Science

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

What technologies are gathering the most attention in the field of antineoplastic therapy in 2022?

Other than that, in lung cancer, it is definitely the ctDNA-MRD technique.

Perhaps some may have a different opinion.

Why not open Checkmate 816 and Impower 010 for perioperative immunotherapy?

Why not open JCOG0802 for intentional segmental lung resection for early lung cancer?

Of course not, because these are techniques that are used clinically all the time.

The disclosure of these data above only allows us to have more confidence in the practical clinical application.

However, ctDNA-MRD is not.

This technology, in the past, was not available.

In the traditional era, we predicted prognosis for patients based on staging, assessed the effectiveness of treatment decisions for patients based on staging, and used 5 years without recurrence to set clinical cure criteria.

All assessments and decisions are made based on clinically assessable lesions.

Until the advent of ctDNA-MRD technology.

If anything, LUNGCA1 on 2021, which took us through the effectiveness of postoperative MRD testing in lung cancer, ignited the flame of ctDNA-MRD in the field of lung cancer.

It detects recurrent lesions that are invisible to PET/CT.

What is the value of ctDNA-MRD testing after surgery for early stage lung cancer?

Well, this recent study brought by the team of Prof. Yilong Wu of Guangdong Provincial People's Hospital is bound to burn this fire even brighter until it starts a prairie fire.

So what kind of research is this?

Without further ado, let's get right to the point.

Research Sharing

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

In May 2022, a prospective clinical study by Prof. Yilong Wu's team for ctDNA-MRD in lung cancer was put online.

In this study, the authors included 261 patients with non-small cell lung cancer with a maximum tumor diameter greater than 2 cm, stage I to III, and treated with complete surgery to assess the impact of ctDNA-MRD on prognosis, recurrence, and even adjuvant treatment decisions.

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

The ctDNA-MRD assay, was scheduled to be performed in 4 stages.

Phase I, one preoperative measurement.

Phase II, Landmark testing (landmark testing), scheduled within one month of the procedure.

If this patient will receive postoperative adjuvant therapy, an additional ctDNA-MRD test will be performed prior to postoperative adjuvant therapy.

The third stage, Longitudianl testing (long axis testing), which is entered after postoperative testing, every 3-6 months.

The fourth phase, Surveillance testing (follow-up testing), is the testing phase 6 months before relapse.

The study aims to answer the following four questions.

Q1 Is there a lung cancer cell that does not release ctDNA

In this issue, the authors performed an unconventional operation.

That is, 11 patients were selected and residual blood from resected lung tissue was drawn for ctDNA testing after the lung cancer surgical specimen was isolated.

Residual blood from lung tissue specimens was eventually found to fail to measure ctDNA in six patients.

These results suggest that there are differences in the ability to release ctDNA between lesions in the broader lung cancer population, and there may even be a subset of patients who do not release ctDNA.

It is also known as non-shedding tumor.

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

Q2 Accuracy of ctDNA-MRD for predicting distant recurrence

Statistically, there are two types of accuracy descriptions, one called positive predictive value and one called negative predictive value.

Let me explain briefly.

Positive predictive value (PPV), which is the accuracy of predicting positivity.

Negative predictive value (NPV), is the accuracy of predicting negativity.

PPV, say you can do it and you can do it, look at the accuracy of this.

NPV, say you can't you can't, look at the accuracy of this.

The study analyzed the predictive efficacy of both Landmark and Longitudinal test results (MRD negative or positive) for recurrence.

A positive MRD that eventually recurred, or a negative MRD that eventually did not recur, was considered accurate.

Ultimately, the landmark assay had a negative predictive accuracy of 86.6% and a positive predictive accuracy of 81.0%.

The negative predictive value accuracy of the long-axis test was 96.8% and the positive predictive accuracy was 89.1%.

On average, MRD positivity appeared 3.4 months earlier than the time of recurrence.

