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Late Breast Cancer Recurrence Less Aggressive and Associated with Better Prognosis Compared to Early Recurrence

Findings from the Danish Breast Cancer Group
23 Feb 2022
Breast cancer

In a first large population-based cohort study to investigate the impact of late breast cancer recurrence on mortality, to evaluate prognostic factors, and to compare survival after late recurrence with survival after early recurrence, women who developed late recurrence had better prognosis compared with those with early recurrence. It was illustrated by lower hazard ratio (HR) of breast cancer-specific mortality, lower cumulative breast cancer-specific mortality, lower breast cancer-specific mortality rate, and longer survival time. The HR was lowest when comparing late versus early locoregional recurrence. Findings are published by Prof. Deirdre P. Cronin-Fenton of the Danish Breast Cancer Group, Rigshospitalet, Copenhagen University Hospital in Copenhagen, Denmark and colleagues on 16 February 2022 in the Journal of Clinical Oncology.

The authors wrote in the background that nowadays in Nordic countries between 72% and 83% of women with breast cancer survive at least 10 years after primary diagnosis and treatment. However, little is known about long-term prognosis. Previous data from this study group among 20,315 women who were 10-year disease-free survivors showed a 10- to 32-year cumulative incidence of breast cancer recurrence of 17%. The risk was highest in women with an oestrogen receptor (ER)–positive tumours and lymph node involvement.

Cancers that recur late are thought to arise from micrometastases or single dormant cancer cells that reactivate and proliferate. Low-risk cancers have lower reactivation rates than high-risk cancers. ER-positive and low-risk ER-negative cancers may have longer periods of dormancy. Such less aggressive biologic behaviour is likely to incite slower disease progression, also after a breast cancer recurrence.

Few studies have investigated survival after late breast cancer recurrence, e.g. recurrence occurring at least 10 years after primary diagnosis. No studies have investigated the potential impact of prognostic factors on mortality after such late breast cancer recurrence.

Therefore, the Danish researchers conducted a population-based cohort study to investigate the impact of late breast cancer recurrence on breast cancer-specific mortality and all-cause mortality. They evaluated potential prognostic factors including characteristics of the primary tumour, and localisation and treatment of the late recurrence. Furthermore, they compared survival after late breast cancer recurrence with survival after early breast cancer recurrence.

From the Danish Breast Cancer Group and other nationwide databases, the study team identified women with early or late breast cancer recurrence during a period from 2004 to 2018, who were alive 6 months after recurrence. They followed these women until breast cancer death, death from other causes, emigration, 10 years, or 31 December 2018, whichever came first. The study team calculated mortality rates per 1,000 person-years and cumulative breast cancer mortality, for early versus late recurrence, and by characteristics of the primary tumour and the late recurrence. Using Cox regression, the researchers calculated adjusted HRs for breast cancer death, accounting for death from other causes as competing risks.

Among 2,004 patients with late recurrence, 721 died of breast cancer with a median survival time of 10 years; mortality rate was 84.8 per 1,000 person-years and 10-year cumulative mortality 50%. Among 1,528 patients with early recurrence, 1,092 breast cancer deaths occurred with a median survival time of 4 years; mortality rate was 173.9 per 1,000 person-years and 10-year cumulative mortality 72%. The study team observed a lower hazard of breast cancer-specific death among patients who developed late compared with early recurrence (HR 0.72; 95% confidence interval 0.62 to 0.85).

Advanced stage at primary diagnosis, distant metastases, adjuvant treatment for locoregional recurrence, and systemic treatment for distant recurrence were associated with increased mortality after late recurrence.

Breast-conserving surgery at primary diagnosis, locoregional recurrence, and surgery for recurrence were associated with lower mortality after late recurrence.

The authors concluded that patients with late recurrence had more favourable prognosis than patients with early recurrence. The localisation of recurrent disease was the main prognostic factor for breast cancer death. As late breast cancer recurrence appears to be less aggressive and is associated with better prognosis compared with early recurrence, this may provide some reassurance to patients who develop late breast cancer recurrence and may affect quality of life after a late recurrence. Future studies should aim to distinguish the biology of early versus late recurrence.

The study was supported by grants from the Danish Cancer Society.


Pedersen RN, Mellemkjær L, Ejlertsen B, et al. Mortality After Late Breast Cancer Recurrence in Denmark. Journal of Clinical Oncology; Published online 16 February 2022. DOI: 10.1200/JCO.21.02062

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