New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study and the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study
Reporter: J. Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2012
Presenter: Chaya S. Moskowitz, PhD Presenter's Affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY
With recent improvements in pediatric oncology, modern overall survival rates approach 80% for childhood cancers. Unfortunately, second malignant neoplasms are the leading cause of death among long-term survivors of Hodgkin’s lymphoma.
Multiple studies have shown an increase risk of breast cancer after radiation to the chest. Cumulative incidence ranges between 13-20% for women at 40 years of age, and breast cancer has been seen to occur as soon as 8 years following radiation. Previous studies have demonstrated that both volume of tissue irradiated as well as total dose of radiation plays a significant role in the development of subsequent breast cancer.
The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study which examines patients who have survived at least 5 years after diagnosis of childhood cancer. Patients with cancers diagnosed before the age of 21 during 1970-1986 were enrolled from 26 institutions across the US and Canada, and data is maintained and accumulated via review of medical records as well as healthcare provider and survivor survey-based reporting. The database is publicly accessible for research purposes.
The Women's Environmental Cancer and Radiation Epidemiology study (WECARE) is a large international multi-center, population-based case-control study with female breast cancer survivors recruited through 5 population-based registries in the US and Denmark. The study was designed to evaluate the susceptibility of carriers of certain genetic mutations, specifically BRCA-1/ BRCA-2, to second cancers.
In order to screen for second malignancies, the Children’s Oncology Group developed risk definitions and recommended surveillance guidelines. For survivors at increased risk for breast cancer, the recommended screening for female patients having received >20 Gy to breast tissue includes annual physical exam, mammogram, and breast MRI starting at age 25, or 8 years following radiotherapy.
The purpose of this study was to estimate breast cancer risk in patients that received chest radiation as treatment for childhood cancer and compare that risk with patients known to carry BRCA1 and BRCA2 as well as the general population. Additionally, the authors attempted to evaluate subpopulations of child cancer survivors not previously studied for increased risks of breast cancers.
Materials and Methods
Using the Childhood Cancer Survivor Study, the authors evaluated the risk of breast cancer in a cohort of 1286 female childhood cancer survivors treated with chest radiation and estimated the cumulative incidence of breast cancer non-parametrically treating death as a competing risk.
The cumulative incidence of breast cancer in BRCA1/2 mutation carriers was estimated using the first-degree relatives in the WECARE cohort. In that study, there were 1397 participants with unilateral breast cancer and known BRCA carriers. This study focused on data from 4570 female first-degree relatives of women diagnosed with unilateral breast cancer participating in the WECARE Study.
In order to calculate the absolute excess risks relative to the general population, the rates of breast cancer for the U.S. population and standard incidence ratios (SIR) were estimated using population-based data from the SEER program.
From the CCSS cohort, 53% of females enrolled were previously treated for Hodgkin’s lymphoma. Wilm’s tumor, leukemia, and neuroblastoma were the next three most common diagnoses.
With a median follow-up of 26 years (range 5-39 years) for the CCSS cohort, 176 women were diagnosed with breast cancer at a median age of 38 years (range 24-53) following chest irradiation.
Median latency for the development of breast cancer following radiation was 23 years (range 7-38); 84% of women that subsequently developed breast cancer had Hodgkin’s lymphoma with a median age at diagnosis of childhood cancers of 16 years old (range 3-20).
For patients that received chest radiation, the overall cumulative incidence of breast cancer by age 40 was 10%. This climbed to 24% by age 50. Among patients treated for Hodgkin’s lymphoma, the rate of breast cancer in survivors was 30%. This is more than 20 times higher than that expected for individuals in the general U.S.
In comparison, among first-degree relatives of WECARE Study participants, 324 were diagnosed with breast cancer (median age at diagnosis, 55 yrs (range 26-90)). The estimated cumulative incidence by age 50 was 31% and 10% in carriers of BRCA1 and BRCA2mutations, respectively.
The general U.S. population cumulative incidence of breast cancer is 4% by age 50.
Among the childhood cancer survivors, absolute excess risk for breast cancer diagnosed per 10,000 person-years of observation were respectively 34, 27, and 95 among women treated with 10-19 Gy (23%), 20-29 Gy (17%), and 30+ Gy (56%) of chest RT.
When radiation field design was examined, women treated with whole lung radiation had rates of breast cancer nearly equal to those associated with the mantle field.
Women treated for childhood cancer with chest radiation have a substantial risk of breast cancer comparable to BRCA1/2 mutation carriers and considerably greater than that of the general population.Women treated for Hodgkin’s lymphoma with chest irradiation had a risk of breast cancer comparable to carriers of BRCA1.
Women treated for other types of childhood cancer with chest irradiation had a risk of breast cancer comparable to carriers of BRCA2.
Women treated with whole lung radiation and women treated with radiation doses of 10-19 Gy to the chest had an increased excess risk, warranting consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with > 20 Gy.
Second malignancies are the leading cause of death among long-term survivors of Hodgkin’s lymphoma, and female survivors have a markedly increased risk of breast cancer. In fact, the incidence of second cancers surpasses risk of relapse by 20 years from lymphoma diagnosis.
This study was well conducted and utilized multiple patient cohorts to compare rates of breast cancer in childhood cancer survivors with both BRCA carriers as well as the general population.
As expected, the results are humbling, with more than 20 fold increases in breast cancer following chest radiation for Hodgkin’s lymphoma. The study also identified lower doses (10-19 Gy) as well as other cancers with elevated risk, prompting the extension of screening recommendations to these groups.
It must be noted that the radiation techniques during the 1970-1980’s are vastly different from those of today, and we hope the recent changes in radiation techniques will decrease this risk.
Mechanisms for decreasing both total dose of radiation as well as volume of radiation are of great interest. Both adult and pediatric protocols have lowered the total dose of radiation and decrease field size. In recent years, the dose for lymphomas has declined from 40 Gy to 15-20 Gy. Similarly, mantle fields have decreased and frequently, involved region and involved node techniques are utilized. Proton therapy may also offer unique techniques for normal tissue sparing.
Although interest in eliminating radiation is significant, it must be noted that several studies have demonstrated the continued importance of radiation in lymphoma with improved progression free survival though no change in overall survival in those studies. Additionally, as radiation’s role is diminished, the accelerated chemotherapy regimens certainly have long-term toxicities that must be considered as well.
As noted in the presentation, the rates of breast cancer development in childhood cancer survivors never reach a plateau, highlighting the critical nature of continued follow-up. Previous studies have reported astonishingly low rates of compliance with screening for second malignant neoplasm, indicating severe insufficiencies in survivorship care.
With much deserved attention now turning to survivorship plans, the challenge now becomes identifying strategies to decrease the risk and mechanisms to improve compliance with recommendations.
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