Homologous recombination deficiency predicts neo-adjuvant chemotherapy response in triple-negative breast cancer

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Published: 17 Dec 2015
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Dr Virginia Kaklamani - UT Health Science Center, San Antonio, TX

Dr Kaklamani talks to ecancertv at SABCS 2015 about a pooled analysis of five phase II studies showing that homologous recombination deficiency predicts response to neo-adjuvant platinum-based therapy in patients with triple-negative breast cancer.

Indeed, significantly higher pathologic complete response (pCR) rates were observed when women had TNBC tumours that were homologous recombination deficient than when tumours were not (44% vs. 8% (p < 0.01), even after adjusting for potential confounding factors.

Prospective studies are needed before a test for homologous recombination deficiency is commercially available, Dr Kaklamani observes.

She also comments on other data presented at the meeting:

Results of the CREATE-X trial presented by Dr Masakazu Toi (Kyoto University, Kyoto, Japan)

Outcomes from the CALGB 40603 study presented by Dr William Sikov (Women & Infants Hospital of Rhode Island, Providence, USA)

ecancer's filming at SABCS 2015 has been kindly supported by Novartis through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

Patients with triple negative breast cancer are now being assessed by your team for homologous recombination deficiency. Explain to me what this is all about.

So this is a different type of breast cancer compared to what we’re used to when we look at genomic markers which we typically look at the oestrogen receptor positive breast cancers. Triple negative breast cancers are the ones that do not express the oestrogen receptor, do not express the progesterone receptor or the HER2. What we now look at is different changes that don’t allow the DNA to repair itself and that’s this homologous recombination deficiency. What we found was that by performing this test, which is a test that we perform on the cancer, we were able to predict the patients that would respond to chemotherapy and the patients that would not respond to chemotherapy.

What exactly is homologous recombination because it being deficient confers a lower risk so what is it?

It’s changes in the DNA that do not allow the DNA to repair itself.

And doctors should glean from this clinically what?

Right now this test is not commercially available yet so we have a few months, maybe a year or so, to go and we still need to be doing prospective studies. These are studies that we did where they were prospective but we looked at the test retrospectively, so after the fact. So we still want a little bit more data on this and this is triple negative breast cancers where we don’t have a lot of other treatments besides chemotherapy and the chemotherapies that were given in this study were pretty good. So we still have a little bit of work to do but it points towards the direction that we can again tailor our treatment based on the kind of breast cancer that it is, whether it has homologous recombination deficiency or not.

Now, there is a relationship, is there not, between that study and another study that you discussed yesterday in the news briefing in which Dr Toi presented on capecitabine improving outcomes for patients with breast cancer with residual disease after neoadjuvant chemotherapy. What was going on there and what’s the relationship with all of this?

There’s actually a relationship with a third paper from Dr Sikov on a study where they looked at patients being treated before surgery, again it was triple negative breast cancer patients, and they looked at the women that responded well to chemotherapy and had a complete pathologic response where the surgeon went in, did surgery and couldn’t find any cancer left behind, and women where the chemotherapy didn’t work very well and they had residual disease. They found that the women whose cancer was not eradicated didn’t do as well. So fast-forwarding to Dr Toi’s study, these women who did not have a benefit from chemotherapy and whose cancer was not eradicated, he took those women and gave them a different kind of chemotherapy and found that by doing so, by giving them a different kind of chemotherapy after surgery, and the name of the chemotherapy was capecitabine, those women were able to live longer, showing us that we can start with a specific chemotherapy, see how well that works and if it doesn’t work that well switch to a different kind of chemotherapy and really benefit our patients.

This seems to be opening up possibilities because Dr Sikov was showing that if you get a pathological complete remission then you have a good chance. But I suppose the thing is how do you get that CR.

I think the way we’re looking at all three of these studies is that initially you’re doing the homologous recombination test. If that test tells you that there’s a good chance of the cancer responding to this platinum based chemotherapy then you offer that to your patient. If it tells you that that chemotherapy may not benefit your patient that well then you may need to start thinking about other chemotherapies or adding capecitabine to your chemotherapeutic regimen to again benefit your patients.

And what about tolerability of these complex regimens?

The more chemotherapy you give the more toxicity you will cause. Now, interestingly, in Dr Toi’s study where the patients had already received chemotherapy before surgery and were receiving another form of chemotherapy for six months after surgery, it was pretty well tolerated. However, Dr Toi’s study was done in Japan and Korea and capecitabine in previous studies has been shown to be better tolerated in that part of the world compared to the United States or even Great Britain. So we still have some ways to go. We probably need to do our own studies.

These multiple studies are sounding a bit complex but are they helping us get towards more personalised therapy?

Absolutely they are. This is where you’re looking at the individual’s cancer and the changes in the cancer. We used to have three or four different categories in breast cancer, now we’re up to ten or twelve of those categories based on the specific gene expression in those cancers. By doing that, you can predict chemotherapy benefit and we’re getting to the point where we might even be able to predict what kind of chemotherapy to give to different patients.

Bringing it all back to your homologous recombination deficiency as a predictor of lower risk, how would you sum all of this up, the clinical implications and the promise for working cancer doctors?

By performing genomic tests you’re able to identify patients that might get a benefit from chemotherapy and identify a group of patients that may not get a benefit from chemotherapy. The patients that will benefit from chemotherapy you should be giving them the standard chemotherapy and chances are they’re going to do very well, like Dr Sikov’s study showed. The patients who are not going to get a benefit from chemotherapy and may not have as good a prognosis you need to start thinking about clinical trials; you need to start thinking of other treatments other than chemotherapy. We’re going to be hearing at the conference about immunotherapy and other targeted therapies that this patient population may benefit more from.