The lingering mysteries of metastatic recurrence in breast cancer

Abstract

Despite being the hallmark of cancer that is responsible for the highest number of deaths, very little is known about the biology of metastasis. Metastatic disease typically manifests after a protracted period of undetectable disease following surgery or systemic therapy, owing to relapse or recurrence. In the case of breast cancer, metastatic relapse can occur months to decades after initial diagnosis and treatment. In this review, we provide an overview of the known key factors that influence metastatic recurrence, with the goal of highlighting the critical unanswered questions that still need to be addressed to make a difference in the mortality of breast cancer patients.

Fig. 1. The metastatic cascade as a multistep process.

a Escape of tumour cells from the primary site and local invasion of surrounding tissues. Breast cancer is depicted here as the primary tumour. b Intravasation and survival of metastatic tumour cells into the circulation. Please note that this process can occur via both the haematogenous and lymphatic systems. c Extravasation of tumour cells from the circulation and metastatic seeding at distant sites. While dissemination of breast tumour cells can occur to the bones, lungs and liver, the brain is depicted here as the deadliest metastatic site for breast cancer patients. Figure created with BioRender.com.

Fig. 2. Tumour cell dissemination: the route to metastatic success or failure.

(1) Escape of DTCs at early (parallel model) or late (linear model) stages of tumorigenesis, either as single cells or clusters. (2) Local invasion of nearby host tissues. (3) Intravasation into the circulation. (4) Survival in the circulation. (5) Extravasation from the circulation into distant sites. (6) Metastatic seeding at distant loci, wherein crosstalk between DTCs and host cells of the TME takes place (DTCs are now depicted in grey as the fate of early and late tumour cells at this stage is unclear). This is the most critical step of the metastatic cascade in which a fine balance between cell-extrinsic and cell-intrinsic factors seems to dictate DTC fate. Underlined are adjuvant therapy and hormone-receptor regulation as two key cell-extrinsic and cell-intrinsic determinants, respectively, of metastatic success or failure in HR⁺ breast cancer. (7a) metastatic outgrowth, (7b) cell death and (7c) dormancy are three distinct fates that DTCs can undergo through various mechanisms. Whilst cell death is irreversible, ‘unsuccessful’ metastases composed of dormant cancer cells might eventually resume their growth and give rise to deadly lesions. DTCs disseminated tumour cells, RBC red blood cell, T tumour stage, TME tumour microenvironment, macro macroscopic, micro microscopic, WBC white blood cell. Figure created with BioRender.com.

Fig. 3. The puzzling timing of metastatic relapse in breast cancer patients.

Two different models are shown, based on disparate growth rates observed among breast tumours. a The first model is based on fast-growing breast tumours (i.e., non-luminal), which can take ~1 year to give rise to clinically detectable neoplasms (~1 cm in diameter). Assuming comparable proliferative indices for distant lesions, direct metastatic outgrowth of early (parallel progression) or late (linear progression) DTCs could justify cases of early metastatic recurrence. Alternatively, tumour dormancy might be responsible for late relapses of fast-proliferating tumours. b The second model is based on slow-growing breast tumours (i.e., luminal), which can take up to 50 years to become clinically detectable. Assuming comparable proliferative indices for distant lesions, direct metastatic outgrowth of DTCs without dormancy could explain both early and late cases of recurrence, regardless of the timing of DTC spread. DTC disseminated tumour cell, LP linear progression, PP parallel progression, T tumour stage, YRS years. Figure created with BioRender.com.

Fig. 4. The effects of cell-extrinsic and cell-intrinsic determinants in dictating breast cancer outcomes.

Part I The journey of a breast cancer patient from the development of undetectable disease and its clinical discovery (a), through its surgical removal (b) and adjuvant ET (c), to metastatic relapse and death (d). The presence of tumour lesions across the body is indicated by stars—the smaller referring to the clinically undetectable ones (no black borders), the bigger ones to the clinically detectable ones (black borders). Part II The development of an HR⁺ breast tumour lesion in the breast (primary site), comprising a mixture of ER⁺/PR⁺ and ER^–/PR^– cells (a). DTC escape from the primary site can occur early (parallel model, a) and/or late (linear model, b) during tumorigenesis (dotted pink lines), although the HR phenotype of DTCs at these stages is often unclear. Bones, lungs and liver are represented as common secondary sites for breast cancer metastases, albeit the sequential patterns of DTC spread among these organs are still elusive (green, brown and blue dotted lines). Targeted treatment for HR⁺ breast cancer patients relies on adjuvant ET. Several mechanisms of ET resistance (d)—cytostasis, ESR1 mutations and HR function regulation—contribute to DTC outgrowth. DTC disseminated tumour cell, ER oestrogen receptor, ET endocrine therapy, HR hormone receptor, PR progesterone receptor. Figure created with BioRender.com.