Breast cancer remains the most common cancer in women worldwide, affecting one in eight women over their lifetime. Oestrogen receptor-positive (ER+) breast cancer accounts for over 70% of all cases, and is primarily driven by hormones, specifically oestrogen. While endocrine therapies – such as tamoxifen, aromatase inhibitors, and fulvestrant – have revolutionised treatment, up to 30% of patients relapse after treatment, creating an urgent need to understand how breast cancer cells adapt and resist therapy.
At the heart of this issue is the phenomenon of dormancy, a state where disseminated cancer cells stop dividing but remain alive, often undetectable for years or even decades. These dormant cells can later ‘awaken’, leading to cancer recurrence, even long after successful initial treatment. It is critical we begin to understand what triggers this transition from dormancy to active disease to support patient management and surveillance. In a recent webinar, Dalia Rosano (Senior Research Associate, Imperial College London) discussed this phenomenon and potential therapeutic avenues.
Watch Dalia’s full talk here.
Exploring Dormancy
In an effort to unravel the mechanisms behind dormancy and relapse, Dalia Rosano and her team analysed cases where patients refused surgery and opted for endocrine therapy alone. These patients showed stable disease for several years before eventually relapsing. By comparing biopsies taken before and after relapse, they aimed to explore what factors drive the progression of ER+ breast cancer.
Surprisingly, the study did not find the presence of any significant genetic mutations in these samples that could explain the shift from dormancy to relapse, echoing the findings of other similar studies. So, if it’s not genetics, what is driving the adaptation to endocrine therapy?
A New Hypothesis
To answer this, the team designed the TRADITIOM (Tracing Adaptation, Dormancy, and Awakening with Multi-omics) study. Here, they treated breast cancer cell lines with tamoxifen or oestrogen deprivation (mimicking the effects of aromatase inhibitors) and tracked how the cells behaved at different stages across dormancy, awakening and proliferation.
One of the most interesting findings was asynchronous awakening – different cell populations re-entered the cell cycle at distinct times, and in some cases, stayed dormant for over a year. Even more interestingly, the cells that ‘woke up’ showed diverse phenotypes, meaning they adapted in various ways and responded differently to second-line therapies. This highlighted a highly complex and individualised process of resistance.
Lineage Tracing and the Role of Epigenetics
The researchers next traced the lineages of the cancer cells. This revealed that only about 30% of the initial lineages survived the dormancy phase, but those that did underwent ‘barcode sweeps’, where one dominant lineage would take over and become most of the population at awakening. These winning lineages, however, did not have any clear genetic or pre-existing traits that could explain why they were able to survive and proliferate.
The team therefore chose to look more closely at epigenetic changes that could explain this phenomenon. They discovered that dormant cells exhibited a very specific epigenetic state, marked by a high level of heterochromatin, a form of tightly packed DNA associated with gene repression. As cells awakened, this repressive state was gradually lost, suggesting that epigenetic changes are key to the transition out of dormancy.
Targeting the Epigenome
Given the importance of epigenetic changes in dormancy and awakening, Dalia and the team explored whether targeting these modifications could offer new treatment strategies. They tested epigenetic inhibitors in combination with endocrine therapies and found that certain inhibitors were able to reduce the number of cells entering dormancy and the number of target cells already dormant.
Furthermore, epigenetic signatures of dormancy were able to predict relapse risk in patients treated with endocrine therapy. This opens the door to opportunities in exploiting epigenetic markers as a tool for patient stratification – identifying those who are more likely to relapse and tailoring treatments accordingly.
Next Steps
The study highlights the critical role of dormancy in breast cancer adaptation and relapse. By better understanding the epigenetic landscape of dormant cells, we can identify new vulnerabilities and develop therapies that prevent the awakening of dormant cancer cells. This research provides exciting new opportunities to improve the long-term outcomes of patients with ER+ breast cancer.
As researchers continue to explore the mechanisms of dormancy and awakening, they aim to provide more personalised and effective treatments for breast cancer patients, ultimately improving survival rates and reducing relapse.
References and further reading
Rosano D, Sofyali E, Dhiman H, Ghirardi C, Ivanoiu D, Heide T, Vingiani A, Bertolotti A, Pruneri G, Canale E, Dewhurst HF, Saha D, Slaven N, Barozzi I, Li T, Zemlyanskiy G, Phillips H, James C, Győrffy B, Lynn C, Cresswell GD, Rehman F, Noberini R, Bonaldi T, Sottoriva A, Magnani L. Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells. Cancer Discov. 2024 May 1;14(5):866-889. doi: 10.1158/2159-8290.CD-23-1161. PMID: 38527495; PMCID: PMC11061610.
