CTA: So, C-509T status did not predict women’s response to the different radiotherapy regimens. That being the case, what are the clinical implications of your findings? How might C-509T status inform clinical decision-making?

Dr Smith: I think the most immediate implication is determining which patients we can safely receive a tumor-bed radiation boost without increasing the risk of fibrosis. It is well known that a radiation boost can yield a significant increase in the risk of fibrosis and an adverse cosmetic outcome. 

In our trial, every patient received a boost. I think it’s reasonable to conclude that if you do not have this variant allele and you do receive a boost, you’re not very likely to experience fibrosis (4% in our study). I think it’s reasonable to take it a step further and say, we know the boost is the key reason patients experience fibrosis in the first place, so if you have that allele and get the boost, that will increase your risk substantially. 

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So,you have to weigh a very small 1% to 3% 10-year incremental benefit in tumor control versus a potentially meaningful increase in the risk of fibrosis, specifically in the patients with the variant allele. 

I think that information could be very helpful in counseling patients and helping to make more personalized decisions about who should receive a boost and who should not. It would be plausible, in my mind, to omit a boost in a patient with the variant allele and a biologically favorable tumor. Such a decision would have a negligible negative impact on tumor control and a significant positive impact on toxicity by lowering risk of fibrosis.

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The hypothesis that I am interested in studying, however, as an implication of our finding, is focused on a different clinical question. That clinical question centers around the best way to offer breast reconstruction for a patient who requires mastectomy and radiation therapy. 

Based on this finding, we would hypothesize that patients with the variant allele are at higher risk of fibrosis of the reconstructed breast and that these patients might require different approaches to breast reconstruction than patients without the variant allele. This really comes into play in making a decision about whether or not a patient should undergo implant reconstruction or autologous tissue-based reconstruction. 

Implant reconstruction with radiation typically caries a much higher risk of fibrosis than autologous reconstruction. I wonder if this allele could be used as a biomarker to select which patients may be safely treated with implant reconstruction — for example., those patients who do not have the variant alleles — and patients who may do better with autologous reconstruction, for example, those with the variant allele.

We don’t know that for sure. It’s a hypothesis I’m very interested in evaluating, in light of our data.

We’re working with our lab at MD Anderson to develop a CLIA [Clinical Laboratory Improvement Amendments]-certified test for this polymorphism, which would allow us to request it for any of our patients, making it easier to do future research.


  1. Grossberg AJ, Lei X, Xu T, et al. Association of transforming growth factor β polymorphism C-509T with radiation-induced fibrosis among patients with early-stage breast cancer: a secondary analysis of a randomized clinical trial[published online July 19, 2018]. JAMA Oncoldoi: 10.1001/jamaoncol.2018.2583