Predicting disease recurrence in patients with early triple-negative breast cancer using circulating tumour DNA

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Published: 18 Dec 2019
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Dr Milan Radovich - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA

Dr Milan Radovich speaks to ecancer at the 2019 San Antonio Breast Cancer Symposium about the association between disease recurrence in early-stage triple-negative breast cancer and circulating DNA (ctDNA) and CTCs (circulating tumour cells) after neoadjuvant chemotherapy.

He gives an overview of the study design which used genomic sequencing to sequence residual disease tumours from patients participating in the BRE12-158 study.

Dr Radovich reports the main findings from this study and noted that patients who were ctDNA-positive had an inferior, distant disease-free survival (DDFS) with an estimated DDFS of 56 percent versus 81 percent in patients who were ctDNA-negative.

He believes that future trials should focus on evaluating the use of ctDNA to guide therapy for high-risk patients.

Watch the press conference here.

Read more about the study here


Predicting disease recurrence in patients with early triple-negative breast cancer using circulating tumour DNA

Dr Milan Radovich - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA

We’re very excited here at the San Antonio Breast Cancer Symposium to release these ground-breaking results on the use of ctDNA and CTCs to predict recurrence in early stage triple negative breast cancer. For our analysis we utilised samples from our recently completed trial, BRE12-158, which enrolled women with triple negative breast cancer who had residual disease after neoadjuvant chemotherapy. What we know is that these women are at very high risk of disease relapse based on this residual disease.

This trial actually genomically sequenced the residual disease tumour and then randomised patients to either a genomically directed therapeutic or treatment of physician’s choice. For the pre-planned correlative results that we presented today we actually drew blood from both ctDNA and CTCs after surgery and then followed these patients for outcomes.

Can you tell us about the results and how they are significant?

They were actually absolutely dramatic. What we identified was that patients who were CTC positive they had an inferior distant disease free survival with an estimated two year DDFS of 56% in patients who were positive for ctDNA versus 81% in patients who were ctDNA negative. So a huge stratification in the disease free survival for these high risk patients.

What was also neat is that we also combined the use of CTCs, or circulating tumour cells. These are live tumour cells that float in the circulation and using very sensitive techniques we can identify these cells. When we combined the ctDNA and CTCs we found stark differences in outcomes. Patients who were positive for both ctDNA and CTCs had a two year distant disease free survival of 52%. Those who were negative, however, had a two year DDFS of 89% so a group of patients do exceptionally well. That’s what was really interesting from the study is that we first found a group of patients who actually had very poor outcomes but also a group of patients that did quite well. These patients who did quite well actually had clinical parameters of high risk disease – many of them had large tumours or lymph node involvement – yet still did well when they were negative for both biomarkers.

The main conclusion here is that this is an absolutely necessary stratification factor for future post-neoadjuvant studies. We at IU are very excited about the launch of our new study, the PERSEVERE study, which will actually incorporate this powerful information provided by molecular MRD. In our new trial we will enrol women again who have residual disease after neoadjuvant chemotherapy but this time stratify them by the presence of ctDNA. For those women who are ctDNA positive and harbour an actual genomic marker they will be assigned to one of a set of therapies based on the genomic alteration observed.  Then for those patients who are negative for ctDNA we’re going to assign them to treatment of standard of care and watch and wait.

Why combine ctDNA and CTCs?

It’s a great question. What we know is that ctDNA is more sensitive to detect the presence of minimal residual disease but what we found with CTCs was actually complementary to ctDNA. So when we looked at our patients who recurred our sensitivity to detect recurrence went from 79% with ctDNA alone to 90% when we combined with CTCs. So we believe this is really powerful when used in combination.

Is there a potential association with the residual cancer burden score?

That’s a great question. One of the powerful results of our studies was these results were significant above and beyond standard use clinical parameters. So we did, we considered RCB, we considered tumour size at surgery, lymph node involvement and a variety of other factors. The presence of these circulating biomarkers portended inferior outcomes even above and beyond standard clinical parameters.

Anything you would like to add?

We’re just really excited that we have these results ready for our patients. An important point is that many will ask is this something we should do in clinic on Monday? The answer is no. We don’t know if having this information will actually improve outcomes but what we do know and what we’re excited about are these new trials where we wanted to intervene therapeutically in these patients who we know are high risk and see if we can really improve outcomes for this high risk population.