The obvious outcome from this study would seem to be to recommend breast cancer screening for female childhood cancer survivors, but the researchers emphasized that more discussion may be required before guidelines can be drafted.

“Obviously screening guideline groups will have to thoroughly review the existing data in order to formulate consensus-based recommendations. However, the magnitude of risk that we observed related to anthracycline doses of 250 mg/m2 or above is similar to that related to higher doses of radiation in cancer survivors, BRCA mutations in the general population, and in our study, [to] having any one of the known predisposition mutations modeled,” said Dr Ehrhardt.

The mechanism of action of anthracyclines is complex, but it is possible that there is a dose-dependent risk increase for breast cancer risk — rather than an ultimate threshold — with lower doses of anthracyclines still conferring some increased risk of breast cancer.

“I think between the 3 studies mentioned, there’s a compelling argument to screen those exposed to higher doses of anthracyclines, such as 250 mg/m2 or greater, but for those with intermediate exposures, we really need large, pooled studies powered to more definitively define risk in this group before coming to any conclusions,” said Dr Ehrhardt.


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No guidance currently exists specifically on screening for breast cancer after anthracycline exposures, but there are already several schemes established to come to a consensus for what care is appropriate for survivors of childhood cancers, including one from The International Late Effects of Childhood Cancer Guideline Harmonization Group and another from the Children’s Oncology Group.

“The International Guidelines Harmonization Groups are carefully reviewing these data to refine recommendations for the long-term follow-up of childhood cancer survivors,” said Lindsey Morton, PhD, senior investigator in the division of cancer epidemiology and genetics at the National Cancer Institute in Maryland. “Future collaborative efforts are planned to combine these results with those from several other recently published studies. These combined analyses will enable better understanding of joint effects of anthracyclines and other treatments on breast cancer risk, and whether that risk varies, for example, by breast cancer subtype,” she added.

As well as previous treatment history, there are other factors to consider when deciding whether and when to start breast cancer screening in female survivors of childhood cancers.

“There is consensus among experts in childhood cancer survivorship that young women who have risk factors for breast cancer start screening with yearly mammogram and breast [magnetic resonance imaging] at a younger age than what is recommended for women in the general population,” said Lisa Kenney, MD, MPH, senior physician at Dana-Faber Cancer Institute and Boston Children’s Hospital, and assistant professor of pediatrics at Harvard Medical School, Boston, Massachusetts. “All known risk factors for breast cancer are taken into account when recommending breast cancer screening for childhood cancer survivors, including medical history, family history, and prior cancer history, including treatments with radiation and chemotherapy,” she added.

The use of anthracyclines for some childhood cancers, such as certain types of leukemia, has been greatly reduced in recent decades. But for some types of malignancies, high doses are still given and are considered essential for successful treatment. There are more than 400,000 childhood cancer survivors in the US,3 and St Jude’s has robust long-term follow-up programs in place. But how can these results be applied to other centers and used to benefit survivors who are perhaps older and not as likely to be engaged with long-term follow-up care?

“We strongly recommend that all survivors have access to a summary of their cancer treatment,” said Dr Kenney. “We also strongly recommend that all cancer survivors receive cancer-related follow-up care either through a designated long-term follow-up program or [through] their primary care provider. When patients have access to a summary of their prior cancer treatments, they can have ongoing discussions with their health care providers to understand how new research may impact their follow-up care,” asserted Dr Kenney.

The researchers are also pursuing further studies, including working with international collaborators to include more survivors.

“Given everything we have learned in recent years regarding doxorubicin-equivalent cardiotoxic doses of anthracyclines, it is certainly important that we establish preclinical models and pooled cohorts in order to better understand which threshold doses are most damaging to breast tissue in children with cancer,” said Dr Ehrhardt.

Children with cancer can receive a mix of chemotherapy agents, surgical procedures, and sometimes radiation. These results on the long-term effects of radiation and anthracyclines are likely to only be scratching the surface.

“With recent advances in genomics and international collaborative efforts to combine data from multiple studies of treatment-related second cancers, this is an exciting time for researchers and clinicians to improve long-term care for childhood cancer survivors,” concluded Dr Morton.

References

  1. Ehrhardt MJ, Howell CR, Hale K, et al. Subsequent breast cancer in female childhood cancer survivors in the St Jude Lifetime Cohort Study (SJLIFE). J Clin Oncol. 2019;37(19):1647-1656.
  2. Henderson TO, Moskowitz CS, Chou JF, et al. Breast cancer risk in childhood cancer survivors without a history of chest radiotherapy: a report from the childhood cancer survivor study. J Clin Oncol. 2016;34(9):910-918.
  3. Teepen JC, van Leeuwen FE, Tissing WJ, et al. Long-term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG LATER study cohort: role of chemotherapy. J Clin Oncol. 2017;35(20):2288-2298.
  4. American Cancer Society. Protecting health after childhood cancer. Published August 28, 2015. Accessed August 14, 2019.