NCCN Guidelines for Colon Cancer: The MRD assessment based on ctDNA guidance

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NCCN Guidelines for Colon Cancer: The MRD assessment based on ctDNA guidance listed!

Although micro/molecular residual disease (MRD) assessment can effectively indicate the cure of colon cancer patients after receiving treatment, more reliable biomarkers are still needed. Recent studies have shown that ctDNA can “take this responsibility” and it can guide MRD Evaluation, has the potential to change the mode of colon cancer treatment! “

MRD, Minimal Residual Disease, refers to a small amount of cancer cells remaining in the body after cancer treatment (Measurable Residual Disease (MRD) can also be used to measure residual disease);
Molecular Residual Disease (MRD) can also be used in solid tumors, that is, molecular residual disease, which is based on ctDNA to judge the residual disease at the molecular level, and provides guidance information for prognosis and prediction.

Therefore, we can abbreviate the solid tumor MRD as ctDNA MRD (except for other markers). Don’t worry, the article published in “Nature Cancer” also calls it that way. 1

Early colon cancer (ESCC) is a curable malignant tumor, which is defined as a tumor confined to the intestine, with or without regional lymph node involvement. Current treatment strategies for ESCC patients include pre-surgical resection, followed by adjuvant chemotherapy for specific populations considered at risk of cancer recurrence. The purpose of adjuvant chemotherapy is to eradicate possible micrometastasis, or MRD, in order to achieve the purpose of cure. The decision of adjuvant chemotherapy is based on clinicopathological risk factors, which have been considered as surrogate indicators of MRD for decades.

At present, more and more data show that the choice of adjuvant chemotherapy for ESCC patients based on clinicopathological risk factors is flawed, leading to overtreatment and undertreatment of a large number of ESCC patients. For example, about 50% of stage III colon cancer patients can be cured by surgery alone, although current guidelines advocate that all resected stage III colon cancer patients should receive adjuvant chemotherapy.

In addition, only one-fifth of patients with stage III colon cancer have been found to benefit from adjuvant chemotherapy. 2, 3 These data emphasize the need to find a reliable biomarker for MRD assessment. Recent studies have shown that ctDNA can “take this responsibility”, and ctDNA-guided MRD (ctDNA MRD) assessment can prompt the cure of colon cancer patients after treatment. Happening.

On January 21, 2021, the NCCN 2021.V2 version of colon cancer guidelines was released, and “ctDNA” was added to the discussion section of “Resectable Colon Cancer Adjuvant Chemotherapy”, stating that some detection methods have been developed and hope to provide prognosis And predictive information to help decide adjuvant treatment for patients with stage II and stage III colon cancer (note the wording of the NCCN expert group here: I hope to provide…to help determine…, that is to say, there are still difficulties ). In addition, postoperative ctDNA is also considered to be a marker of increased risk of recurrence of stage I-III colon cancer. 4

▲ The ctDNA part of the NCCN 2021.V2 guidelines for colon cancer

ctDNA MRD

The latest data show that ctDNA can be used as a reliable biomarker for MRD in ESCC patients. The content of ctDNA released into the peripheral blood in the early stage of solid tumors is generally very small, less than 1%, but there are several techniques for detecting plasma ctDNA. 5 At present, ctDNA analysis used for MRD evaluation of colorectal cancer (CRC) can be roughly divided into the following two categories:

⑴ tumor-informed assays (tumor information analysis), the primary tumor is sequenced to identify the patient’s specific genomic mutations, and then primers are designed for ctDNA detection, such as SignateraTM products (Natera); 6

*In addition, there is a safe-sequencing system (Safe-SeqS, safe sequencing system) method, when testing, add UID (UMI) for testing to further improve sensitivity and accuracy. 7

▲ Signatera’s MRD workflow

⑵ tumor-agnostic assays (analysis independent of tumor type), relying on a set of pre-selected primers, designed to detect known genomic variation (ctDNA mutation) and epigenetic characteristics (ctDNA methylation) associated with CRC , Such as LUNAR-1 product (Guardant Health). 8

▲ MRD detection method of LUNAR-1

It should be noted that these detection platforms use different methods and their analytical sensitivity is different. Therefore, the lack of standardization among these testing platforms also limits the interpretation of reported data. Future research should focus on the standardization of ctDNA testing procedures to make full use of the technical potential of ctDNA!

