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Rates of breast cancer among female childhood cancer survivors have declined significantly since 1970, coinciding with changes in treatment for childhood cancers, a large retrospective cohort study showed.

Overall, women who survived childhood cancers had an increased risk of breast cancer versus an age/sex/calendar year-matched population. However, the rate of invasive breast cancer decreased by 18% for each 5-year diagnostic period for childhood cancers.

The declining breast cancer rate had a temporal association with declining use of chest radiotherapy (RT), from 34% of cases in the 1970s to 17% in the 1990s, as well as decreased use of pelvic irradiation in the treatment of childhood cancers. The impact of trends in RT were tempered to some extent by increased use of anthracycline chemotherapy, reported Tara Henderson, MD, MPH, of the University of Chicago Comer Children's Hospital, and co-authors in .

"As the cancer survivor population has grown, the significant risk for treatment-related health outcomes of therapies has become clear," the authors wrote. "These findings provide important insight into temporal patterns in treatment-associated breast cancer risk."

"With the consideration of age at childhood cancer diagnosis and attained age, we observe a significant decline in survivors' invasive breast cancer incidence rate in more recent treatment eras," they continued. "We document for the first time, to our knowledge, that this decline remains statistically significant, although slightly attenuated, after accounting for detailed cancer treatment exposures."

Results in Context

The study corroborated previous research showing decreased incidence of secondary breast cancer (SBC) over time and an increased risk associated with prior chest RT and anthracycline exposure, noted the authors of an . The study also highlighted two challenges confronting survivorship research: the long delay in outcomes from exposure and the change in exposures over time.

"It is important to note that the treatments studied by Henderson and colleagues are vastly different than modern childhood therapeutic approaches," wrote Kelsey L. Corrigan, MD, MPH, and Michael Roth, MD, both of the University of Texas MD Anderson Cancer Center in Houston. "During the past 20 years, technologic advances have transformed the use of 2- and 3-dimensional RT with large treatment fields into image-guided, conformal, and more precise RT."

Given the challenges noted, the impact of newer RT approaches and modern systemic therapy on SBC might not be known for years to come, they continued. Consequently, the findings are difficult to interpret within the context of modern therapies for childhood cancers.

"Risk-adapted, response-based approaches for RT inclusion are increasingly being used in upfront Hodgkin lymphoma trials, and immunotherapy is being used in addition to or in place of standard chemotherapeutic agents," Corrigan and Roth noted. "We anticipate these changes will be associated with further declines in the incidence of SBC."

"However, while we wait for these long follow-up data to mature, many more patients with childhood cancer will be treated with RT and chemotherapy," they added. "Thus, we must use the information gleaned from this study and others to counsel patients, inform clinicians, and mitigate the risk of SBC."

Although 5-year survival of childhood cancers has improved over time, survivors continue to have an excess risk of premature mortality, and treatment-related (secondary) malignancies make a substantial contribution to the excess mortality risk. SBC has been driven by chest RT, attenuated by RT to the ovaries, and potentially modulated by exposure to alkylating agents, Henderson and co-authors noted in their introduction. In particular, female have a significantly increased 10-year mortality risk as compared with women with de novo breast cancer.

Approaches to treating childhood cancers have evolved considerably in recent decades, particularly with regard to frequency and dose of chest RT, the authors continued. Conversely, use of multi-agent chemotherapy has increased. Previous studies have suggested a decline in SBC in association with modifications in RT, but data on patients treated in the 1990s remain limited.

Study Design, Key Findings

To address the limitation, Henderson and colleagues analyzed data from the , a cohort of childhood cancer survivors treated at 31 North American centers. The analysis included 11,550 female participants, treated for childhood cancer from 1970 to 1999.

The participants had diagnoses from a specified group of childhood hematologic and solid malignancies, were younger than 21 at diagnosis, and remained alive 5 years after diagnosis. Treatment exposures were determined from medical records at the treating centers.

The authors found that 489 female childhood cancer survivors developed 583 SBCs, comprising 156 diagnoses of ductal carcinoma in situ (DCIS) and 427 invasive breast cancers. The study population had a cumulative breast cancer incidence of 8.1% by age 45, representing a standardized incidence ratio (SIR) of 6.6 versus the matched general population (95% CI 6.1-7.2). The SIR for invasive breast cancer was 6.1 (95% CI 5.6-6.7) and the SIR for DCIS was 8.5 (95% CI 7.3-10.0).

Although the cumulative incidence of SBC remained elevated among the childhood cancer survivors, the cumulative incidence of SBC declined with each decade from childhood cancer diagnosis. In the 1970s, the cumulative incidence of SBC by age 40 was 8.4%, declining to 5.4% in the 1980s and 5.3% in the 1990s (P_trend=0.002).

An analysis of the treatment for childhood cancers showed that use of chest RT decreased by about 50% from the 1970s through the 1990s, as did use of pelvic RT (26% to 13%). Use of anthracycline-containing chemotherapy increased from 30% of cases in the 1970s to 64% in the 1990s.

The 18% relative decrease in SBC risk by 5-year era of childhood cancer diagnosis decreased to 11% after adjustment for changes in chest RT. Additional adjustment for anthracycline use and pelvic RT resulted in a 14% decline in relative risk for each 5-year era of diagnosis.

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