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Old 01-15-2020, 10:50 AM   #1
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Join Date: Nov 2005
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Monitoring Tumor-Specific Mutations in Early-Stage Breast Cancer With ctDNA


Monitoring Tumor-Specific Mutations in Early-Stage Breast Cancer With ctDNA

Dr. Haffizulla: Dr. Park, thanks again for joining us.

Dr. Park: Thank you.

Dr. Haffizulla: So, you are the senior author in a pilot study looking at the use of targeted gene panels to evaluate tumor-specific mutations in circulating tumor DNA among patients with early breast cancer. Can you tell us first about the technique and then maybe share some of the details of the study design?

Dr. Park: Yeah. So, this is one of the few studies that are using newer technologies or what we call ultra-deep next-gen sequencing. The problem with traditional next-gen sequencing is that thereís often a lot of mistakes that get made just from the process of doing the technique. We have to amplify the DNA and then we have to submit it for various types of sequencing, and it can introduce errors. And so when youíre looking for small numbers or amounts of cancer DNA amongst a sea of normal, itís often very difficult to say, hey, is this real or is this just an artifact because of the error that can be introduced in the next-gen sequencing process? So, my former mentor at Johns Hopkins, Bert Vogelstein, developed this technique a number of years ago that they termed Safe-SeqS, itís an acronym, which I donít remember what it stands for, but ultimately, it allows us to do whatís called barcoding so that we can actually distinguish between true mutations at a low frequency versus artifacts, and what that has allowed us to do now is confidently use this technology to look for minimal residual diseaseóhere weíre talking about disease we canít see by CAT scansóand see what whether or not we can detect the cancer DNA thatís floating in the bloodstream.

Dr. Haffizulla: Thatís phenomenal. Can you share more of, not just the design of the study itself, but results related to that, and the feasibility of identifying tumor-specific mutations without tissue biopsy?

Dr. Park: Exactly. So, part of this trial, itís a big trial thatís through what we call the Translational Breast Cancer Research Consortium as well as Johns Hopkins Clinical Research Network. We had 22 sites, enrolled 228 patients who are stage II and stage III breast cancer patients undergoing neoadjuvant therapy, and they were HER2-positive or triple-negative breast cancer patients. The premise of this is that weíre going to take a diagnostic biopsy, do sequencing, find trackable mutations that are in the tumor and then look for them in the pre-therapy blood, because this is neoadjuvant therapy and then see whether or not they clear those mutations in the post-neoadjuvant therapy blood sample, right before surgery. The overall goal of this would be that if we can show that if you clear your cancer DNA in the blood, are you actually predicting for pathological complete response at the time of surgery with the intent that in the future we can actually offer patients a no therapy option, or no surgical therapy option. Now, part of the problem that we and many others have encountered doing this is that when all you have is a diagnostic biopsy to find those mutations, many times you donít have enough tissue to do it. There have been some studies that have said up to 50% of the time, youíre not going to be able to have a tissue thatís going to allow you to do next-gen sequencing and find mutations. So, we posited the question, hey, since these are bulkier stage breast cancer patients with a heavier volume of disease, maybe we donít need the biopsy, maybe we can just take the blood and see whether or not we can find these mutations. And so, we did this, we did not push the envelope in terms of sensitivity because we didnít want to burn all our plasma, again, itís a pilot study, but we found that probably about 50% of the time, we can detect something so we donít need the biopsy. So, Iím hoping the Venn diagram isnít so overlapping that the 50% of patients that donít have usable tissue diagnostic isnít completely overlapping with these patients that we can or cannot find it. It will really open up the doors to allow us to this technique in the future.

Dr. Haffizulla: Thatís phenomenal. Can you share more detail regarding the possible influence of this on clinical practice?

Dr. Park: Yeah. So, when I started this with many other folks, jeez, about 7 or 8 years ago, I think at the time it was kind of controversial, could you really do this? Itís been a little bit gratifying over the years to see that many other studies now are actually doing very similar types of approaches, and I think the biggest impact of this would be that we can use blood as a monitor of whether a patient is cured or not. And that has huge implications because rather than throwing the kitchen sink at patients, which is what we currently do for early-stage breast cancer, we can really individualize approaches by the presence or absence of microscopic residual disease, ie, using the liquid biopsy. So, not everyone has to get chemo, not everyone has to get surgery, not everyone has to get radiation. It will really be individualized based upon, again, whether they have evidence of disease or not.

Dr. Haffizulla: Thatís excellent. Thank you very much, Dr. Park.

Dr. Park: Thank you.
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