45G>A | – | – | 19.46% | – | – | – | 3.19% | |
This includes the name of the mutated gene, transcript information, reference genome location, protein changes, nucleotide variation, and mutation frequency. The mutation frequencies were determined by DNA panel testing of paraffin sections of surgical tissue, as well as the results of the first MRD (2023-03-02), second MRD (2023-05-09), third MRD (2023-08-07), and fourth MRD (2024-03-02). ctDNA, circulating tumor DNA; MRD, molecular residual disease; NGS, next-generation sequencing.
MRD assessments in this case were performed at key clinical decision-making time points, including postoperative evaluation, completion of adjuvant chemotherapy, and follow-up disease reassessment. These time points were determined according to routine clinical practice and physician discretion rather than a predefined MRD surveillance protocol.
From November 2022 to January 2023, the patient received 3 cycles of neoadjuvant chemotherapy with an etoposide 120 mg + cisplatin 50 mg (EP) regimen. Although the second cycle of chemotherapy was stopped due to fever, overall, the treatment went smoothly. After the end of three cycles of neoadjuvant chemotherapy, the patient was evaluated as having a complete response according to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1, and no brain metastasis was found in the preoperative imaging examination. On February 10, 2023, the patient underwent single-port complete thoracoscopic right middle and lower lobectomy, systematic lymph node dissection, and chest tube implantation. Postoperative pathology revealed an SCLC tumor measuring 0.6 cm × 0.4 cm × 0.4 cm, and the pathological stage was pT1N1M0IIB, i.e., LS-SCLC (Figure 1). The NGS-DNA panel of 769 genes revealed low expression levels of PD-L1 (TPS: <1%, CPS: <1), MSS, and high TMB-H (10.71 mut/Mb) in the surgical samples (Table 1). Because the MRD detection result was positive (0.17 hGE/mL) after surgery (March 2, 2023) (Figure 1, Table 1), adjuvant chemotherapy was chosen for the patient. After three cycles of adjuvant chemotherapy with the EP regimen, the second MRD test on May 9, 2023 was negative (Figure 1, Table 1).
However, brain metastases were discovered during a follow-up in June 2023. The patient subsequently underwent brain radiotherapy for 6–7 months, after which they disappeared. However, a third MRD test on August 7, 2023 was positive (0.19 hGE/mL) (Figure 1, Table 1).
From September 2023 to April 22, 2024, the patient received adjuvant chemotherapy and radiotherapy combined with immune consolidation therapy (irinotecan combined with serplulimab). On March 2, 2024, the patient underwent a fourth MRD test, and the result was still positive (183.75 hGE/mL) (Figure 1, Table 1). The dynamic changes in ctDNA mutation frequency during the treatment of the patient are shown in Figure 2. The mutation frequency of each gene increased sharply at the time of the fourth MRD detection. The last efficacy evaluation revealed that the patient had stable disease in the lung, but the patient had progressive disease in the brain and extensive metastasis in the liver (Figure 1).
