Second cancers in 475 000 women with early invasive breast cancer diagnosed in England during 1993-2016: population based observational cohort study.

To describe long term risks of second non-breast primary cancers and contralateral breast cancers among women with early invasive breast cancer after primary surgery. Population based observational cohort study. Routinely collected data from the National Cancer Registration and Analysis Service for England. All 476 373 women with breast cancer as their first invasive (index) cancer registered in England from January 1993 to December 2016 with follow-up until October 2021. Rates and cumulative risks of subsequent primary cancers, compared with those occurring in the general population; associations with characteristics of patients, index tumours, and adjuvant treatments. Although 64 747 women developed a second primary cancer, the absolute excess risks compared with risks in the general population were small. By 20 years, 13.6% (95% confidence interval 13.5% to 13.7%) of women had developed a non-breast cancer, 2.1% (2.0% to 2.3%) more than expected in the general population, and 5.6% (5.5% to 5.6%) had developed a contralateral breast cancer, 3.1% (3.0% to 3.2%) more than expected. The absolute excess risk of contralateral breast cancer was greater in younger than in older women. Among specific types of non-breast cancer, the largest 20 year absolute excess risks were for uterine and lung cancers. Although for cancers of the uterus, soft tissue, bones and joints, and salivary glands, as well as acute leukaemias, standardised incidence ratios exceeded those of the general population by a factor of at least 1.5, absolute excess risks at 20 years were <1% for every individual non-breast cancer type. When patients were categorised according to adjuvant treatment, radiotherapy was associated with increased contralateral breast and lung cancer, endocrine therapy with increased uterine cancer (but reduced contralateral breast cancer), and chemotherapy with increased acute leukaemia. These were consistent with effects reported in randomised trials, but positive associations for soft tissue, head and neck, ovarian, and stomach cancers were also identified, and these have not previously been observed in trials. This suggested that approximately 2% of all the 64 747 second cancers and 7% of the 15 813 excess second cancers in the cohort may be attributable to adjuvant therapies. The risk of a second primary cancer in women treated for early invasive breast cancer is slightly higher than for women in the general population. Contralateral breast cancer accounts for around 60% of the overall increase, with higher risks in younger women. The risk associated with adjuvant therapies is small.