A new study published in JAMA Oncology reports that for women who have survived Hodgkin's lymphoma, the risk for subsequent estrogen-receptor (ER)–negative breast cancer is nearly six times greater than for the general population. The study also found that the increased risk for ER-positive breast cancer is not as significant and is primarily associated with the previous radiotherapy.

The overall risk for breast cancer is known to be high among young survivors of Hodgkin's lymphoma, particularly those who receive radiotherapy to the chest when they are younger than 30 years. However, there has been little research involving large cohorts in which the role of radiotherapy has been evaluated in subtypes with respect to ER status.

For the study, the researchers used data from 12 US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries. They identified 7355 female patients aged 10 years to 39 years who had been diagnosed with first primary Hodgkin's lymphoma. After a follow-up of a minimum of 5 years after diagnosis, 377 patients were found to have developed invasive breast cancer.

Among the breast cancers, 57% were ER-positive, and 34% were ER-negative; for 9%, ER status was unknown. Compared with the general population, however, the relative risk of ER-negative breast cancer was significantly higher than the risk for ER-positive breast cancer. The increase in ER-positive disease was only observed among women treated with radiotherapy.

For those who did not receive radiotherapy, the risk was similar to that of the general population. Of those who received radiotherapy, the relative risk for ER-positive breast cancer was lower if treatment also included chemotherapy, compared to those who did not receive chemotherapy or whose chemotherapy status was unknown.

Studies supporting the argument for using chemotherapy alone, without radiotherapy, include a randomized trial of 405 patients with stage IA or IIA Hodgkin's lymphoma that was published in the New England Journal of Medicine. In that trial, chemotherapy alone was associated with higher overall survival, owing to a lower death rate from other causes at a median follow-up of 11.3 years.

In that study, the rate of overall survival was 94% in patients who received chemotherapy alone, compared with 87% in those who received radiotherapy, with or without chemotherapy. Given the increased risk of second cancers, including breast cancer related to the use of radiation therapy for Hodgkin lymphoma, current recommendations aim to minimize the use of radiation therapy.

The findings of an absence of an association between prior treatment and ER-negative breast cancer were particularly noteworthy. This suggests that different factors may be at play in increasing the risk of ER-negative breast cancer.

In conclusion, the ratio of estrogen-receptor status so skewed toward ER-negative disease, compared to the general population, and this risk was elevated regardless of treatment modality. The elevated risk for ER-positive disease only with radiotherapy suggests the opportunity for chemoprevention, which has been successful in lowering risk for other high-risk women.