From the Journals

Risk of contralateral breast cancer highest for women under 40



Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.

The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.

“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”

The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.

The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.

At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.

For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.

Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.

Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.

But when examined by total GRS score, differences emerged.

“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.

Again, there was no increased risk for women aged older than 40 years at first diagnosis.

“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.

Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.

“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.

Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.

SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.

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