Researchers at the St. Jude Children?s Research Hospital in Memphis, Tennessee, found that common genetic variations can help to identify pediatric cancer survivors who are at increased risk for developing breast cancer while relatively young.

The researchers found that a combined evaluation of common variants with small effects and rare predisposing mutations among young female childhood cancer survivors may further stratify this high-risk population for subsequent breast cancer risk.

This is the conclusion from a study supported by funding from the American Lebanese Syrian Associated Charities and by grants from the National Institutes of Health. The study results were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.[1]

Photo 1.0: Zhaoming Wang, Ph.D., used data from the St. Jude Lifetime Cohort study to find evidence that common genetic variations can help to identify pediatric cancer survivors who are at increased risk for developing breast cancer. The findings suggest that personalized breast cancer surveillance and prevention for childhood cancer survivors is on the horizon.

?Our findings suggest that polygenic screening can inform personalized breast cancer surveillance in female childhood cancer survivors,? noted Zhaoming Wang, PhD, associate member in the Department of Epidemiology and Cancer Control at the St. Jude Children?s Research Hospital.

?This method can be utilized in the clinical setting to enhance the identification of high-risk survivors to enable the early detection and potential prevention of subsequent breast cancer,? Wang added.

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Increased risk
“Female childhood cancer survivors have an increased risk of developing subsequent breast cancer compared with the general population. This increased risk has largely been attributed to cancer treatment regimens, such as chest irradiation and/or exposure to high-dose chemotherapeutic agents. Current screening of this population relies on treatments and doses used to treat childhood cancer,” Wang explained.

However, Wang further explained that for survivors at some of the highest risk, the collective effect of the common genetic variants is comparable to having a high-risk mutation in a breast cancer predisposition gene like BRCA1 or BRCA2.

And, according to Wang and his colleagues, these mutations are associated with a 2- to 100-fold increased breast cancer risk.

Previous findings
Wang previously found that survivors of childhood cancer have an increased risk of subsequent breast cancer if the survivors carry pathogenic or likely pathogenic (P/LP) mutations, such as mutations to the BRCA1 gene*. [2]

?Our current study attempts to investigate the contributions to the risk of subsequent breast cancer by considering the full picture of breast cancer genetic susceptibility, which includes common genetic variants with small effects (polygenic determinants) in addition to P/LP mutations (monogenic determinants),? he noted.

Trial design
Wang and colleagues utilized information from the St. Jude Lifetime Cohort Study (SJLIFE),?a retrospective hospital-based study with prospective clinical follow-up, by analyzing whole-genome sequencing data for 1,133 female cancer survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4). Of these survivors, 47 developed one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0).

The researchers constructed a polygenic risk score (PRS) for individual survivors by calculating the weighted sum of 170 common breast cancer risk alleles present in each survivor?s genome. The researchers also evaluated the presence of P/LP mutations in 11 breast cancer predisposition genes. Relative rates and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.

Following a multivariable analysis, the researchers found that survivors in the highest PRS quintile had 2.7 times the risk of subsequent breast cancer compared to survivors in the lowest quintile (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1) and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively.

Survivors treated with chest irradiation had even higher risk; those in the highest PRS quintile treated with radiation had three times the risk of subsequent cancer compared to those in lowest quintile treated with radiation.

Survivors who carried P/LP mutations had 21.8 times increased risk for subsequent breast cancer compared with those who didn?t have P/LP mutations. Survivors treated with chest irradiation and who carried P/LP mutations had 10.3 times increased risk for subsequent breast cancer compared with those who didn?t have P/LP mutations treated with chest irradiation.

?The PRS can identify individuals with high breast cancer risk that do not carry known pathogenic mutations,? Wang said. ?Our results indicate that both polygenic determinants and large-effect rare mutations (monogenic determinants) contribute to the risk of subsequent breast cancer independently,? he added.

Notably, PRS was significantly associated with risk of subsequent breast cancer only in women less than 45 years old (RR = 3.2; 95% CI, 1.2-8.3).

?Our data supports the hypothesis that genetic risk factors play a more important role in the development of subsequent breast cancers in younger women,? Wang said.

?However, this observed age-specific association could be partly due to the smaller sample size of older survivors in our study.

?Our results indicate that personalized breast cancer surveillance strategies for survivors should incorporate prior exposure to specific anti-cancer treatments, the presence of P/LP mutations, and the cumulative presence of small-effect common variants, as represented by a polygenic risk score.?

Conclusion
Based on these findings, the researchers believe that including a risk score in screening would help identify more than 50 survivors in this study at high risk for breast cancer in addition to 34 carriers of predisposing mutations,? Wang said.

?These women would be candidates for more intensive breast cancer screening and follow-up.?

The analysis showed that survivors with some of the highest scores, those in the top 1 percent, are about four times as likely to develop breast cancer as survivors with average risk scores.

Limitations
Limitations of the study include a relatively young cohort of childhood cancer survivors. Additionally, analysis was restricted to survivors of European ancestry.

The results must be validated in additional pediatric cancer survivors before common genetic variations are used clinically to help guide their follow-up care. Follow-up studies should also be conducted within other non-European ethnic groups.

Reference
[1] Wang Z, Liu Q, Wilson CL, Easton J, Mulder H, Chang TC, Rusch MC, et al. Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE). Clin Cancer Res. 2018 Oct 26. doi: 10.1158/1078-0432.CCR-18-1775. [PubMed][Article]
[2] Wang Z, Wilson CL, Easton J, Thrasher A, Mulder H, Liu Q, Hedges DJ, et al Genetic Risk for Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer.J Clin Oncol. 2018 Jul 10;36(20):2078-2087. doi: 10.1200/JCO.2018.77.8589. Epub 2018 May 30.[PubMed][Article]


* Pathogenic or likely pathogenic (P/LP) mutations were defined as mutations to the following breast cancer predisposition genes: BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, and NBN.

Last Editorial Review: October 29, 2018

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