New Strategy May Prevent Breast Cancer Relapse

Researchers at Penn Medicine are exploring a new strategy to prevent breast cancer from returning by targeting so-called “sleeper” cancer cells, according to Dr. Angela DeMichele.

In an interview with CURE, DeMichele, the Mariann T. and Robert J. MacDonald professor in Breast Cancer Research, explained that these cells can leave the breast, travel to other parts of the body and enter a dormant state, where they survive without dividing — making them resistant to traditional treatments.

By using two oral drugs, hydroxychloroquine and everolimus, researchers were able to disrupt the cells’ survival mechanisms and eliminate them in about 80% of patients studied. After seven years of follow-up, only about 4% of patients relapsed, compared with an expected rate of about one-third. In addition, the three-year survival rate without any disease recurrence was greater than 90% in patients who received one drug and 100% for patients who received both drugs.

CURE: What do you hope the big takeaway is for patients?

DeMichele: I hope the big takeaway from this study is that we are really narrowing in on how we can monitor patients to detect the cells that ultimately lead to recurrence. By being able to identify those cells, we have the opportunity to eliminate them before they can turn into a relapse. The goal here is to prevent women from developing metastatic breast cancer, which remains incurable. This is an important step forward in finding and treating one of those cell types that can lurk and ultimately lead to metastatic breast cancer — the dormant or sleeper cells.

If those sleeper cells are detected, what options are available for a patient and their care team?

It’s important to understand how this process seems to work. What we know right now is that these specialized cells are able to leave the breast and travel to other parts of the body before they essentially go dormant or hibernate — kind of like a bear in the wintertime going into a cave. These cells stop dividing, shut down and remain alive. That’s a very unique state for a cancer cell, because cancer cells typically like to divide.

All of our treatments so far target dividing cancer cells. But through the important work of my colleague, Dr. Lewis Chodosh, we learned that these cells stop dividing and sit in this hibernating state. We had to figure out how they were surviving, which led to studies identifying the ways they stay alive. One is called autophagy, which is how they get their energy. Another is called mTOR, which is sort of like the electrical or nerve system of the cell. These processes allow the sleeper cells to survive until they can wake up.

We then had to find drugs to attack and interrupt those processes, so the cells would lose their energy source and electrical system. It turned out these were drugs we already knew about — off-the-shelf, no longer on patent and oral. We repurposed them for this situation. One was hydroxychloroquine, used in the past for malaria and rheumatoid arthritis, which at higher doses turns off autophagy. The other was everolimus, an inhibitor of the mTOR pathway, which disrupts the cell’s nerve center. By using each drug and then combining them, we were able to eliminate sleeper cells in about 80% of patients we treated. Those patients have not relapsed over the seven years we’ve been following them.

We hope eliminating these cells will spare patients from relapse. Now, some of these women may never have relapsed even without treatment, so this is still proof of concept. But based on their risk, we would have expected about a third to relapse, and instead we’ve seen about 4%. We think we’re on to something. It’s early, and we need confirmatory trials, which are ongoing now. We have two open trials — one nationally and one here at Penn — to confirm these findings. We don’t want people to start taking these drugs or asking doctors to look for the cells until we know for sure that this works and that it’s worth it for patients.

What are the next steps to move this approach closer to being available for patients?

This is going to be a stepwise process to get to the point where it’s really ready for patients. Right now, the way we find the cells is through a bone marrow aspiration — inserting a small needle into the hip bone to collect liquid marrow. It’s done under local anesthesia in the clinic. There’s a little pain, but it’s how we find the reservoir where the cells hide.

We’re working on developing a better test, because the one we have can miss these very rare cells and requires sophisticated filtering steps. The first step is improving the test. The second step is completing the current trials to refine the treatment cocktail. The final step will be conducting a large, comprehensive study to confirm these findings, validate the test, and prepare this approach so it’s ready for patients.

Transcript has been edited for clarity and conciseness.

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