Abstract and Introduction
Abstract
Background: Extended, more effective breast cancer treatments have increased the prevalence of long-term survivors. We investigated the risk of late breast cancer recurrence (BCR), 10 years or more after primary diagnosis, and associations between patient and tumor characteristics at primary diagnosis and late BCR up to 32 years after primary breast cancer diagnosis.
Methods: Using the Danish Breast Cancer Group clinical database, we identified all women with an incident early breast cancer diagnosed during 1987–2004. We restricted to women who survived 10 years without a recurrence or second cancer (10-year disease-free survivors) and followed them from 10 years after breast cancer diagnosis date until late recurrence, death, emigration, second cancer, or December 31, 2018. We calculated incidence rates per 1000 person-years and cumulative incidences for late BCR, stratifying by patient and tumor characteristics. Using Cox regression, we calculated adjusted hazard ratios for late BCR accounting for competing risks.
Results: Among 36 924 women with breast cancer, 20 315 became 10-year disease-free survivors. Of these, 2595 developed late BCR (incidence rate = 15.53 per 1000 person-years, 95% confidence interval = 14.94 to 16.14; cumulative incidence = 16.6%, 95% confidence interval = 15.8% to 17.5%) from year 10 to 32 after primary diagnosis. Tumor size larger than 20 mm, lymph node–positive disease, and estrogen receptor–positive tumors were associated with increased cumulative incidences and hazards for late BCR.
Conclusions: Recurrences continued to occur up to 32 years after primary diagnosis. Women with high lymph node burden, large tumor size, and estrogen receptor–positive tumors had increased risk of late recurrence. Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches.
Introduction
Survival after breast cancer has improved due to mammographic screening, facilitating earlier stage at diagnosis and increasingly effective systemic therapy.[1] In women with estrogen receptor (ER)–positive and HER2 receptor–negative tumors, at least one-half of breast cancer recurrences (BCRs) occur more than 5 years after primary diagnosis.[2] Adjuvant endocrine therapy has therefore been extended to up to 10 years of treatment.[3] Yet, the incidence of BCR beyond 10 years after primary diagnosis is not well understood.
Approximately 75% of primary breast tumors have already spread at the time of diagnosis,[4] seeding micrometastases at a regional or distant anatomic site.[5] These micrometastases survive in a state of tumor dormancy, whereby cell growth is balanced by apoptosis.[4,6,7] Alterations in cytokines, immune cells, and growth factors in the tumor microenvironment lead to the cessation of tumor dormancy, prompting full metastatic growth.[7]
Circulating tumor cells have been detected in breast cancer survivors decades after their primary cancer treatment.[8–10] Case reports document breast tumors that recurred 39 years after primary diagnosis.[11,12] A Danish study showed a cumulative incidence of local recurrence of 15% and distant metastases of 21% 20 years after diagnosis among 1847 patients treated with breast-conserving surgery (BCS) during 1989–1999.[13] A meta-analysis by Pan et al.[14] included 88 trials representing over 60 000 women with ER-positive breast cancer treated with tamoxifen for 5 years. Between 5 and 20 years after primary diagnosis, the risk of distant recurrence ranged from 13% to 41% depending on the tumor and nodal status of the primary tumor. Similar findings were reported in a study of 3128 breast cancer patients in the United Kingdom[15] and in a Swedish study including 336 luminal A and 126 luminal B patients.[16] Higher lymph node burden, larger tumor size, and higher grade were associated with increased risk of recurrence (from 5 years after primary diagnosis).[14]
Better understanding of the risk of late BCR, that is, recurrence 10 years or more after primary diagnosis, will help delineate patients who may be candidates for prolonged follow-up. We therefore used Danish population-based and medical registries to investigate the incidence of late BCR up to 32 years after primary diagnosis. We examined the association of tumor and patient characteristics at primary diagnosis with the risk of late BCR.
J Natl Cancer Inst. 2022;114(3):391-399. © 2022 Oxford University Press