Discussion
SCLC is highly invasive and has a high recurrence rate. Traditional imaging methods, such as CT and MRI, have limitations in monitoring disease progression. With the development of molecular pathology in tumor research, liquid biopsy has become a new trend in clinical tumor detection due to its advantages of being non-invasive, convenient sampling, and overcoming tumor heterogeneity, and has been widely applied (11,12). We summarized the current studies on the SCLC and ctDNA (Table 2). These studies have used a wide range of technologies [such as ctDNA detection, cell-free DNA (cfDNA) sequencing, and polymerase chain reaction (PCR)] and methods (such as tumor-naïve and tumor-informed methods) to detect and analyse tumors in different stages of SCLC. Some studies [e.g., PMC10261918 (9) and PMC8720633 (13)] have shown that compared with traditional imaging, ctDNA-based methods can be used to identify disease progression and recurrence earlier, possibly improving the opportunities for early intervention. Other studies [e.g., PMC8474488 (14) and PMC6079068 (15)] have shown that low ctDNA levels are significantly associated with longer progression-free survival (PFS) and OS in patients. In 2020, Sumitra Mohan noted that genome-wide and targeted cfDNA sequencing data can reveal tumor-associated changes in 94% of LS-SCLC patients and 100% of extensive-stage SCLC patients. Subgroup analysis revealed that the cfDNA copy-number alteration (CNA) method was effective in monitoring disease progression and treatment response in SCLC patients (16). Iams et al. reported that after radical treatment, the median OS (18.2 vs. over 48 months, P=0.081) and PFS (9.1 vs. over 48 months) of patients with or without detectable ctDNA (P<0.001) were significantly different (14). The IFCT-1603 trial evaluated the efficacy of atezolizumab in SCLC and confirmed that, regardless of the treatment, the disease control rate at week 6 in patients with detectable ctDNA was significantly lower than that in patients without detectable ctDNA and was related with OS. These findings further confirm that ctDNA could be used to predict the efficacy of second-line immunotherapy (17). However, many current studies have limitations, i.e., the sample size is small, the studies mainly focus on extensive-stage SCLC, or the proportions of LS-SCLC and extensive-stage SCLC are unbalanced, and most are observational studies. In future studies, prospective, larger-sample LS-SCLC studies should be considered to increase the reliability and applicability of the results.
Table 2
| PMID/PMCID | SCLC stage | Number | Technology | Method | Gene | Results |
|---|---|---|---|---|---|---|
| PMC10261918 (9) | Metastasis | 33 | Tumor-naive | TEC-seq | 58 | Patients with sustained molecular responses: longer OS (log-rank P=0.0006); longer PFS (log-rank P<0.0001) |
| Molecular responses detected 4 weeks earlier than imaging | ||||||
| PMC8720633 (13) | Limited-stage: 1 | 5 | Tumor-naive | QIAseq Targeted DNA Panels (12)-Human Lung Cancer Panel | 72 | Three patients (60%) had a decrease in dVAF, and the tumor volume also decreased accordingly |
| Extensive-stage: 4 | Longitudinal ctDNA analysis reveals resurgence of disease earlier than radiography | |||||
| PMC8474488 (14) | Surgical limited-stage: 2 | 23 | Tumor-naive | – | 14 | Using plasma based ctDNA detection method to sequence 14 common mutant genes |
| Chemoradiotherapy: 21 | Median OS: detect ctDNA vs. no ctDNA =18.2 vs. over 48 months (P=0.081) | |||||
| Median PFS: detect ctDNA vs. no ctDNA =9.1 vs. over 48 months (P<0.001) | ||||||
| PMC6079068 (15) | Limited-stage (n=7 or 8, 1/3) | 22 | Tumor-naive | SeqCap EZ Library (Roche NimbleGen) | 430 | High ctDNA (ctDNA >0.18): mOS =9.3 months, mPFS =5.3 months |
| Extensive-stage (n=15, 2/3) | Low ctDNA (ctDNA ≤0.18): mOS =25.0 months, mPFS =10.0 months | |||||
| Correlation: PFS, HR =8.4 (P=0.008); OS, HR =4.7 (P=0.021) | ||||||
| PMC7001105 (16) | Limited-stage: 39 | 69 | Tumor-naive | Agilent SureSelectXT | 110 | Genome-wide and targeted cfDNA sequencing data identified tumor-related changes: LS-SCLC (94%), extensive-stage SCLC (100%) |
| Extensive-stage: 30 | CTCs based on at least 1 CTC/7.5 mL of blood increased detection frequencies to 95% | |||||
