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Study Identifies Genetic Markers That Predict Radiation-Induced Breast Cancer After Hodgkin Lymphoma

December 30, 2021

The risk of developing breast cancer is high in women with Hodgkin lymphoma (HL) who have undergone chest radiotherapy (RT), but the role of genetic risk factors in this risk is unclear. In a new study published in Blood, investigators genotyped blood samples of women with RT-induced and primary breast cancer to identify nine genetic variants that interacted with RT and increased patients' susceptibility to breast cancer.

From this discovery, researchers developed the RT-interaction-polygenic risk score (PRS) to predict which patients were more likely to develop RT-induced breast cancer. Lead author Flora van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, suggested that this new score can be used along with an existing breast cancer polygenic risk score (BC-PRS).

"BC-PRS can be used in the clinic to identify women with HL who have a high genetic risk of breast cancer and RT-interaction-PRS can identify irradiated survivors at the highest risk of breast cancer who need intensive annual screening with mammography and MRI," Dr. van Leeuwen told ASH Clinical News. "New patients with HL and their physicians could opt for treatment regimens without radiation (chemotherapy alone), or with lower radiation doses to breast tissue, using the latest radiation techniques which can substantially reduce radiation doses to the breast."

To study the interaction between RT and genetic variation on post-HL breast cancer, the researchers used a two-step design: First, they examined gene-radiation interaction for 211,155 single nucleotide polymorphisms (SNPs) in a case-only analysis comparing patients with RT-induced post-HL breast cancer (n=327) and primary breast cancer (n=4,671).

Median age at breast cancer diagnosis was 45 years (range = 24-76 years) in patients who developed breast cancer after HL and 46 years (range = 22-84 years) in patients with primary breast cancer. In patients with HL, breast cancer developed a median of 24 years after HL diagnosis (range = 9-46 years).

The authors identified nine SNPs that showed a statistically significant interaction with RT on breast cancer risk.

Next, they estimated the interaction odds ratio (OR) for the risk of breast cancer for each SNP and created a risk score that combined these RT-interacting SNPs, finding that a higher score on the RT-interaction-PRS was associated with greater breast cancer risk after chest RT for HL:

  • middle versus lowest tertile: OR = 1.2 (95% CI 0.8-1.7; p=0.348)
  • highest versus lowest tertile: OR=1.6 (95% CI 1.1-2.4; p=0.007)

The OR per one standard deviation of the RT-interaction-PRS was 1.3 (95% CI 1.1-1.5; p=0.002), they added.

The authors also conducted a case-control analysis to test the association of the RT-interaction-PRS and a standard PRS for breast cancer (BC-PRS) after HL in patients with RT-induced breast cancer and a control group of RT-treated HL survivors without breast cancer (n=491). The BC-PRS contained 76 SNPs that are known to increase breast cancer risk in the general population.

According to the BC-PRS, women in the highest quintile were more than twice as likely to develop RT-induced breast cancer than women in the lowest quintile (OR=2.4; 95% CI 1.4-4.2; p=0.002). There was no interaction between the RT-interaction-PRS and the BC-PRS (p=0.645).

"Annual breast cancer surveillance is already recommended for women between the ages of 25 and 50 who received chest radiation of ≥20 Gy before age 30," Dr. van Leeuwen concluded. "Based on our findings, these screening recommendations could be extended, perhaps to women who received chest radiotherapy between ages 30 and 40 who have a high genetic risk of [radiation-induced] breast cancer."

Dr. van Leeuwen noted that the RT-interaction-PRS requires "external validation in an independent study" to confirm these findings, adding that "further research should focus on the implementation of clinical prediction models and the inclusion of both common and rare genetic risk variants into [existing] genetic risk scores."

The authors report no relevant conflicts of interest.


Opstal-van Winden AWJ, de Haan HG, Hauptmann M, et al. Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma. Blood. 2018 December 20. [Epub ahead of print]

There is much debate about the role of radiation in the management of HL, and this debate is somewhat geographic, insofar as there is much more support for combined-modality therapy in Germany and Europe than in the U.S. and Canada. Taking all the studies of patients with HL who were treated with chemotherapy or with combined-modality therapy, there is a small advantage in favor of radiation for progression-free survival, but not overall survival. Overall, these findings, if validated in an independent cohort, will allow us to move toward a more personalized schema for treatment recommendations.

Catherine M. Diefenbach, MD
NYU Langone Health
New York, NY


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