Survival analysis revealed that although both landmark and long-axis test results were good predictors of prognosis, the survival curves of the long-axis test-negative population were largely undiminished and largely consistent with the survival characteristics of the cured population.

Even in the relatively progressive stage III population, persistent MRD-negative patients have a low relapse rate and a survival curve that approximates a curative effect.

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seenRemaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

In further analysis, the authors tabulated the chance of recurrence at different time periods and plotted the trend of recurrence risk.

As shown in the figure below, the risk of recurrence gradually increases until 18 months after lung cancer surgery and then gradually decreases.

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

Q3 Missed diagnosis rate of recurrent events by ctDNA-MRD

The ctDNA-MRD technique is good, but it is not without the possibility of missing the diagnosis.

How much is that exactly?

The original text uses sensitivity as a description, but sensitivity is slightly obscure.

Therefore, in this post, I have translated it into a more understandable explanation of the underdiagnosis rate.

The analysis found that

A positive Landmark (landmark test) alone is a weak predictor of recurrence, with a high miss rate of 63.8% (false negative rate).

In contrast, a positive Longitudinal (long axis test) was a stronger predictor of recurrence, with a missed rate of only 12.8% (false negative rate).

However, ctDNA-MRD testing appears to have weaker diagnostic efficacy for brain metastases.

Five patients in the entire group developed brain metastases during the follow-up phase, while no metastatic lesions were seen in other extracranial lesions (i.e., intracranial metastases alone), and only one test was found to be positive for MRD.

Q4 Correlation between ctDNA-MRD and adjuvant therapy efficacy

Of the entire group, 55 patients received postoperative adjuvant therapy.

Twenty-three received postoperative chemotherapy, 26 received postoperative targeted therapy, and 6 received postoperative immunotherapy.

For this group of patients, in addition to testing ctDNA-MRD within 1 month after surgery, ctDNA-MRD will be retested once before adjuvant therapy, and a positive Landmark test will be determined with one of the two positive tests.

Ultimately, adjuvant therapy exhibits a completely different treatment response for different results of the Landmark (landmark test).

First, in the landmark test-positive group, adjuvant therapy can reduce the risk of recurrence by about 66%, which is very effective.

And in the landmark test-negative group, adjuvant therapy actually led to a 2.29-fold increased risk of recurrence, which is alarming.

Even after paired balancing for the landmark test negative group, adjuvant therapy did not result in any survival benefit and still resulted in a 1.59-fold increased risk of recurrence.

However, the increased risk of recurrence due to adjuvant therapy after clinical paired balancing did not reach statistical significance, P=0.482.

Therefore, with caution, it can be interpreted that the MRD-negative population, given adjuvant therapy does not provide any survival benefit.

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seenRemaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

Moreover, the ctDNA-MRD shift after adjuvant therapy is also closely related to the long-term outcome.

Best results in patients with sustained MRD conversion after adjuvant therapy.

intermediate effect in patients with late post-positive transitions of MRD transient transitions.

Patients with persistently positive MRD had the worst outcome.

Write at the end

Remaining tumor cells in your body after surgery? With this technology, they're nowhere to be seen

When Dr. Zheng was in high school, he was very fascinated by a game called Starcraft.

I really like the human race in it, but hate the insect race.

On the one hand, insects are very capable of reproducing, and a little seed left behind can quickly multiply.

On the other hand, the insects with high reproduction ability are not weak in attacking.

How many people have experienced this desperation with the puppy fast attack.

In that era when the single player was prevalent, whenever I encountered insects, I always did not hesitate to enter Mintu's cheat command into the computer.

Let every insect relic lurking in the corners of the map has nothing to hide, completely eliminate to eliminate the future.

After I started working, I often felt powerless in the face of lung cancer.

Obviously the lung cancer was very early, obviously the surgery was clean and the lymph nodes were completely cleared, but why did a new tumor grow back not long after.

I was just thinking that it would be nice if I could input a Mintu cheat command to the lung cancer cells in the human body as well.

