Breast Radiotherapy May Up Risk of Contralateral Disease

Studies seeking to establish whether radiotherapy or chemotherapy to treat breast cancer negatively affects the risk of developing cancer in the contralateral breast have produced inconclusive results. New data from the Netherlands suggest that young patients who undergo postlumpectomy radiotherapy using tangential fields have an increased risk of cancer arising in the other breast. Lead author Maartje Hooning, MD, of The Netherlands Cancer Institute in Amsterdam, explained that while experts have quantified the risks for contralateral breast cancer associated with older radiotherapy techniques, studies on the relationship between modern methods of radiotherapy and contralateral disease have not been definitive.

Dr. Hooning and colleagues used the registries of 2 cancer centers in The Netherlands to identify 7221 patients who were 1-year survivors of breast cancer and assess their risk of contralateral disease. Researchers looked at key dates and treatment methods related to the diagnosis of primary breast cancer and recurrence, discovery of contralateral tumor, history of breast cancer in first- and second-degree relatives, and date of last follow-up or date. Dr. Hooning emphasized the value of knowing the patients’ family history of breast cancer, and she noted that their study was “the first to investigate the combined effect of radi1otherapy and family history on risk of contralateral breast cancer.”

Dr. Hooning said a patient’s age at diagnosis is an important factor when assessing risk for contralateral breast tumors, and 30% of their study population consisted of younger patients (aged <45 years). “We expected increased risks specifically in patients treated at ages <45 years,” she said. This expectation was borne out, as the data showed an increase in the risk of radiotherapy-associated contralateral breast cancer that corresponded with a decrease in the age at first treatment. The hazard ratio (HR) for patients aged <35 years was 1.78 compared with 1.09 in patients aged >45 years.

Postmastectomy radiotherapy using direct electron fields resulted in significantly lower radiation exposures to the contralateral breast than postlumpectomy radiation treatments using tangential fields. In women aged <45 who underwent radiotherapy postlumpectomy, investigators observed a 1.5-fold increase in the risk for contralateral tumors compared with women who had postmastectomy radiotherapy. Adjuvant chemotherapy appeared to reduce a patient’s risk for contralateral breast cancer in the first 5 years after surgery, but the effect was not significant and did not persist beyond 5 years.

Dr. Hooning stressed that the radiotherapy techniques evaluated in the study are already considered outdated. She said that applying dosimetry and estimating the risk of contralateral breast cancer per Gy increase allows the results to be extrapolated to modern techniques. If the dose absorbed by the contralateral breast is known, she explained, it is possible to estimate the excess risk of contralateral breast cancer corresponding to this specific dose.

Dr. Hooning said today’s radiotherapy techniques expose the contralateral breast to lower doses of radiation than the older techniques in their study. She noted, however, that data showed there was a dose-response relationship in the risk of contralateral breast cancer that should be taken into consideration. “Especially in young women, the radiation dose to the contralateral breast should be kept as low as possible,” she said.

SuEllen Pommier, PhD, research professor of surgery at Oregon Health and Science University (OHSU) in Portland had reservations about the study’s methodology. “They never proved their comparison group very well,” said Dr. Pommier, who was not involved in the study. “For example, they mixed the stages of cancer together, which is a confounding problem since we know that stage I is not going to act like stage III.” She also noted that the researchers did not compare the incidence and cumulative risk between the postlumpectomy and postmastectomy radiation groups and similar cohorts that did not undergo radiotherapy.

Rodney Pommier, MD, a professor of surgery at OHSU, said he would not change clinical practice based on these results. He expressed concerns about selection bias or a distilling effect associated with this type of study, because for people to have developed a contralateral tumor, they have to have survived their initial breast cancer. “As time goes on, young people die from their first cancer and older patients die from other things, dropping out of the study,” he explained. “You are distilling down your cohort to this young group of patients who survived their initial breast cancer. The second tumor in the contralateral breast may be as much a function of time as radiation exposure.”

Dr. Pommier questioned the study’s exclusion of information on the impact on survival, an important clinical consideration in cancer patients. “What we found in a recent study is that second breast cancers are generally found at an earlier stage and do not show an adverse impact on survival,” he said. “This study doesn’t talk about survival at all.”

Ben Smith, MD, adjunct assistant professor at the University of Texas M. D. Anderson Cancer Center in Houston, said the study was done well. He pointed out that investigators had comprehensive data regarding treatment and follow-up for >7000 patients. “This adds to a growing body of literature that exposure of the female breast to radiotherapy at a relatively young age leads to an increased risk of radiation carcinogenesis,” he said. “It includes data on a very large cohort strengthening the assertion that radiation can have a carcinogenic effect.”

He pointed out that researchers found a synergistic relationship between family history and radiation, suggesting that limiting radiation doses to the contralateral breast is of particular concern for young women with a positive family history for breast cancer.

Dr. Smith theorized that the increased risk for these women might be related to the BRCA1 and BRCA2 genes, which are the 2 most commonly associated with familial breast cancer syndromes. “BRCA1 and BRCA2 are both implicated in DNA repair,” he said. “We also know that radiation induces DNA damage. The results suggest that those with a baseline deficiency in DNA repair are potentially more sensitive to the carcinogenic effects of radiotherapy.”

“Paradoxically, I think this study provides reassurance that modern radiotherapy should not cause excessive harm to even our younger patients,” he continued. “The results show that low doses of radiation—typical of current techniques such as field-in-field intensity-modulated radiation therapy&mdash;did not lead to excess risk of contralateral breast cancer, even in younger patients.”

J Clin Oncol

Hooning MJ, et al. Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer. . 2008;26:5561-5568.