AACR 2016

Risk of breast cancer after chest radiotherapy may be affected by genetics

Dr Lindsay Morton - National Cancer Institute, Bethesda, USA

The population of cancer survivors in the United States has grown dramatically over the last several decades, in fact it’s more than quadrupled since the late 1970s to reach about 15 million survivors today. One in five cancers that’s diagnosed today is diagnosed in this population of cancer survivors and so understanding their long-term health is a really important clinical and public health issue.

Unfortunately some of these survivors are at elevated risk for developing additional malignancies and we do research trying to figure out what causes these new malignancies. We look at a variety of factors – genetic susceptibility, environmental or medical history or lifestyle factors and possibly also the treatments for the first cancer.

So the study that we presented today looks at childhood cancer survivors and there are over 400,000 childhood cancer survivors in the United States. I think they’re the best studied population when it comes to looking at treatment related second cancers because their prognosis tends to be very good for many of the childhood cancer survivors and also because they have many years in which to live and to experience any potential late effects of the treatment.

Are these relapses of their initial cancer?

Survivors experience a number of potential health effects as time goes on and one of the primary concerns is relapse of their initial cancer. Another one is the development of a new malignancy, so this is not a relapse of their initial cancer, it’s actually a separate primary cancer. Over time often the data have shown that the risk for developing a new primary cancer increases as the years go on whereas there tends to be a little bit of a tail after a certain period of time, the risk of relapse actually is not as much of a concern as the risk of developing a new malignancy.

How have treatments improved for long term health?

I think childhood cancer treatment is one of the great success stories of cancer research over the last several decades because there have been so many improvements in treatment. Even though I am focussed on the adverse late effects of treatments it’s really important to keep in mind that most of the story about childhood cancer treatment really is a success story and it’s very important to treat the cancer that the patient is initially presenting with. Keeping that in mind, once the success story has happened then it becomes really important for us to look at a patient’s long-term health and the goal is to figure out whether or not we can reduce the risk of late adverse effects without sacrificing any of the benefits of the treatments. There have been a lot of changes, some of the changes, it depends on the type of first primary cancer. So some children receive lower doses than they received in the past, others receive lower treatment volumes. So, in other words, for Hodgkin lymphoma, for example, in the past patients often were treated with an extended field radiotherapy to cover most of the lymph nodes in their chest whereas now the radiotherapy approach is to target only the lymph nodes in a specific area that really seem to be involved in the disease and that doesn’t seem to reduce the benefits of the treatment over time.

There also are different techniques that can be used, of course there have been a lot of advances in systemic therapies with chemotherapies and now people are increasingly wondering about using different types of radiotherapy such as proton therapy. I think it’s really important that there are studies that are going to be able to evaluate the risks and the benefits, both in terms of the initial disease as well as late adverse effects of the new treatments.

I was reading recently about using just a single high dose which rather than the burden that it puts on the patient of coming back week by week to have core sample, core sample, core sample, just the pure ablation wiping out. It comes with its own risks but do you believe that there’s a broader benefit that can provide or that can come from a targeted, more personalised approach [?? 4:09]?

I think those are two separate questions actually. That’s OK, I just think they’re two separate questions.

Do you think there’s a benefit to using a targeted personalised approach?

I think it’s really exciting to see the developments in the radiotherapy field and that oncologists and physicists are really challenging clinical practice to see if new approaches can be developed, whether it’s using protons or intensity modulated radiotherapy or perhaps changing the doses or changing what we call the fractionation and that’s what you are referring to. So it’s this schedule that the patients receive the therapy, a common schedule is to receive thirty fractions, so it’s five days a week for six weeks, and there are questions about the optimal fractionation of the dose. It’s really important that these changes are studied in order to understand the risks and the benefits of the changes.

And then more out of the clinic but towards the patient’s perspective, when it comes to the effects of childhood cancer, that’s something that affects not only the direct patient but their family as well and for them to have either any assurances or any valid concerns around the risks facing their treatment in the first instance and then the risks with second primary malignancies. Is there anything that you think might be of interest to them to hear or to be more familiar with, engaged with, in the coming future?

What do you think the future holds?

I think the future holds great promise for childhood cancer survivors as we can bring genomics into looking at second malignancy risk and risk of other late adverse effects. So the results of the study that we are presenting today are not ready to come into the clinic. It’s a discovery study and while we identified two positions in the genome that appear to increase the risk for breast cancer only in the children who were treated with chest radiotherapy there’s a lot of work that we still have to do. It’s really in two dimensions: one, we need to go into the lab and we need to figure out exactly what’s going on in the genome and two, we need to look in other studies because we need to really figure out if we can identify the different factors that would help us really hone down to which survivors would be most impacted. So, for example, does the age at treatment make a big difference? It’s an important question for us to ask before we can then evaluate in the clinic whether or not genetic susceptibility can be used to either tailor our understanding of the risks and benefits of the treatment or to tailor the screening recommendations. So I think patients should be very hopefully that genomics will come into survivorship guidelines in the future such as the guidelines by the children’s oncology group which are the current standard in the United States. But we’re not quite there yet. So I’d also like to mention that the survivors should have great hope because of the tremendous collaboration amongst the scientists in the area, the partnerships from individuals from different institutions and from different disciplines. Working on our project I often say you need four PhDs and an MD to do the work. So we have oncologists and radiation oncologists and surgeons and medical physicists and geneticists and biostatisticians and epidemiologists. Everyone’s working together in order to try and improve the long-term health of childhood cancer survivors.