Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions

Abstract

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.

Figure 1.

Metastatic spread of human breast cancer. Metastatic spread and tumor outgrowth at a distant site require the completion of a number of critical steps, each involving complex interactions between cancer cells and the local microenvironment. Cells at the primary site invade tissue architecture and spread through the basement membrane (1: invasion), after which they enter blood vessels (2: intravasation). These cells then enter the circulation, where they must survive in the blood vessels before adhering to a vessel wall at a distant site. Cancer cells in the bloodstream can now be detected by various methods and enumerated to provide prognostic information. After adhering to a vessel wall, cancer cells then extravasate and enter normal tissue at a secondary site (3: extravasation). Interactions between cancer cells and the local microenvironment, which may include various growth factors, cytokines, and immune cells, may lead to the induction of dormancy for long periods of time (4: dormancy). Later, changes in these same factors, or the presence of new molecules, can induce an exit from dormancy, leading to full metastatic outgrowth and disease recurrence (5: metastatic outgrowth).

Figure 2.

Colonization of bone by breast cancer (BC) cells. BC cells frequently metastasize to the bone where a series of complex interactions between tumor cells and normal cells in the microenvironment mediate colonization and dormancy. For example, RANKL and CXCL12 are produced by normal cells and attract tumor cells to home towards the bone and initiate bone colonization. Cadherins and integrins are also implicated in this process. Conversely, annexin, IL-6, and GAS6 are secreted by normal cells within the bone niche and engage their cognate receptors on tumor cells to enable survival within the bone microenvironment and subsequent dormancy. RANK-L: RANK Ligand, CXCL12: C-X-C motif chemokine 12, also known as stromal cell-derived factor 1 (SDF1), IL-6: interleukin-6, GAS6: growth arrest-specific-6.

Figure 3.

Theoretical classification of dormancy status in patients with estrogen receptor-positive breast cancer and possible outcomes. Three categories are possible: Those with 1) no dormant cells present, 2) cells present, but still dormant, and 3) cells present that have escaped dormancy; although patients may move between categories over time. Adj = adjuvant; Tx = treatment.

Figure 4.

Patient outcomes according to the presence or absence of disseminated tumor cells (DTCs) in bone marrow. Kaplan–Meier plots of long-term survival and outcome according to the presence or absence of DTCs in bone marrow. Vertical dotted lines indicate the cutoff point at 5 years of follow-up used in the piecewise Cox regression modeling. A–D, All patients in the study. E–H, Patients receiving adjuvant systemic treatment. CI = confidence interval; HR = hazards ratio. CSS = cancer-specific survival; DFS = disease free survival; DDFS = distant disease free survival; OS = overall survival. ñ = “to”. Reprinted from (52). Copyright©(2011) with permission from AACR.

Figure 5.

Circulating tumor cell positivity and time to recurrence in patients with hormone receptor-positive breast cancer. CI = confidence interval; CTC = circulating tumor cell; HR = hazard ratio. Modified and reproduced with permission from (60). Copyright©(2018) American Medical Association. All rights reserved.

Figure 6.

Schemas of hypothetical clinical trials including circulating tumor cells and/or other “liquid biopsy” assays as for testing novel treatment intervention to prevent metastasis.