Abstract
Breast cancer, a multifaceted disease, presents a dynamic ecosystem where the primary tumor interacts intricately with its microenvironment, circulatory system, and distant organs. Circulating tumor cells (CTCs) disseminate from the primary tumor to organs, such as the brain, lungs, liver, and bones, encountering various fates: cell death, cellular dormancy, or senescence. Dormant cells, characterized by reversible growth arrest at the G0/G1 phase of the cell cycle, pose a significant challenge as they evade conventional treatments and can later reawaken, leading to cancer relapse. The phenomenon of tumor dormancy is influenced by the tumor microenvironment, immune modulation, and cellular adaptations. Emerging evidence suggests that breast-conserving surgery coupled with radiation therapy offers superior survival benefits compared to mastectomy, potentially due to the ‘breast homing phenomenon.’ This hypothesis posits that residual breast tissue provides a niche for reactivated dormant cells, reducing distant metastasis. Immunotherapy and lifestyle modifications, including diet and exercise, show promise in managing dormant cells. Understanding the mechanisms of dormancy and developing targeted therapies are crucial for achieving long-term remission and potentially curing breast cancer.
Breast cancer unfolds as a complex ecosystem within the human body, akin to a thriving community where survival of the fittest prevails. The primary tumor acts as the nucleus, orchestrating a symphony of interactions with its microenvironment, peripheral circulation, and distant organs, notably the bone marrow (1, 2).
Within this ecosystem, cancer cells evolve and adapt, acquiring genetic mutations akin to animals honing their survival skills through evolution. The fittest among them develop the ability to break free from the primary tumor and venture into the bloodstream, exploring new territories.
Remarkably, these cancer cells communicate with nearby lymph nodes, persuading immune cells to aid their growth rather than attack them. Simultaneously, the primary tumor manipulates the bone marrow, recruiting immune cells and fostering an environment of immune tolerance, allowing cancer cells to evade detection (1, 2).
As cancer cells journey through the bloodstream to disseminate to other organs like the bone marrow, lungs, liver and brain they face formidable challenges, leading some of them to die in the new hostile environment, other cells to enter an irreversible cell cycle arrest known as senescence, and others to enter states of dormancy. Cancer dormancy can be broadly categorized into two main types: tumor mass dormancy and cellular dormancy. In tumor mass dormancy, a balance is maintained between the proliferation of cancer cells and their death. This equilibrium is thought to be achieved through limited angiogenesis (the formation of new blood vessels) and immune surveillance mechanisms. In cellular dormancy, individual cancer cells enter a quiescent state characterized by temporary cell-cycle arrest reducing their metabolic demands to survive in hypoxic, acidotic, and low glucose environments (1). This allows the cells to survive in a dormant phase without proliferating. Figure 1 illustrates the outcomes of circulating and disseminated breast cancer cells.
The outcomes of circulating and disseminated breast cancer cells (1).
Certain cancer cells, endowed with stem cell characteristics, transition to a mesenchymal phenotype as they leave the primary tumor, rendering them resistant to conventional treatments. Although surgery, radiation and systemic drugs may eradicate clinically detectable tumors, dormant cells often survive, lying in wait for opportune moments to awaken and proliferate. Recent studies have demonstrated that women treated with lumpectomy and radiation therapy for early breast cancer live longer than those having more radical surgery in the form of mastectomy (2).
A recently proposed hypothesis, known as the breast homing phenomenon, suggests an explanation for why lumpectomy combined with radiation therapy may be more effective than mastectomy for early breast cancer (2). According to this hypothesis, the primary breast and regional lymph nodes serve as preferred sites for these reawakened cells to flourish, driven by familiarity and the availability of suitable infrastructure. Consequently, patients who underwent lumpectomy and radiation therapy are more susceptible to local rather than distant relapse. In the absence of the breast following mastectomy, reawaken dormant cells may seek refuge in distant organs, increasing the risk of distant metastasis and mortality (2). According to this hypothesis, the locoregional microenvironment extends beyond the breast of primary tumor origin to encompass the axillary region and some axillary recurrences represent reverse metastatic events mediated by CTCs rather than a direct lymphatic spread. This could potentially explain why radical axillary surgery does not improve overall survival despite reducing the rate of axillary recurrence compared with less radical sentinel lymph node biopsy in patients with a low axillary disease burden (2).
Notably, treatments like immunotherapy and radiation therapy stimulate immune responses against breast cancer, potentially reducing the risk of distant metastasis. However, the dormancy characteristic of hormone-dependent cancers presents distinct challenges, as hormonal therapy induces dormancy rather than eradication. These dormant cells include a subpopulation of mammary cancer stem cells and may attempt reawakening triggered by changes in their epigenome and the host’s vulnerability. If they succeed, they reenter the growth phase of the cell cycle and start proliferating, leading to cancer relapse. Host factors that may contribute to the cancer cells exiting dormancy include chronic inflammation and compromise of the immune system. Chronic inflammation can be caused by small particles air pollution (3), unhealthy diet (4) and obesity.
The reawakening of these cells serves as a warning sign of further reawakening in other dormant cancer cells, which could be resistant to the ongoing treatment the patient is receiving (5). Conversely, cancers susceptible to immunotherapy, such as ER-negative breast cancer responsive to checkpoint inhibitors and HER2-positive tumors responsive to anti-HER2 antibodies, are more likely to achieve a permanent cure in responders.
In this complex ecosystem, less aggressive breast cancer cells compete with their fitter counterparts for resources, prompting a crucial question: Can systemic therapy be adjusted to spare some less aggressive cells? This delicate balance might be the key to restraining the growth of more aggressive cells by limiting their access to vital resources. Employing drugs in mixtures, sequences, and rotations, akin to using insecticides, could offer a more effective approach to prevent the proliferation of treatment-resistant cells.
To attain a permanent cure for breast cancer, the focus must shift towards eradicating dormant stem cells or preventing their reactivation through molecular targeting drugs that can be used in combination with existing therapies. Immunotherapy holds promise for cancers with clear molecular targets, offering hope for a future free from the shadow of breast cancer. Currently, the challenge lies in our limited understanding of the dynamics of the dormant breast cancer cells and our inability to identify reliable targets unique to them. Furthermore, the environment surrounding these breast cancer cells attempts to shield them from all treatments, including immunotherapy. Recent advances in various liquid biopsy approaches (CTCs and ctDNA) have enabled us to detect, characterize, and monitor minimal residual disease (MRD) and dormancy in breast cancer patients. The presence of MRD precedes clinically detectable metastatic disease by at least four years.
It is worth highlighting that certain diet and lifestyle modifications are likely to play an important role in eradicating dormant cancer cells or preventing them from reawakening (4). These include regular aerobic exercise, optimizing body mass index, adoption of Mediterranean dietary patterns, ensuring adequate serum levels of certain vitamins like vitamin D, antioxidant rich diet, and optimal sleeping patterns.
Acknowledgements
The Author extends his gratitude to Jocelyn Rosenberg and her late husband, Michael Rosenberg, for their support of his research program.
Footnotes
Conflicts of Interest
The Author has no conflicts of interest to declare.
Funding
This study received no external funding.
- Received June 10, 2024.
- Revision received June 18, 2024.
- Accepted June 19, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
