Circulating tumour DNA used to predict disease recurrence for early triple-negative breast cancer

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Published: 19 Dec 2019
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Dr Milan Radovich - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA

Dr Milan Radovich gives a press conference at the 2019 San Antonio Breast Cancer Symposium about predicting disease recurrence in patients with early triple-negative breast cancer using circulating tumour DNA.

Watch our interview with Dr Radovich here.

Read more about the study here.  

Good morning and I’d like to personally thank the members of the media for being here bright and early this morning to hear these exciting results from the San Antonio Breast Cancer Symposium. I’d like to also acknowledge my very good friend and colleague Dr Bryan Schneider, a medical oncologist and Professor of Medicine who is the senior author of this study and will also be available to answer questions after my presentation.

It’s well known to this audience that triple negative breast cancer, while it comprises a minority of breast cancers, about 15-20%, is a considerably more aggressive form of the disease. This is a disease that tends to affect women of African American descent and Hispanic descent but it also disproportionately affects women who are younger and also women who carry BRCA1 germline mutations. Unfortunately, women with triple negative breast cancer have not benefitted from the advances in hormonal and targeted therapies seen in other subtypes of breast cancer and unfortunately most are treated with just chemotherapy, radiation and surgery.

What we know with triple negative breast cancer, unfortunately, is that these cancers tend to recur at a very high rate, particularly peaking in the first three years after surgery. This unfortunately causes a very untenable situation for our patients who live in constant fear and uncertainty of their cancers recurring after chemotherapy and surgery. I would like to highlight Miss Ginny Mason, a 25 year survivor of inflammatory triple negative breast cancer who is sitting in the front row of the audience, who can speak to the media about the patient experience and the fear and uncertainty that occurs when patients have completed chemotherapy and surgery in fear of their cancers coming back. She is also the director of the Inflammatory Breast Cancer Research Foundation and can also speak to you about the advances in research for this aggressive disease.

The current typical standard of care for triple negative breast cancer in the early stages is for patients to be treated with neoadjuvant chemotherapy, typically with a three drug combo of Adriamycin, Cytoxan and Taxol, and then these patients go to surgery. As Dr Symmans mentioned, about one-third will get a pathologic complete response, meaning the chemotherapy melted the entire tumour away, and these patients do really quite well; their long-term survival is quite high. But unfortunately two-thirds will have residual disease, meaning the chemotherapy did not melt all the tumour away, there’s residual disease that is present at the time of surgery, and these patients tend to have a very poor survival outcome.
In our study we really focussed on this residual disease population and harnessed the power of circulating tumour markers. The first marker we focussed on was a marker called circulating tumour DNA, or ctDNA. ctDNA is actually DNA that is shed from tumours into the circulation such that one can use really powerful next generation sequencing techniques to detect these tumour markers in circulation in a very non-invasive manner.

We also studied circulating tumour cells, or CTCs, and these are actually live tumour cells floating in the circulation where one can use, again, very sensitive techniques with a simple blood draw to detect the presence of these CTCs. The question is, if we detect these ctDNA and CTCs in patients who have completed neoadjuvant chemotherapy and surgery, are they at high risk of their cancers coming back? Again, these patients after chemotherapy and surgery are, quote-unquote, disease free – we don’t detect any cancer, we can’t feel it, we can’t see it, we can’t scan for it. But we know that a proportion of them their cancers will come back.

So for our analysis we analysed samples from our recently completed clinical trial, BRE12-158. This trial was very innovative in that it took women with triple negative breast cancer who underwent neoadjuvant chemotherapy and were determined to have significant residual disease at the time of surgery. On trial their residual disease tumour was genomically sequenced and patients were then randomised to either a genomically directed therapeutic or treatment of physician choice. The primary endpoint of this trial is two year disease free survival of which the primary endpoint is still currently maturing and the results will be presented at a later date.

For the studies that we will be presenting today blood and plasma for both ctDNA and CTCs were collected at cycle 1, day 1 of patients enrolled on arm A and then at the first routine visit for patients enrolled on arm B and then followed for clinical outcomes.

Here are the main results. The results are absolutely striking. Patients who have ctDNA in their circulation after surgery have a significantly inferior distant disease free survival compared to patients who are ctDNA negative. The estimated two year DDFS was 56% in patients who were ctDNA positive versus 81% in patients who were ctDNA negative, a highly significant p-value of 0.0055 with a hazard ratio of 2.99.

We next looked also at the combination of ctDNA and CTCs – what happens when we combine these two powerful markers for circulating tumour material? What we observed was a step-wise gradation in the outcomes shown here with distant disease free survival. If patients were negative for both ctDNA and CTCs they had an exceptionally superior outcome. If they were positive for one marker or the other they had intermediate outcomes and if they were positive for both ctDNA and CTCs they had the worse inferior outcomes. If we compare patients who are double positive versus double negative the two-year DDFS for patients who are double positive is 52% and patients who were double negative was 89% with a p-value of 0.0095 and a hazard ratio of 5.29.

To this point in my talk here I’ve been pretty morbid, I’ve been telling you what are the markers that really point to patients who do poorly. But what I would like to highlight here is the patients who do exceptionally well. This population that is both ctDNA negative and CTC negative had a two year DDFS of 89% even though based on standard clinical parameters are at very high risk of relapse. When you analyse and look at their detailed clinical data many of these patients have large tumours, greater than 5cm, several had lymph node involvement, yet they were biomarker negative for both and have now had exceptional long-term outcomes.

So, in conclusion, patients with triple negative who have an incomplete response to neoadjuvant chemotherapy can be further risk stratified based on the presence of MRD with technologies such as ctDNA, the addition of CTCs as complementary information to ctDNA detection and, as I mentioned, the absence of both of these markers has a superior ability for predicting patients who have no relapse.

Importantly, and as mentioned by one of the members of the press, the detection of ctDNA in early stage TNBC after neoadjuvant chemotherapy is an independent predictor of disease recurrence and represents, we think, an important novel stratification factor for future post-neoadjuvant trials. So while I think it’s important now that we have a technology that can tell us which patients do poorly, the more important thing now is we need to learn how to act. So we are excited to announce the launch of our new trial, BRE18-334, also known as the PERSEVERE trial, which will open in the first half of 2020. This trial will enrol women with triple negative breast cancer who have residual disease but then will be stratified by the powerful information provided by molecular MRD. Patients who are positive for ctDNA, based on actionable genomic markers either identified in the plasma or on the residual disease tumour, will be assigned to one of four arms in an umbrella style design based on the genomic alteration observed, including mutations in DNA repair, PI3K/AKT and markers for immunotherapy, all with the backbone of capecitabine. Patients who are positive for ctDNA but lack one of the pre-specified actual genomic markers will be assigned to an arm of standard of care with capecitabine or treatment of physician’s choice. Patients, however, who are negative for ctDNA will be assigned to an arm of treatment of physician’s choice which can include no therapy or chemotherapy of choice at the physician discretion.

It goes without saying that we would like to deeply acknowledge our patients and families for their participation in the BRE12-158 trial and deeply indebted to the numerous co-investigators at 25 sites across the US for their participation. I thank you for your attention as well.