Clinical and Biological Aspects of Disseminated Tumor Cells and Dormancy in Breast Cancer

Abstract

Progress in detection and treatment have drastically improved survival for early breast cancer patients. However, distant recurrence causes high mortality and is typically considered incurable. Cancer dissemination occurs via circulating tumor cells (CTCs) and up to 75% of breast cancer patients could harbor micrometastatses at time of diagnosis, while metastatic recurrence often occurs years to decades after treatment. During clinical latency, disseminated tumor cells (DTCs) can enter a state of cell cycle arrest or dormancy at distant sites, and are likely shielded from immune detection and treatment. While this is a challenge, it can also be seen as an outstanding opportunity to target dormant DTCs on time, before their transformation into lethal macrometastatic lesions. Here, we review and discuss progress made in our understanding of DTC and dormancy biology in breast cancer. Strides in our mechanistic insights of these features has led to the identification of possible targeting strategies, yet, their integration into clinical trial design is still uncertain. Incorporating minimally invasive liquid biopsies and rationally designed adjuvant therapies, targeting both proliferating and dormant tumor cells, may help to address current challenges and improve precision cancer care.

“Diagnostic and Prognostic Biomarkers of Luminal Breast Cancer: Where are We Now?”

“… 194 , 195 DTCs may enter a (initially indolent) state of dormancy that protects them from detection and eradication with current clinical standard of care strategies. 196 , 197 Novel strategies for detection (including liquid biopsies) and targeting of dormant disease (eg, enforcing a dormant state, awakening or targeted eradication of dormant tumor cells) are subject to intensive research efforts. 197 , 198 …”

“… 196 , 197 Novel strategies for detection (including liquid biopsies) and targeting of dormant disease (eg, enforcing a dormant state, awakening or targeted eradication of dormant tumor cells) are subject to intensive research efforts. 197 , 198 …”

“…194,195 DTCs may enter a (initially indolent) state of dormancy that protects them from detection and eradication with current clinical standard of care strategies. 196,197 Novel strategies for detection (including liquid biopsies) and targeting of dormant disease (eg, enforcing a dormant state, awakening or targeted eradication of dormant tumor cells) are subject to intensive research efforts. 197,198 Secondly, the dearth of therapies that specifically target the metastatic processes such as intra-and extravasation, circulating tumor cell dissemination, homing of tumor cells at distant sites.…”

How circulating tumor cluster biology contributes to the metastatic cascade: from invasion to dissemination and dormancy

“…Interestingly, knocking down plakoglobin in lung metastatic breast cancer cells significantly reduced CTC cluster formation and lung metastatic nodules in NOD-SCID gamma (NSG) mice while having no effect on tumor growth [ 5 ]. Overall, more studies are required to strengthen our knowledge about CTC cluster invasion such as the use of intravital imaging and assessing cancer cell collective migration next to tumor microenvironment of metastasis (TMEM) doorways [ 64 , 65 ].…”

“…There has been tremendous effort to study differences between solitary and clustered CTCs, with evidence pointing toward the superior efficiency of CTC clusters to disseminate and survive compared to solitary CTCs. This may be due in part to environmental factors (heterotypic nature), physical factors (clustering and cell-cell contact), biological factors (differential effect of circadian rhythm), and molecular factors [ 32 , 35 , 64 ]. However, many areas remain understudied such as investigation of the collective intravasation of CTC clusters possibly through TMEM doorways, the seeding differences among CTCs in different soils, metabolic differences in CTC clusters that enable survival during metastasis, cellular and molecular interactions of CTC clusters in early dissemination phases of metastasis, and investigating the role of different cellular compartments within CTC clusters using in vitro coculture methods.…”