Circulating tumor DNA for therapy guidance

[jondunn]

Circulating tumor markers to reduce adjuvant therapies

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[jondunn]

 

[RickyScott]

Even if the first attempt failed, this approach will just improve over time. Luckily for me, would take 5-10 years to see first results in early stage breast cancer w/cooperative group trial.

 

[deleted941485]

Even if the first attempt failed, this approach will just improve over time. Luckily for me, would take 5-10 years to see first results in early stage breast cancer w/cooperative group trial.

Why would it be relevant for what is essentially a local disease?

So if I did Ct DNA on a skin cancer and it was negative should nothing be done?

 

[RickyScott]

Why would it be relevant for what is essentially a local disease?

So if I did Ct DNA on a skin cancer and it was negative should nothing be done?

If it is sensitive enough and there is microscopic residual disease- which is the reason for adding xrt-why couldn’t it pick it up?

 

[StIGMA]

Why would it be relevant for what is essentially a local disease?

So if I did Ct DNA on a skin cancer and it was negative should nothing be done?

ctDNA can be from malignant cells in the blood (circulating tumor cells) or from DNA shedding during tumor cell turnover/death (ctDNA). Tumors that are actively dividing should shed some ctDNA, and especially so if they are actively dying. They may stop shedding ctDNA if they are mostly dead/senescent, but they could still grow back again. Undetectable ctDNA doesn't mean a 0 recurrence risk as it isn't known if there is necessarily viable tumor (but it is probably a good surrogate for a pCR or significant cell death). This isn't my area of expertise, but there's a reason this is a hot research topic-- a whole lot isn't known yet.

There is certainly a role for serial ctDNA tests to detect for early increase in levels (similar to tumor antigens). Maybe someone could convince me why this isn't just another tumor marker type of test (CEA, PSA etc)(acknowledging could look at targetable mutations, etc on recurrance with this test).

 

[StIGMA]

Circulating tumor markers to reduce adjuvant therapies

0 post-op PSA, no radiation. Can think of this the same way. But this is new and fancy and hot so let's pretend it will completely transform oncology.

It would be nice if there were more cooperative group efforts to establish definitive radiation/chemoradiation in some controversial areas and exclude surgery (rectal watchful waiting for instance). It would seem this would be an area where rad oncs could also advocate for some industry funding if we were to incorporate these tests routinely.

 

[RickyScott]

ctDNA can be from malignant cells in the blood (circulating tumor cells) or from DNA shedding during tumor cell turnover/death (ctDNA). Tumors that are actively dividing should shed some ctDNA, and especially so if they are actively dying. They may stop shedding ctDNA if they are mostly dead/senescent, but they could still grow back again. Undetectable ctDNA doesn't mean a 0 recurrence risk as it isn't known if there is necessarily viable tumor (but it is probably a good surrogate for a pCR or significant cell death). This isn't my area of expertise, but there's a reason this is a hot research topic-- a whole lot isn't known yet.

There is certainly a role for serial ctDNA tests to detect for early increase in levels (similar to tumor antigens). Maybe someone could convince me why this isn't just another tumor marker type of test (CEA, PSA etc)(acknowledging could look at targetable mutations, etc on recurrance with this test).

Ctdna is in its infancy and these tests will only improve over time. Even senescent cells produce exosomes containing dna, rna etc which circulate. Exosomal tests are already commercially used to detect prostate cancer:

https://www.exosomedx.com/#:~:text=The%20ExoDx%20Prostate%20test%20is%20a%20simple%20urine%20test%20that,should%20undergo%20a%20diagnostic%20biopsy.

 

[yesmaster]

For the most part, the GI medical oncologists are cautious regarding deescalating adjuvant therapy. For the DYNAMIC stage II colon cancer patients, those that are ctDNA negative BUT with high-risk clinical features or high T stage still do poorly, so they'll still get adjuvant chemotherapy.

The ctDNA assays for minimal residual disease are tumor-informed (e.g. Signatera), and it's likely that MRD tests will be tumor-specific rather than tumor-agnostic tests like Guardant360. The test sensitivity is also a problem, Grail's screening test only detects 20% of stage 1 NSCLC, so I don't see this being sensitive enough for to be useful for a lot of scenarios, like adjuvant radiotherapy for skin squamous cell carcinoma.

It would be better if radiation oncologists used ctDNA selectively in clinical trial development. There are patients in my practice that I wish I could use ctDNA for, but without clinical trials, it's totally speculative whether it would improve management. Besides escalating therapy for ctDNA positive patients, there are other ways we could benefit from ctDNA. It doesn't have to be used for radiotherapy omission, just don't design the trials in a way to cast doubt on the benefit of radiotherapy.

 

[gmsquid]

0 post-op PSA, no radiation. Can think of this the same way. But this is new and fancy and hot so let's pretend it will completely transform oncology.

It would be nice if there were more cooperative group efforts to establish definitive radiation/chemoradiation in some controversial areas and exclude surgery (rectal watchful waiting for instance). It would seem this would be an area where rad oncs could also advocate for some industry funding if we were to incorporate these tests routinely.

