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Treating unilateral breast cancer with a bilateral mastectomy substantially reduced the risk of contralateral breast cancer compared with unilateral mastectomy or lumpectomy, yet not breast cancer mortality, according to a cohort study.

Over 20 years of follow-up in three matched groups totalling more than 108,000 women, contralateral breast cancers occurred in about 2% of the unilateral mastectomy and lumpectomy groups versus 0.3% of the bilateral mastectomy group, reported Steven Narod, MD, of Women's College Hospital in Toronto, and colleagues.

Once a patient experienced a contralateral breast cancer, their subsequent risk of breast cancer mortality increased fourfold, yet preventing contralateral cancer through preemptive surgery did not appear to reduce the risk of death over the long term, they detailed in .

Across the three groups, there was no appreciable difference in breast cancer mortality rates at 20 years: 9.1% died of breast cancer in the unilateral mastectomy group, and 8.5% died in both the lumpectomy and bilateral mastectomy groups.

"It is generally presumed that a contralateral breast cancer is a new primary tumor with the potential to metastasize," the researchers wrote. "Our findings question this interpretation. If the increase in deaths after a contralateral breast cancer were due to metastasis of the second cancer, we would expect bilateral mastectomy to be beneficial."

Overall, the cumulative breast cancer mortality rate was 32.1% at 15 years for patients developing a contralateral cancer and 14.5% for those who did not develop a contralateral cancer (HR 4.00, 95% CI 3.52-4.54).

"The findings of this cohort study indicate that women with unilateral breast cancer should be advised that bilateral mastectomy greatly reduces the risk of a second cancer, but does not affect mortality," Narod and colleagues concluded.

In an , Seema Ahsan Khan, MD, and Masha Kocherginsky, PhD, both of Northwestern University Feinberg School of Medicine in Chicago, said that the study's findings are consistent with the literature.

However, the finding that breast cancer mortality risk was substantially higher among women who developed a contralateral breast cancer is a "disturbing finding ... particularly for patients," they suggested. "Therefore, caution is needed when interpreting these analyses."

Khan and Kocherginsky also noted that the issues of preference and risk tolerance will vary among patients.

"There are certainly those who, with a good understanding of the risks and quality of life problems associated with [bilateral mastectomy] with or without reconstruction, would prefer to avoid both the imaging experience of breast surveillance and the burden of undergoing treatment for a second breast cancer (even if highly likely to be cured)," they wrote. "The education of patients as well as surgeons regarding the risks and benefits of [bilateral mastectomy] is a continuing and necessary endeavor given existing interventions have not impacted the rates of contralateral phylactic mastectomy."

For this study, Narod and colleagues used the National Cancer Institute's SEER Program registry database to evaluate survival outcomes of women diagnosed with unilateral stage 0 to III breast cancer (invasive and ductal carcinoma in situ) from 2000 to 2019. The study sample included 661,270 women (mean age 58.7 years). After matching according to surgical approach, there were 36,028 women in each of the three groups.

The authors found that the hazard ratio for dying of breast cancer was higher for women initially treated for ductal carcinoma in situ (HR 10.30, 95% CI 5.17-20.49) compared with women initially treated for invasive cancer (HR 4.04, 95% CI 3.54-4.60).

In addition, the hazard ratio for breast cancer mortality was similar for time from primary diagnosis to contralateral breast cancer for all matched patients. After experiencing a contralateral breast cancer in the first 5 years, the hazard ratio was 3.89 (95% CI 3.36-4.49); in 5 to 10 years, it was 4.12 (95% CI 3.24-5.23); and in 10 to 15 years, it was 4.48 (95% CI 2.73-7.35).

The hazard ratio for breast cancer mortality slightly declined with increasing age at diagnosis of the contralateral cancer (30-39 years: HR 5.16, 95% CI 3.17-8.39; 40-64 years: HR 4.19, 95% CI 3.62-4.84; 65 years and older: HR 3.25, 95% CI 2.55-4.14).

The authors acknowledged their study had limitations. For example, they did not have data on the use of endocrine therapy, which may have affected the risks of contralateral cancer among patients with estrogen receptor-positive breast cancer, nor did they have data on family history or whether the patients had BRCA1 or BRCA2 mutations, which would have put them at higher risk of contralateral breast cancer.

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