| PMC7760916 (17) | Metastasis | 68 | Tumor-naive | QIAseq Targeted DNA Custom Panel | 5 | IFCT-1603 trial |
| Median PFS: atezolizumab =1.4 months (95% CI: 1.2–1.5) vs. chemotherapy =4.3 months (95% CI: 1.5–5.9); adjusted HR atezolizumab arm =2.26 (95% CI: 1.30–3.93), P=0.004 | ||||||
| Median OS: atezolizumab =9.5 months (95% CI: 3.2–14.4) vs. chemotherapy =8.7 months (95% CI: 4.1–12.7); adjusted HR atezolizumab arm =0.84 (95% CI: 0.45–1.58), P=0.60 | ||||||
| Week 6 DCR: detectable mutation vs. no detectable mutation =29.5% vs. 58.8%(P=0.030); detection mutation had poor prognosis in OS [HR mutation detected =2.63 (95% CI: 1.14–6.08), P=0.0238] | ||||||
| OS: detectable mutation vs. no detectable mutation =7.6 vs. 13.3 months [HR mutation detected =2.63 (95% CI: 1.14–6.08), P=0.0238] | ||||||
| PMID36758321(18) | Extensive-stage | 69 | Tumor-naive | MuTect2 | 425 | Overall detection rate: individual tissue testing vs. ctDNA and tissue combined testing =19.4% vs. 26.9% |
| PMC10938094 (19) | Limited-stage | 50 | Tumor-naive | AlphaLiquid 100 | 106 | RFS: TP53 mutation vs. wild-type TP53 =11.2 months vs. not reached (P=0.05); RB1 mutation vs. wild-type RB1 =8.9 months vs. not reached (P=0.0014); ctDNA-based high risk vs. ctDNA-based low risk =7.55 months vs. not reached (P=0.002) |
| PMC9296939 (20) | Limited-stage (n=24, 68.6%) | 35 | Tumor-informed | – | 1021 | Perform tumor and longitudinal plasma ctDNA sample analysis on 1,021 genes. PyClone was used to infer the mTBI |
| Extensive-stage (n=11, 31.4%) | mPFS: subtype I =4.5 months (95% CI: 2.6–5.8); subtype II = not reached (P<0.001); subtype III =10.8 months (95% CI: 6.0–14.4, P=0.002) | |||||
| mOS: subtype I =16.3 months (95% CI: 5.3–22.9); subtype II =not reached (P=0.01); subtype III = not reached (P=0.02) | ||||||
| PMC5827950 (21) | Limited-stage: 11 | 27 | Tumor-naive | – | 14 | 85% patients were detected disease-associated mutations (frequency 0.1–87%). Most common mutations: TP53 (70%), RB1 (52%), PTEN, NOTCH1 and NOTCH2 |
| Extensive-stage: 16 | Increased cfDNA GEs was associated with worse OS | |||||
| Univariate analysis (HR =2.65, 95% CI: 1.41–4.98, P=0.0024) | ||||||
| Multivariate analysis (HR =2.73, 95% CI: 1.27–5.86, P=0.0099) | ||||||
| PMC4326280 (22) | IV stage | 3 | Tumor-naive | PCR | 1 (mSHOX2) | The mSHOX2 level has a high ability to distinguish between patients with and without response (AUC =0.844) |
| Strong relationship between survival and plasma mSHOX2 value (P≤0.001, HR =11.08) |
AUC, area under the curve; cfDNA, cell-free DNA; CI, confidence interval; CTC, circulating tumor cell; ctDNA, circulating tumor DNA; DCR, disease control rate; dVAF, delta variant allele frequency; GEs, genome equivalents; HR, hazard ratio; LS-SCLC, limited-stage small cell lung cancer; mOS, median overall survival; mPFS, median progression-free survival; mSHOX2, methylated SHOX2; mTBI, molecular tumor burden index; NOTCH1, notch homolog 1; NOTCH2, notch homolog 2; OS, overall survival; PCR, polymerase chain reaction; PFS, progression-free survival; PMID, PubMed Identifier; PMCID, PubMed Central Identifier; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; RFS, relapse-free survival; SCLC, small cell lung cancer; TEC-seq, targeted error-corrected sequencing; TP53, tumor protein p53.
Currently, several multifaceted clinical studies on the treatment of SCLC are registered with ClinicalTrials.gov (Table 3). These clinical trials cover a variety of treatment modalities, including observational studies on combined drug therapy, preventive brain radiation, and the application of PD-1 inhibitors. Several trials have focused on dynamic changes in ctDNA and its role in the assessment of treatment effects and outcomes (such as NCT05066945, NCT04562337, NCT06287775, and NCT03382561), and researchers are actively searching for molecular markers that can predict efficacy and toxicity to personalize treatments and improve success rates. However, almost all current clinical studies involve extensive-stage SCLC, and the sample sizes of some trials (such as NCT03971214 and NCT05066945) are small. The results of prospective, interventional studies with large cohorts are needed to guide the clinical treatment of LS-SCLC.