To be fair ctDNA has got to be more sensitive than PSA testing.

 

[sloh]

Any of you see Vinay's commentary on this?



His argument summed up here:

"This person is interpreting the study exactly how others will interpret it.

"For truly high risk patients T4, do not skip chemo even if ctDNA is negative. For low risk patients, positive ctDNA seems reasonable to offer chemo."

If you take him at his word, what does this mean? 33 people plus 45 people out of 291 or 26% of people will get chemotherapy. This is the IDENTICAL percentage of people getting chemotherapy as the CONTROL arm. You're not sparing anyone chemo. When this company gets this approval, we will not cut down on chemotherapy. We will likely increase chemotherapy usage bc people will be thinking like this.

We are going to hemorrhage money to these companies. If I was a consultant to these companies, I would know how to bleed the healthcare system so badly. It's so easy to bleed them for billions.

Undercut chemo with a big margin—you will claim the market share."

 

[RickyScott]

Any of you see Vinay's commentary on this?



His argument summed up here:

"This person is interpreting the study exactly how others will interpret it.

"For truly high risk patients T4, do not skip chemo even if ctDNA is negative. For low risk patients, positive ctDNA seems reasonable to offer chemo."

If you take him at his word, what does this mean? 33 people plus 45 people out of 291 or 26% of people will get chemotherapy. This is the IDENTICAL percentage of people getting chemotherapy as the CONTROL arm. You're not sparing anyone chemo. When this company gets this approval, we will not cut down on chemotherapy. We will likely increase chemotherapy usage bc people will be thinking like this.

We are going to hemorrhage money to these companies. If I was a consultant to these companies, I would know how to bleed the healthcare system so badly. It's so easy to bleed them for billions.

Undercut chemo with a big margin—you will claim the market share."

From the #radonc perspective, these tests, unfathomable 10 years ago, will no doubt improve over the coming years. Even without the residency expansion, if they end up having a big impact on adjuvant radiation, that would pose an existential threat to the job market. If 10-20% of radoncs become unemployed, woul put a huge downward pressure on salaries.

 

[CaesarRO]

I know this comes up repeatedly, but since we're talking 10-20 yr horizon as the oncology landscape changes, I see it as a necessity that a certain fraction of Rad Onc will have to retrain. The question will be what pathways develop to allow for that.

I'm becoming more and more certain that I'll have to do that at some point in my career, but will try to enjoy from this career as long as I can.

 

[deleted941485]

I know this comes up repeatedly, but since we're talking 10-20 yr horizon as the oncology landscape changes, I see it as a necessity that a certain fraction of Rad Onc will have to retrain. The question will be what pathways develop to allow for that.

I'm becoming more and more certain that I'll have to do that at some point in my career, but will try to enjoy from this career as long as I can.

Pathways? Yeah it’s called an eras application. Good luck filling that out again.

 

[OTN]

I've thought extensively about retraining, just in case it has to happen. I'd probably give it a 25% chance I will have to during my career.

I would go with palliative medicine. I've been fortunate in my career in that I don't necessarily have to go for a high-paying specialty. Palliative medicine would deliver a great schedule, a full patient load with no issues, greatly diminished IT coverage, and I could stay with my group. Relieving arthritic pain with low-dose RT has been more satisfying than I thought it would be.

I think we could get into a fellowship after being a radonc without having to go through a residency all over again.

 

[evilbooyaa]

I've thought extensively about retraining, just in case it has to happen. I'd probably give it a 25% chance I will have to during my career.

I would go with palliative medicine. I've been fortunate in my career in that I don't necessarily have to go for a high-paying specialty. Palliative medicine would deliver a great schedule, a full patient load with no issues, greatly diminished IT coverage, and I could stay with my group. Relieving arthritic pain with low-dose RT has been more satisfying than I thought it would be.

I think we could get into a fellowship after being a radonc without having to go through a residency all over again.

RO docs can move on to palliative care fellowship. Assuming no pathways open to systemic therapy and I had to re-train, that'd definitely be my path. If ctDNA does become a thing I might just do a fellowship for a year in preparation for the eventual nutpunch it will be to the concept of 'adjuvant RT'.

 

[deleted941485]

RO docs can move on to palliative care fellowship. Assuming no pathways open to systemic therapy and I had to re-train, that'd definitely be my path. If ctDNA does become a thing I might just do a fellowship for a year in preparation for the eventual nutpunch it will be to the concept of 'adjuvant RT'.

Palliative to me is a garbage specialty that formed the same way hospital medicine became a thing. It’s a handful a **** that specialists and office pcps didn’t want to be bothered with every second of the day so they made a fellowship or whatever in it.

I couldn’t think of a worse way to pivot.

 

[medgator]

Palliative to me is a garbage specialty that formed the same way hospital medicine became a thing. It’s a handful a **** that specialists and office pcps didn’t want to be bothered with every second of the day so they made a fellowship or whatever in it.

I couldn’t think of a worse way to pivot.

Not a lot of other choices out there with our current training

 

[deleted941485]

Not a lot of other choices out there with our current training

See prior post. Use the “network” to get a new training spot