Cohort study suggests a relatively low 5- and 10-year cumulative incidence of second primary breast cancer among patients aged 40 years or younger with breast cancer who are non-carriers of germline pathogenic variants, emphasizing the importance of genetic testing among patients with breast cancer. The carriers had more than a 4-fold higher risk of second primary breast cancer compared with non-carriers, although absolute case numbers were low.
While most demographic, lifestyle, and clinical characteristics measured at the time of primary breast cancer diagnosis were not associated with second primary breast cancer risk, patients with an initial diagnosis of in situ breast cancer, as opposed to invasive primary breast cancer, had an approximately 5-fold higher risk of second primary breast cancer. Findings from the Young Women’s Breast Cancer Study are published by Kristen D. Brantley, PhD, MPH of the Department of Epidemiology, Harvard T. H. Chan School of Public Health in Boston, MA, US and colleagues on 11 April 2024 in the JAMA Oncology.
Given the increased availability of genetic testing for germline pathogenic variants that predispose young women to breast cancer, it is important to recognise that a heightened risk of second primary breast cancer may not apply to all young women. There is a need to better classify young patients with breast cancer by their risk of developing second primary breast cancer, defined as a new breast cancer, distinct from the original, arising in either the ipsilateral or contralateral breast, to inform treatment decisions and surveillance options.
The authors wrote in the background that prior data suggest that risk of a second primary breast cancer is higher in young than that of women who are older when they develop a first primary breast cancer. However, most of previous studies included mainly postmenopausal patients, limiting generalisability to young adult patients. The few studies that have examined contralateral breast cancer risk in younger women have included patients who received older treatment regimens or for whom complete tumour and treatment information and germline genetic testing results were lacking.
Several studies have reported substantial differences in contralateral breast cancer risk for germline pathogenic variant carriers and non-carriers, with greater risk differences noted among the youngest women, emphasising the need to study these groups independently among young survivor populations.
To better characterise the development of second primary breast cancer among young women in the contemporary treatment landscape, the investigators estimated the cumulative incidence (risk) of second primary breast cancer among patients enrolled in the Young Women’s Breast Cancer Study, all of whom were aged 40 years or younger at primary breast cancer diagnosis. They evaluated the association of demographic factors, primary tumour characteristics, treatments, and germline genetics with risk of second primary breast cancer.
The Young Women’s Breast Cancer Study is a prospective cohort study of 1297 women diagnosed with stage 0-IV breast cancer at age 40 years or younger between August 2006 and June 2015. Participants were enrolled typically within 6 months of diagnosis. Women were recruited from 13 academic and community sites in the Massachusetts region; Denver, Colorado; Rochester, Minnesota; and Toronto, Ontario, Canada.
Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of second primary breast cancer, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and second primary breast cancer risk. Data were analyzed from January to May 2023. Main outcomes and measures are the 5- and 10- year cumulative incidence of second primary breast cancer.
In all, 685 women with stage 0 to III breast cancer (mean age [standard deviation] at primary breast cancer diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for breast cancer were included in the analysis. Over a median (interquartile range, IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed a second primary breast cancer; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary breast cancer diagnosis to second primary breast cancer was 4.2 (3.3-5.6) years.
Among 577 women who underwent genetic testing, the 10-year risk of second primary breast cancer was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of second primary breast cancer was higher among germline pathogenic variant carriers versus non-carriers (subdistribution hazard ratio [sHR] 5.27; 95% confidence interval [CI] 1.43-19.43) and women with primary in situ breast cancer versus invasive breast cancer (sHR 5.61; 95% CI 1.52-20.70).
The authors commented that to date, understanding of second primary breast cancer risk has largely relied on studies that did not separate germline pathogenic variant carriers and non-carriers, resulting in overestimation of second primary breast cancer risk among non-carriers and underestimation of risk among carriers.
Rates of bilateral mastectomy remain high among individuals youngest at diagnosis; as many women consider bilateral mastectomy in the setting of ipsilateral breast cancer. The finding of a low risk of contralateral breast cancer among non-carriers of germline pathogenic variants, provide new risk estimates to inform surgical decision-making. Low observed rates of ipsilateral second primary breast cancer may also inform decisions to undergo unilateral mastectomy among women at low risk of local recurrence.
Finding of a higher risk of second primary breast cancer among those diagnosed with in situ primary breast cancer merits further investigation in larger patient cohorts with more diverse treatment regimens.
The study findings were previously presented at ASCO 2023 Annual Meeting.
Funding for design and conduct of the study was provided by Susan G. Komen and the Breast Cancer Research Foundation to Dr. Ann H. Partridge.
Reference
Brantley KD, Rosenberg SM, Collins LC, et al. Second Primary Breast Cancer in Young Breast Cancer Survivors. JAMA Oncology; Published online 11 April 2024. doi:10.1001/jamaoncol.2024.0286