This makes it easy to find those missed obscenely developing lung cancer cells, and also allows those who are truly fine to start a whole new life again without having to worry about it all day.

The idea was wonderful, but the reality was harsh until the advent of ctDNA-MRD technology.

In theory, ctDNA is released by the tumor and can serve as a perfect tracer for the tumor.

It allows us to completely transcend visual limitations, identify and detect residual lung cancer lesions in the body in advance before they have fully developed, and achieve accurate assessment of tumor control status.

If there is a problem, a positive MRD will tell you so that treatment can be intervened on in advance.

No problem, MRD negative will also be conveyed, so you can not have to worry about the whole day.

It's good to think about it.

Of course, the new technology that even I know is good, the national lung cancer bigwigs naturally know it too.

So, at the end of 2011, Prof. Lunxu Liu from the renowned academic institution Huaxi Medical College brought the LUNGCA1 study.

For the first time, the effectiveness of MRD technology in predicting the prognosis of lung cancer and the efficacy of adjuvant therapy was confirmed based on data from a prospective clinical study.

Less than six months later, Professor Yilong Wu's team at Guangdong Provincial People's Hospital, a top expert in lung cancer in China, also reaffirmed the effectiveness of MRD based on a large-scale clinical study.

Compared to the short-term postoperative MRD results of LUNGCA1, Prof. Yilong Wu further deepened the data analysis of MRD to complement the validity of MRD technique in follow-up and found a series of interesting and meaningful important phenomena.

First, short-term postoperative MRD testing does have an important predictive role for adjuvant treatment efficacy.

In this study, they included 261 patients in stages I-III, of which 55 were adjuvant, encompassing adjuvant chemotherapy, adjuvant targeted therapy and adjuvant immunotherapy.

Ultimately, the efficacy of adjuvant therapy was nevertheless observed only in MRD-positive patients.

In the MRD-negative population, adjuvant therapy is imposed without any survival benefit and may even increase the risk of recurrence in vain.

Here, Dr. Cheng was actually curious about the results of the subgroup analysis of adjuvant targeted therapy.

Because it is accepted that targeted therapy has lower side effects, does the imposition of adjuvant targeting for MRD-negative populations pose a higher risk of relapse?

Second, compared to short-term postoperative MRD testing, long-term follow-up with MRD is more beneficial in detecting recurrent lesions earlier, reducing the rate of missed diagnoses, and identifying the truly cured population.

In this study, a short-term postoperative MRD test alone would have missed approximately 63.8% of cases, whereas with long-term follow-up using MRD techniques, this missed rate would have been significantly reduced to 12.8%.

Moreover, those who do remain consistently MRD-negative at long-term follow-up have a low rate of distant recurrence of 3.2%, which is essentially close to cure status.

Even in the stage III high-risk population, long-term MRD-negative patients, recurrence events are rare.

Such data are sufficient to confirm the value and validity of MRD follow-up.

Third, as an emerging technology, MRD is currently expensive and causes many problems for ongoing follow-up testing.

On this basis, Prof. Yilong Wu's team further analyzed the correlation between postoperative MRD positive detection rate and time, and found that the risk of positive MRD detection gradually increased during the period from 1 to 19 months after surgery, and then steadily decreased.

This certainly offers an important alternative to the group of patients, who, because of their own financial situation, have a scientific follow-up of 19 months, which can detect the vast majority of recurrent lesions.

At the end of the study, Prof. Yilong Wu's team provided a general summary of the value of MRD technology in lung cancer.

noted that long-term follow-up of MRD after lung cancer surgery helps identify those patients who are truly clinically cured, and that 18 months of scientific follow-up is perhaps the most cost-effective option.

Therefore, after lung cancer surgery, what if you are worried that there are still residual tumor cells in your body?

Don't worry and don't be afraid. Besides sitting back and waiting for a recurrence, we can use MRD technology for long-term follow-up monitoring.

It is like prescribing a Minto cheat instruction to a residual lung cancer lesion in the body.

Let them have nothing to hide.