Metastasis is the primary cause of death in patients with breast cancer, with estrogen receptor-negative (ER-) breast cancers having a worse prognosis than ER+ breast cancers. In contrast, although ER+ breast cancers have a lower risk of recurrence in the first 5 years, patients with ER+ disease have a higher risk of late recurrence that can occur even decades after the initial treatment. This is because of dormant disseminated tumor cells (DTCs) that can reawaken at secondary sites. The microenvironment of the secondary site plays a crucial role in controlling tumor cell survival and proliferation.
However, the understanding of the microenvironmental cues that control recurrence is limited because of the lack of suitable preclinical models of ER+ metastatic relapse. Patients with even low-grade, node-negative tumors have a continued risk of distant recurrence. Therefore, there is a pressing need to investigate metastatic relapse in models of the aging microenvironment.
New research, funded by Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research in London, has discovered the mechanism that triggers DTCs in the lungs to form incurable secondary tumors in patients with breast cancer. Scientists now believe they can prevent this "time bomb" of breast cancer cells from activating months or even years later by targeting these molecular changes (Nat Cancer 2023; https://doi.org/10.1038/s43018-023-00525-y).
In this research, scientists used mouse mammary tumor cell lines to study the development of metastatic lesions and identify factors upregulated in aged mouse lungs that promote metastatic colonization in ER+ breast cancer. For the first time, the researchers discovered that molecular changes in the lung, resulting from aging, lead to secondary cancer growth.
The investigators identified Pdgfc as a crucial factor that is upregulated in aged and fibrotic lungs, where it is associated with the accumulation of activated fibroblasts and enhanced metastatic outgrowth. Conversely, in young mice, low-level expression of Pdgfc by disseminated ER+ tumor cells is necessary for their survival in secondary sites, but insufficient to support the development of macrometastases.
Additionally, they observed that the platelet-derived growth factor (PDGF)-Chi environment of aging or fibrotic lungs promotes DTC proliferation and upregulates tumor cell Pdgfc expression, stimulating further stromal activation. Next, the team worked with mice that had ER+ tumors to investigate whether targeting PDGF-C signaling with imatinib, which is currently used to treat chronic myeloid leukemia patients, can limit metastatic outgrowth cancer in the lung. The mice were treated with imatinib both before and after the tumors had developed. The results demonstrated that the cancer growth in the lung was significantly reduced in both groups.
For additional insights into ER+ breast cancer and the implications of their study, Oncology Times reached out to study authors, Clare Isacke, DPhil, and Frances Turrell, PhD. Isacke is Professor of Molecular Cell Biology at The Institute of Cancer Research in London and Turrell is a postdoctoral training fellow in the Division of Breast Cancer Research at The Institute of Cancer Research. They equally contributed to the interview responses.
Oncology Times: Why do patients with ER+ breast cancer have a substantial risk of late recurrence?
"All breast cancers have a risk of recurrence. For ER+ breast cancers, the late recurrence (5 years of endocrine therapy) is likely to be because the disseminated ER+ breast cancer cells have the ability to enter a state of therapy-resistant dormancy in the metastatic site. The question our team at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, addressed in this paper is what triggers their awakening."
Oncology Times: Why are preclinical models of ER+ metastatic relapse needed and what are the benefits of using syngeneic models of ER+ breast cancer?
"Late metastatic recurrence is much more common in ER+ breast cancers compared to ER- breast cancers. Therefore, it's important to study the phenomena of late metastatic recurrence using ER+ pre-clinical models. But this has been challenging as the majority of mouse mammary carcinoma cell lines and genetically modified mouse models are ER-. Scientists have also used ER+ human cells in immunocompromised mice, but this doesn't allow you to study the role of the immune system.
"It's been proposed that dormancy could represent a true cellular dormancy where single cells stop dividing-or 'tumor mass dormancy' where the disseminated tumor cells can divide but are kept in check by the immune system-or a mixture of both. The benefit of using syngeneic models is that the mice have an intact immune system."
Oncology Times: How is Pdgfc expression related to the accumulation of activated fibroblasts and enhanced metastatic outgrowth? Additionally, how does expression of Pdgfc by disseminated ER+ tumor cells affect DTC survival?
"Answering the second part first-our data demonstrate that expression of Pdgfc by disseminated ER+ tumor cells is required for their survival in secondary sites, but this relatively low-level expression is insufficient to drive their proliferation. We predict this is because it's insufficient to promote an activated metastatic niche. When disseminated tumor cells start dividing to create a metastatic lesion, this is associated with the recruitment of activated fibroblasts and other stromal cells. Our data demonstrate that the dividing tumor cells increase their expression of Pdgfc, but that PDGF-C is also produced by macrophages and other cells in the metastatic niche. It also shows that PDGF-C acts mainly to activate stromal fibroblasts, which in turn promote tumor cell proliferation."
Oncology Times: What are the potential clinical implications of this study for limiting ER+ breast cancer recurrence?
"There are three major challenges to address for translating these findings into clinical practice:
1. Identify which patients are at high risk of metastatic recurrence and/or to identify patients (e.g., by plasma ctDNA analysis) at an early stage of metastatic recurrence.
2. Understand better when and how to treat patients for maximum benefit; for example, could blocking PDGF-C prevent further outgrowth of tumor cells in developing metastatic lesions and sensitize metastatic lesions to standard-of-care therapies, such as endocrine therapy, targeted agents, or chemotherapy?
3. Establish the best approach to blocking PDGF-C activity. Our experiments were mostly performed using imatinib, but imatinib is a non-specific kinase inhibitor targeting not only PDGF receptors, but also other kinases. Would a more specific inhibitor be more effective?"
Dibash Kumar Das is a contributing writer.