Table 3
| NCT number | Treatment | Number | Cancer | Abstract | Aims |
|---|---|---|---|---|---|
| NCT05066945 | Observational | 40 | Extensive-stage SCLC | The purpose of this study is to evaluate the application value of ctDNA with efficacy evaluation and prognostic assessment in patients with unresectable SCLC, who were receiving radiotherapy and chemotherapy treatment | (I) According to each point in time of ctDNA, to analyze the dynamic changes of tumor burden and clonal subtypes which to evaluate the application value of ctDNA in curative efficacy evaluation |
| (II) Compare the two time points before and after radiotherapy and chemotherapy treatment of the cfDNA concentration and tumor burden, analysis the correlation between the changes and prognosis | |||||
| NCT04562337 | SHR1316 | 67 | Extensive-stage SCLC | This study is a one arm, open, single center phase II study. The main purpose of this study was to evaluate the tolerance and preliminary efficacy of SHR1316 combined with chest radiotherapy after induction therapy | Changes in ctDNA status in the blood before and after treatment |
| NCT04947774 | Prophylactic cranial irradiation | 100 | Extensive-stage SCLC | The prospective trial included patients with ES-SCLC who responded to standard first-line treatment, with the aim of exploring the safety and efficacy of prophylactic brain irradiation in this treatment approach | Exploring the molecular biomarkers for efficacy and toxicity predicting from tumor tissue and peripheral blood TMB |
| NCT03971214 | PD-1 inhibitor JS-001 | 6 | Extensive-stage SCLC | This study aims to explore comprehensive treatments with low toxicity to further improve the efficacy for these patients with PD-1 inhibitor | Exploring the correlation of PD-1 expression on the tumor tissue, and the TMB, immune repertoire sequencing derived from the tumor tissue and the blood sample with the efficacy of treatment |
| NCT06287775 | Atezolizumab | 45 | Extensive-stage SCLC | This phase I/II trial tests the safety, side effects, and best dose of iadademstat when given together with atezolizumab or durvalumab, and studies the effect of the combination in treating patients with small cell lung cancer that has spread outside of the lung in which it began or to other parts of the body (extensive stage) who initially received standard of care chemotherapy and immunotherapy | To assess whether detection of ctDNA minimal residual disease correlates with disease progression |
| NCT03382561 | Nivolumab + carboplatin | 160 | Extensive-stage SCLC | This randomized phase II clinical trial studies whether the addition of nivolumab to cisplatin (or carboplatin) and etoposide will improve outcomes when treating patients with extensive stage small cell lung cancer | Association between ctDNA and clinical outcome. Circulating tumor DNA was assessed at baseline and 6 weeks |
cfDNA, cell-free DNA; ctDNA, circulating tumor DNA; ES-SCLC, extensive-stage small cell lung cancer; NCT, National Clinical Trial; PD-1, programmed cell death protein 1; SCLC, small cell lung cancer; TMB, tumor mutational burden.
