NEW ORLEANS-Female survivors of childhood cancer who received radiotherapy to the chest are known to have a substantially elevated risk for developing breast cancer as adults, but that risk may be even higher if they have either of two specific genetic variants.
However, those genetic variants increased breast cancer risk only in survivors who received 10 Gy or higher of chest radiotherapy, according to researchers at the annual meeting of the American Association for Cancer Research.
Identification of these variants may help stratify which childhood cancer survivors are at the highest risk of breast cancer as adults, said Lindsay M. Morton, PhD, a Senior Investigator in the Radiation Epidemiology Branch of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, the study's first author.
According to Morton, a variant at position 1q41 was associated with nearly a twofold increased risk of breast cancer in adult survivors (hazard ratio 1.96), and another at position 11q23 was associated with a greater than threefold increased risk (hazard ratio 3.71), compared with controls.
These variants did not increase breast cancer risk in childhood cancer survivors who had not received radiotherapy for their primary malignancy.
"This is the first study that provides evidence that germline genetics outside of the context of high-risk syndromes can modify the risk for breast cancer in childhood cancer survivors treated with chest radiotherapy," Morton explained.
The data presented were based on blood and saliva samples from 3,426 female survivors from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.
Of those, 207 subsequently developed breast cancer. The primary pediatric cancer in those women was Hodgkin lymphoma in 65 percent, leukemia in 10 percent, and 26 percent other.
Two-thirds of the patients had at least 10 Gy radiation during the course of their childhood treatment. Median age of breast cancer in these survivors was 39 years, a much younger age than seen in the general population.
Questions to Be Answered
The research "leads to an intriguing hypothesis, that these germline variants identified could be a pro-proliferative, pro-invasive phenotype that supports the growth of malignant breast cells, but only following the transformation of those cells by ionizing radiation exposure," Morton said.
She added that this is a discovery study, and "much work is needed to be done in the laboratory to determine if these genes are the ones involved in the subsequent breast cancer risk, or if, in fact, these markers are tagging a different effect within the genome that don't even involve these genes."
Morton listed questions yet to be answered:
* What is the relationship between the genotype and the breast cancer risk given the radiation exposure typical of patients treated today, which are often lower treatment doses and volumes than patients in the past?
* Is there an effect of age at treatment?
* Could there be a stronger or weaker effect for a particular breast cancer molecular subtype, considering what has been learned from the general population about different genetic etiologies of different molecular subtypes?
Cancer Screening & Therapy
In the future, understanding these genetic susceptibilities may ultimately alter front-line therapy decisions, and also could have an impact on screening recommendations.
"The Children's Oncology Group recommends annual dual-modality screening for childhood cancer survivors who were treated with chest radiotherapy, beginning at age 25 or 8 years after treatment, whichever is later," Morton said. "If germline susceptibility confers different levels of risk, then perhaps we can use this inherited susceptibility to identify those who would benefit most from screening."
AACR President Nancy E. Davidson, MD, Professor of Medicine and Oncology and Director of the University of Pittsburgh Cancer Institute, discussed this paper with Oncology Times after the meeting.
She noted that, while the findings about the genetic variants isolated by these researchers may not have any immediate clinical implications, they are a proof of principle to focus on going forward.
"This study reminds us that survivorship is going to be increasingly important to us, and so it is becoming more important to think about the long-term consequences of the initial disease as well as the long-term consequences of the therapy these pediatric patients get," Davidson said. "Maybe we will get to a point where we tailor the therapy for the initial cancer and also understand if there is some differential sensitivity to toxicities."
Robert H. Carlson is a contributing writer.