Clinical data support

Let’s look at the clinical evidence of ctDNA MRD introduced in the NCCN 2021.V2 version of the guidelines for colon cancer: 4

▲ The ctDNA part of the NCCN 2021.V2 guidelines for colon cancer

⑴ A multi-center prospective study of 130 patients with stage I-III colon cancer showed that the NGS technology based on multiple PCR capture [Signatera] detected the changes of ctDNA after surgery. 30 days after the operation, patients with positive ctDNA test were compared with Compared with patients with negative ctDNA test, the probability of recurrence is 7 times higher! (HR=7.2); Similarly, after adjuvant chemotherapy, patients with a positive ctDNA test are 17 times more likely to relapse! (HR=17.5); 6

⑵ Another prospective study conducted postoperative ddPCR detection of ctDNA in 150 patients with local colon cancer [29-gene NGS panel detection followed by ddPCR personalized detection of 2 ctDNA mutations, MRD sensitivity is better than a single ctDNA mutation], the results show , Patients with positive ctDNA test are associated with poor DFS (ctDNA positive after surgery, HR=17.56; ctDNA positive during follow-up, HR=11.33); 9

⑶ Other studies have also reported similar results. 10

These findings further support the practicality of ctDNA-guided MRD for the prognosis and prediction of postoperative colon cancer patients.

Obstacles to overcome

Although there are preliminary convincing data, there are still some difficulties in helping patients choose adjuvant therapy based on ctDNA-guided MRD assessment. In this regard, the NCCN Guidelines Expert Group and ESMO also think so. 4

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▲ The ctDNA part of the NCCN 2021.V2 guidelines for colon cancer

A large number of clinical trials are currently underway to verify the role of ctDNA-guided MRD assessment in helping patients choose adjuvant chemotherapy by solving the following problems:

1. Can patients who have a negative ctDNA test after surgery save adjuvant chemotherapy (or degrade treatment)?

2. Do patients who have a positive ctDNA test after surgery need to be upgraded?

3. Can the removal of ctDNA with adjuvant chemotherapy be cured? Is ctDNA a predictive biomarker of treatment effect?

4. For patients whose ctDNA can still be detected after adjuvant chemotherapy, what is the best treatment strategy?

For now, the sensitivity of a single postoperative ctDNA detection is less than 50%. Therefore, treatment degradation based on negative ctDNA results is still within the scope of clinical trials (NCT04068103, NCT03748680). In addition, there are also some trials that are investigating treatment upgrade strategies for ctDNA-positive patients, such as DYNAMIC-III.

So far, published data indicate that ctDNA is a reliable prognostic biomarker, but there is a lack of data supporting ctDNA as a predictive biomarker. However, some prospective cohort studies describe some patients whose ctDNA positive turns negative after adjuvant chemotherapy. These patients have obtained long-term DFS, which provides preliminary evidence to support the predictive ability of ctDNA testing. 10,11

The future of ctDNA technology

The main prospect of ctDNA technology lies in its potential to reliably detect MRD after the resection of the primary tumor, so as to provide accurate selection guidance for patients undergoing adjuvant chemotherapy!

Once ctDNA technology is developed to be able to achieve all of this, several important goals will be achieved:

First of all, for patients whose ctDNA cannot be detected after surgery, they can temporarily not receive adjuvant chemotherapy; patients with ctDNA detected should receive adjuvant chemotherapy according to current guidelines;

Secondly, if the clearance of ctDNA in adjuvant chemotherapy is highly correlated with survival and cure, the clearance of ctDNA can be used as the end point of the adjuvant test, which will promote the timely evaluation of new adjuvant therapies;

Finally, after adjuvant treatment is completed, before the recurrence of cancer is not detected on imaging, new therapies can be tried for people who can still detect ctDNA, which will increase the possibility of long-term survival. Based on these findings, theories and ongoing research, ctDNA technology has the potential to change the mode of colorectal cancer treatment!