Dormant Tumor Cells: Their Role in Recurrence

What are Dormant or Disseminated tumor cells (DTCs)?

Dormant or disseminated tumor cells are micrometastases that have left the primary tumor and moved to other tissues in the body. It is thought that these cells remain dormant until something triggers their "awakening." The study of DTCs is relatively new field but there is a lot of evidence suggesting that the microenvironment of these cells is very important. For now, I will concentrate on literature that relates to DTC and breast cancer recurrence as well as what we can do about them.

How Predictive of recurrence are DTCs?

There are many studies that demonstrate a prognostic correlation between disease recurrence and the presence of dormant tumor cells (DTCs). It appears that just about 30% of patients have DTCs at the time of diagnosis and that, overall, the risk of recurrence is about 2 times that of patients without. Some recent studies suggest that by taking an oral bisphosphonate, these differences in survival disappear.

In a trial including 3072 breast cancer patients published in the Annals of Oncology, Hartkopf, et. al. found that the presence of DTCs was a significant risk for locoregional recurrence. In addition, patients with both locoregional recurrence and DTCs overall survival (OS) was significantly reduced (OS of 20% at approximately 65 months).

In 2011, Janni et al. performed a European pooled analysis of 676 patients who were found to have DTCs at the time of diagnosis. Median follow-up was 89 months from diagnosis. Seventy-one patients (10.5%) relapsed: 54 with distant metastasis (76.1%) and 17 with locoregional relapse (23.9%). DTCs were detectable in 19 patients (35.2%) with distant metastasis and in 1 patient (5.9%) with locoregional relapse. Disease-free survival (DFS) and distant DFS (DDFS) were significantly shorter in patients with DTCs compared with patients with no DTCs. This difference was only significant during the first 5-year interval of follow-up. From 6 to 10 years, there was no survival disadvantage for patients with DTCs during the follow-up period.

An older article summarizing pooled outcomes from 9 different sites and published in the New England Journal of Medicine (8/05) found that approximately 31% of 4,703 patients had DTCs at the time of diagnosis. The presence of DTCs correlated with a poorer outcome over the course of 10 years. The presence of DTCs seemed to correlate with the tumor size and node status, hormone receptor negativity, and higher grade. The presence of DTCs was an independent risk factor for recurrence, meaning prognosis was worse than equally matched patients who did not have DTCs.

In 2014, a study published in the Journal of Clinical Oncology that examined1,066 patients with early stage breast cancer found that those patients who had persistent DTCs despite treatment with additional docetaxel had a markedly reduced disease-free interval (46.7% relapsed). Overall, 7.2% of patients had DTCs by immunocytochemistry using pan-cytokeratin monoclonal antibodies where the cut-off was one or more DTC/2,000,000 bone marrow mononuclear cells.

In the Neotax study, researchers from many Norwegian hospitals over the course of 10 years found that the presence of DTCs and CTCs (circulating tumor cells) following neo-adjuvant therapy to predict a risk of recurrence of slightly greater than two times that of the patients who did not have DTCs or CTCs. The Hazard ratio being 2.2 with a p value of 0.005.

More recently, Hoffman, et. al. in the Archives of Gynecology and Obstrectis (11/15) assessed 394 patients for the presence of DTCs and provided those who were positive with 2 years of oral clodronate (a bisphosphonate that is not currently available in the US) following treatment. DTCs were detected in 41% of patients and significantly correlated with histopathological lobular subtype. After a median follow up of 7 years, there was no significant difference in overall survival compared to patients who did not have DTCs. Of note, only about 50% of patients were compliant. The authors suspect that this lack of difference in outcome is related to the use of bisphosphonates. More studies still need to be done for patients who are pre-menopausal.

What can we do about DTCs?

Bozionellou et al. in the Annals of Oncology found that 3-4 infusions of trastuzumab could eliminate CTCs and DTCs in 67% of patients with CK19 mRNA positive cells. This benefit has also been observed in patients with HER-2 negative tumors. Further studies are needed, however, to see how this translates to survival.

Currently, patients with high risk breast cancer patients who are within their first 5 years of diagnosis and who want to know if they have DTCs may enter the Penn-Surmount trial. Those who are found to be positive may choose to have trial therapy by enrolling in the CLEVER trial. Patients are provided hydroxychloroquine, everolimus, both, or neither for the first 3 months. After 3 months, those patients in the "neither" arm will receive both medications. There are follow-up bone marrows to assess for response. Please refer to the last reference below and video link for information regarding the theoretical benefit of mTOR inhibition. If you are interested in participating in this trial, which is accepting 60 patients, call Isorsis Nivar at 215-615-6823. Also see the video from the 23rd Live After Breast Cancer Conference for more detailed information presented by Dr. DeMichele, the clinical researcher.

A selection of natural mTOR inhibitors and additional information are available on my post.

Also see my post on copper and, basically, the rest of this site, which focuses on altering our microenvironment!

Some related links to DTCs:

#dormanttumorcells #tnbc #triplenegativebreastcancer #bisphosphonatesanddormanttumorcells #trastuzumabeliminatesdormanttumorcells #copperandtnbc #mtorinhibitorsanddormanttumorcells #clevertrial #pennsurmounttrial #autophagy


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