Prevention of Late Recurrence: An Increasingly Important Target for Breast Cancer Research and Control

Breast cancer recurrence has become an increasingly important aspect of cancer control as the number of breast cancer survivors continues to increase (1-3). It was previously thought that the risk of recurrence decreases 5 years after diagnosis; however, an increasing body of literature has sustained a considerable risk of “late recurrence” beyond the canonical time frame (4,5). Further characterizing the risk of recurrence thus remains of key importance both in guiding clinical management and counseling cancer survivors for whom fear of recurrence remains as one of the most frequently unmet needs (6–8).

In this issue of the Journal, Pedersen et al. (9) provide evidence that the risk of recurrence remains elevated more than 2 decades from the primary diagnosis. In fact, some of the risk factors for early recurrence and death are still associated with the risk of recurrence up to 32 years after diagnosis. The analysis of Pedersen et al. (10) expanded on previous work using the Danish Breast Cancer Group clinical database. This data set is particularly valuable for studying long-term recurrence, because there are very few population-based datasets that can guide clinical decision making while considering outcomes 10, 20, or even 30 years after diagnosis. Clinical trials are likewise impractical to answer such research questions that require decades of follow-up. The authors investigated the risk of late breast cancer recurrence for up to 32 years after the primary diagnosis. The study population included cancer survivors diagnosed during 1987-2004 who survived 10 years without a recurrence or second cancer and who were followed until December 31, 2018, or until the earliest of the following events: late recurrence, death, emigration, or second cancer.

Pedersen et al. (9) reported incidence rates per 1000 person-years and cumulative incidence for late breast cancer recurrence, stratifying by both patient and tumor characteristics. In addition, adjusted hazard ratios for late breast cancer recurrence are presented for competing risks. A relatively large sample size (20 315 10-year disease-free breast cancer survivors) allowed for calculation of estimates that are more precise than those reported by randomized clinical trials: incidence rate of 15.5 per 1000 person-years (95% confidence interval = 14.9 to 16.1 per 1000 person-years) and cumulative incidence = 16.6% (95% confidence interval = 15.8% to 17.5%). Confirming previous reports, large tumor size, lymph node–positive disease, and estrogen receptor–positive tumors were associated with increased cumulative incidence and hazard for late breast cancer recurrence.

This is the first report, to our knowledge, providing evidence that recurrence risk remains elevated more than 3 decades from the primary diagnosis. In fact, some of the risk factors for early recurrence and death are still associated with the risk of recurrence up to 32 years after diagnosis. These findings further support the need for “extended surveillance, more aggressive treatment, or new therapy approaches” (9).

The pattern of observational results that came out of the Pedersen et al (9) report in this issue of the Journal are generally in line with those of other investigations using shorter follow-up periods (4,5,11,13). However, not all reports concur with the benefits of more aggressive intervention in preventing recurrence and deaths, and reports that did not find benefits from more aggressive disease management used shorter follow-up points (5 years, 10 years) (14,15). Considering the effect of extended vs shorter surveillance periods may thus be warranted when evaluating the association therapeutic approaches and late recurrence outcomes.

The findings of Pendersen et al. (9) are also of note in light of the logistic difficulties of studying recurrence. Studying long-term recurrence requires long-term follow-up, which is particularly difficult in countries with high population mobility and fragmented health-care systems. Furthermore, over the past 30 years, guidelines for molecular testing and treatment for breast cancer have evolved so the standards of care of the earlier patients in the cohort do not reflect current clinical guidelines (16). Emblematic for the lack of standardization is the term late recurrence in itself: some authors use 5 years of follow-up as the threshold, whereas others reserve the term for recurrence events documented 10 years or later after diagnosis. Moreover, heterogeneity in the current literature has made it difficult to summarize findings. The follow-up protocols used to establish the “disease-free” status can differ substantially between studies, and the definition of what is a recurrence vs a second primary tumor differs between countries using the National Cancer Institute’s Solid Tumor Rules and those that do not (17). Moreover, the cancer surveillance community, which provides the standards for data collection, provides limited guidance regarding the collection of the first type of recurrence (18). Randomized clinical trial investigators have also encountered similar challenges in the lack of standards for recurrence endpoint definitions and initiated an international working group to establish the Definition for the Assessment of Time-to-event Endpoints in CANcer trials to be used for breast randomized controlled trials (19). Despite these difficulties, the current report by Pedersen et al and similar investigations on long-term recurrence have already yielded several salient findings that may affect clinical management.

Several investigators have proposed new techniques to understand recurrence patterns. In Europe, Lafourcade et al. (20) proposed an approach to show that “better predictions of death are obtained by considering the history of relapses rather than only considering prognostic factors.” Ho-Huynh et al. (11) used data from clinical and surveillance systems in Australia to assess prognostic factors for breast cancer recurrence, revealing an effect of surgery type on the likelihood of recurrence. Izci et al (21) demonstrated that algorithms constructed with an administrative claims code can be valuable tools to identify breast cancer recurrences for research at the population level.

To expand our understanding of late breast cancer recurrence, it will be critical to continue to prospectively collect data that support recurrence research. This includes clinical data to elucidate the biology and tumor microenvironment conditions that influence dormancy, anti-tumor immune surveillance which could prompt the development of treatments that maintain longer disease-free time. At the same time, the population “at risk” for late recurrence will continue to increase due to earlier detection, better outcomes of the initial curative-intent treatment, and the general extension of life expectancy (pre-COVID-19 pandemic). The collection of clinical surveillance data that can extend into long-term periods, including recurrence and other clinical outcomes, will be the critical foundational step in supporting future research to understand recurrence.

Funding

Not applicable.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no conflicts of interest to disclose.

Author Contributions: Writing, original draft: SN, ER-P. Writing, reviewing and editing: SN, ER-P.

Data Availability

No new data were generated or analysed in support of this research.