July 25, 2024

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Is MRD detection necessary for lung cancer patients?

Is MRD detection necessary for lung cancer patients?



 

Is MRD detection necessary for lung cancer patients?

MRD (Minimal Residual Disease), also known as minimal residual lesions, refers to a small number of cancer cells (cells that are unresponsive to treatment or resistant to therapy) that remain in the body after cancer treatment.

 

MRD can serve as a biological marker. A positive result indicates that residual lesions are still detectable after cancer treatment. The presence of these cells can become active and start reproducing, leading to disease relapse. A negative result, on the other hand, means that no residual lesions are detected.

 

As we know, MRD detection plays a crucial role in identifying high-risk early-stage non-small cell lung cancer (NSCLC) patients for recurrence and guiding adjuvant therapy after curative surgery.

Back in the 18th Chinese Lung Cancer Summit in 2021, the country achieved its first “Consensus on the Detection and Clinical Application of MRD in Lung Cancer.” This consensus provided definitions for MRD and outlined the basic technical requirements for MRD detection. It also discussed its applications:

 

For Surgically Treatable Early-Stage Lung Cancer:


1. After curative resection of early-stage NSCLC, a positive MRD suggests a high risk of recurrence, necessitating close follow-up. MRD monitoring is recommended every 3 to 6 months.

2. Clinical trials based on MRD are recommended for perioperative treatment of surgically treatable NSCLC, aiming to provide precise treatment strategies.

3. The role of MRD should be explored separately in patients with positive and negative driver gene mutations.

 

For Locally Advanced NSCLC:

1. For patients with complete remission after radical radiotherapy for locally advanced NSCLC, MRD detection is recommended to assess prognosis and plan further treatment strategies.

2. Clinical trials based on MRD-guided consolidation therapy after chemoradiotherapy are suggested to provide accurate consolidation treatment plans.

 

For Advanced NSCLC:

1. There is a lack of relevant research on MRD in advanced NSCLC.

2. For patients achieving complete remission after systemic treatment, MRD detection is recommended to assess prognosis and guide further treatment strategies.

3. Research on MRD-guided treatment strategies should be conducted for patients in complete remission to maximize the benefits.

 

It is evident that due to the lack of research on MRD detection in advanced NSCLC, the application of MRD detection in the treatment of patients with advanced NSCLC has not been clearly defined.

 

In recent years, the advancements in targeted and immunotherapy have completely transformed the treatment landscape for late-stage NSCLC patients.

New evidence indicates that some patients achieve long-term survival and even complete remission as detected through imaging studies. Therefore, as a considerable portion of late-stage NSCLC patients gradually achieve the goal of long-term survival, monitoring disease recurrence becomes a significant clinical challenge. The potential role of MRD detection in this context also merits further exploration through clinical trials.

 


MRD Detection in Late-Stage NSCLC: Targeted Population

 

1. Late-stage lung cancer patients with complete remission observed through imaging studies

After targeted therapy or immunotherapy, the rates of complete remission (CR) among late-stage NSCLC patients range from 1% to 7%, as shown in Table 1.

 

Is MRD detection necessary for lung cancer patients?

 

 

Despite the achievement of CR through systemic therapy, clinical challenges persist:

a. How to monitor recurrence in patients achieving complete remission through imaging.
b. Monitoring resistance to targeted therapy remains challenging when no visible lesions are present on imaging.
c. The use and duration of immune checkpoint inhibitor therapy and the optimal timing for “drug holidays” remain uncertain.

 

While research on MRD in late-stage lung cancer patients achieving CR is still limited, MRD detection based on ctDNA has been widely proven to predict progression-free survival (PFS) in these patients following curative-intent treatment. ctDNA analysis may assist in individualized treatment decisions and relapse risk monitoring for CR patients.

 

 

2. Oligometastatic late-stage lung cancer patients

Oligometastatic disease (OMD) refers to a state where the number of metastatic sites is limited.

This concept was introduced by Hellman and Weichselbaum in 1995, describing an intermediate state between locally advanced and widely metastatic stages.

 

The precise definition of OMD in terms of the number of involved lesions and sites remains debated.

Most retrospective studies define OMD based on synchronous metastasis within 6 months of diagnosis or up to 3 brain metastases, while some define it as ≤5 metastatic lesions.

The European Organisation for Research and Treatment of Cancer (EORTC) consensus defines OMD as ≤3 organs with ≤5 metastatic lesions. The Canadian consensus defines OMD as 3-5 or fewer metastatic lesions and no more than 6 extracranial lesions.

 

The concept of OMD points to a distinct patient population.

Existing studies provide evidence that combining local radical treatment (RLT) and systemic therapy for OMD patients is safe and can extend survival.

This offers new hope for treating OMD lung cancer patients but also presents significant challenges.

The sequence of systemic and local treatments remains debated. Currently, there is no predictive marker to help determine which OMD patients can benefit from postoperative adjuvant therapy.

MRD detection can provide information as part of a more personalized clinical decision-making process, aiding in improving patient quality of life. For patients with detectable MRD, systemic treatment after RLT can be considered. For those without detectable MRD, continuous monitoring of MRD could ease the treatment burden, enabling patients to enjoy “drug holidays.”

 

 

3. Lesions that cannot be assessed through imaging

a. Distinguishing severe disease from treatment-induced inflammation or fibrotic changes, especially after radiation therapy and immunotherapy.

b. Pseudo-progression might occur after immunotherapy, with a rate of approximately 3%-5% in NSCLC. In these cases, ctDNA levels decrease or remain stable, whereas true disease progression results in increased ctDNA levels (sensitivity of 90%-100%).
c. PET-CT might show no metabolic activity after treatment despite stable lesions. In such cases, the lesions might be inactive despite being visible on imaging.

 

 


Challenges and Future Prospects

 

1. Lack of prospective trials to validate the prognostic value of MRD detection in late-stage NSCLC.

2. Limitations in MRD detection techniques, lacking standardized platforms, necessitating improved sensitivity and specificity.

3. Despite the imperfect definitions of MRD in solid tumors and uncertainty around ctDNA detection standards, MRD holds potential as a feasible scientific hypothesis for guiding systemic therapy in locally advanced or advanced lung cancer, as depicted in Figure 1.

 

Is MRD detection necessary for lung cancer patients?

 

For patients who cannot undergo surgery but achieve CR through treatment (chemoradiotherapy, targeted therapy, and/or immunotherapy), MRD detection can help determine the need for maintenance therapy.

 

Following local treatment for OMD, MRD-guided adjuvant therapy can reduce the treatment burden for MRD-negative patients, allowing them to enjoy “drug holidays.”

 

Given the challenges posed by emerging treatments such as immunotherapy on traditional imaging evaluation, including gaps, fibrosis, scar formation, and pseudo-progression, MRD detection can also assist in determining prognosis and planning further treatment strategies.

 

 

 

References:

1. “Consensus on the Detection and Clinical Application of MRD in Lung Cancer”

2. Coexisting opportunities and challenges: In which scenarios can minimal/measurable residual disease play a role in advanced non-small cell lung cancer?

Is MRD detection necessary for lung cancer patients?

(source:internet, reference only)


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