In this study, the patient received comprehensive treatment, including neoadjuvant chemotherapy, surgery, and adjuvant radiotherapy combined with immunotherapy, and MRD detection was performed at key treatment points (such as after surgery and after adjuvant chemotherapy) to provide references for treatment decision-making. The patient’s MRD test was positive after surgery, suggesting the possibility of residual molecular lesions and prompting the continuation of adjuvant chemotherapy. The MRD test subsequently became negative, indicating that the adjuvant therapy was effective. However, 1 month later, the patient developed brain metastases, and the MRD test was positive again. Several factors may explain why MRD monitoring did not anticipate the development of brain metastases. (I) Biological factors: the CNS represents a sanctuary site due to the blood-brain barrier, which may limit ctDNA shedding into peripheral circulation. (II) Technical and logistical factors: the sensitivity of current assays, sampling intervals, and tumor heterogeneity may reduce detection capability. Importantly, MRD negativity should not be interpreted as excluding occult CNS disease. A key concept in MRD monitoring is ‘lead time’—the window where molecular relapse precedes radiological recurrence. In our case, the transition from MRD negativity in August 2023 to positivity in March 2024 synchronized with the imaging confirmation of brain metastases. However, the 7-month interval between these tests may have masked the true molecular lead time. More frequent monitoring, such as every 3 months, might have enabled earlier intervention before the onset of symptomatic brain lesions. The optimal MRD monitoring interval in SCLC remains unknown and should be investigated in future prospective studies rather than inferred from protocols used in other solid tumors. However, this observation should be considered hypothesis-generating rather than confirmatory, and no definitive conclusions regarding the predictive performance of MRD monitoring in LS-SCLC can be drawn from a single case. The LUNGCA-2 study suggested that the sensitivity of MRD detection was related to the site of recurrent metastasis; the highest sensitivity was achieved in detecting bone metastases (83.3%), while the lowest sensitivity was achieved in detecting brain metastases (0%) (23). In their proof-of-concept study, Wu et al. proposed that during drug holiday periods, the progression of brain metastases in NSCLC could not be monitored in advance by MRD detection but was instead discovered with traditional imaging methods (24). In another lung cancer MRD study by Wu et al., 13 patients experienced tumor recurrence despite having a longitudinal undetectable MRD status, and more than half of these patients (7/13, 53.8%) developed brain-only metastases (25). The inability of MRD monitoring to provide early detection of brain metastases may be explained by several biological and technical factors. The blood-brain barrier and blood-tumor barrier significantly limit the release of tumor-derived DNA fragments from intracranial lesions into the systemic circulation. Consequently, ctDNA originating from CNS metastases may remain confined to the cerebrospinal fluid compartment rather than entering peripheral blood at detectable levels. In addition, brain metastases often demonstrate lower ctDNA shedding compared with extracranial disease sites. These biological constraints contribute to reduced sensitivity of plasma-based MRD assays for CNS disease and explain the discordance observed between MRD status and intracranial progression in this case (25).
Prophylactic cranial irradiation (PCI) remains a standard strategy for reducing the incidence of brain metastases in patients with LS-SCLC who respond to initial therapy. In the present case, PCI was considered during multidisciplinary evaluation; however, it was not performed initially due to the absence of radiological evidence of intracranial disease and individualized risk-benefit considerations. The subsequent development of brain metastases underscores the persistent risk of CNS relapse in LS-SCLC. Importantly, MRD monitoring should not be interpreted as an alternative to PCI or routine brain imaging surveillance. Instead, MRD assessment may complement established CNS monitoring strategies by providing additional information regarding systemic disease activity (10,26).
Conclusions
MRD monitoring demonstrated clinical value in assessing systemic disease status and treatment response in this patient with LS-SCLC. However, its failure to anticipate brain metastases highlights important site-dependent limitations. Due to biological constraints such as restricted ctDNA release from intracranial lesions, MRD monitoring currently lacks sufficient sensitivity for CNS surveillance. Therefore, MRD should be considered a complementary modality for systemic disease monitoring rather than a generalized early-warning tool for all recurrence patterns in LS-SCLC. Future studies should focus on improving the ability of MRD to detect SCLC brain metastases and explore more accurate individualized treatment strategies to improve patient outcomes. At present, studies employing MRD detection for SCLC, especially LS-SCLC, are scarce, and large prospective cohort studies are lacking. We look forward to high-quality cohort results to guide clinical practice in the future.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0003/rc
Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0003/prf
Funding: This study was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0003/coif). W.S. and L.Z. are employed by Genecast Biotechnology Co. Ltd. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Guizhou Provincial People’s Hospital [approval No. (2024)004]. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Sun Y, Hu C, Shao W, Zheng L, Long Q. The complete treatment and management of brain metastases in a patient with limited-stage small cell lung cancer under molecular residual disease (MRD) monitoring: a case report. AME Case Rep 2026;10:106.
