Searching for a Solution for When ER-positive Breast Cancers Outsmart Treatment

Most breast cancers depend on the female hormone estrogen to grow and thrive. That's why anti-estrogen drugs like tamoxifen are the cornerstone of therapy for the millions of women with estrogen receptor-positive (ER-positive) breast cancer. While these medications have saved many lives, they don't work for all women. In about a third of patients, the tumors learn to adapt to the estrogen-free environment and hormone therapy stops working.

This form of disease is "virtually incurable with approved therapies," says Todd Miller, PhD, assistant professor of Pharmacology and Toxicology at Geisel School of Medicine at Dartmouth.Todd Miller PhD

Why anti-estrogen resistance occurs is a hot topic of research. In recent years, scientists have learned that a signaling protein, called phosphatidylinositide 3-kinase (P13K), helps drive breast cancer cell growth.

"It's an alternative pathway that breast cancer cells use to compensate for the lack of estrogen signaling, which occurs when you use medications like tamoxifen," explains Miller.

Turning off that pathway then should, theoretically, help halt breast cancer cell growth. The idea has held such promise that ongoing clinical trials have been testing a combination of anti-estrogen drugs and experimental P13K inhibitors in women with ER-positive breast cancer. But there's been a glitch.

"The clinical trial results are not terribly impressive, and they really should be," says Miller, who has been awarded an American Cancer Society research grant to investigate the underlying mechanisms of anti-estrogen resistant breast cancer. "So, we decided to look at this in more detail. Instead of just putting two drugs in patients and expecting the tumors to melt away, we asked the question: 'What's actually happening to the biology of the tumors over time when you use these drugs?'"

Nemesis of the Field

Why hasn't the combination of P13K inhibitors and anti-estrogens worked the way everyone has hoped? Miller believes his findings, in mice and cultured breast cell lines, reveal important clues.

"What you would expect to happen, does happen at first. The tumors melt away and cells start to die really quick," he says. "But then things change over time and the drugs are not doing the same job."

His research suggests that the daily dosing schedules being used in clinical trials may be the culprit. These regimens call for long-term suppression of P13K. Patients are given escalating dosages of the drugs over time until it becomes too toxic and then the dose is scaled back but never stopped.

"This didn't make a lot of sense to us," Miller says. "With the combination of an anti-estrogen and P13K inhibitors, if we are really trying to [kill the] tumors, we shouldn't need to continuously inhibit the pathway. Once the cancer cell is dead, there's nothing else to inhibit."

Yet, most P13K inhibitors are designed to do exactly that – continuously shutdown the signaling pathway.

"This is the often unsubstantiated mainstay of the field for almost ten years, that you need to chronically suppress the signaling in order to see anti-tumor effects. But it's just not true," Miller emphasizes. "Drug companies do not need to design their drug to continuously inhibit the pathway."

During the course of his research, Miller's discovered that different P13K dosing schedules result in different patterns of breast cancer cell death and growth. Intermittent, high-dose treatment appears to work better than long-term, lower-dose regimens that only partially switch off the pathway. After testing a weekly schedule in mice, he found it still halts the growth of ER-positive breast cancer cells and causes the tumors to shrink.

"The current treatment schedules in clinical trials call for patients being treated every day, once a day and they accumulate side effects in the process," Miller says. "Our work suggests if you were to treat once a week or once a month, you may not get the same side effects but you would get the equivalent anti-tumor effects."

Some may fear that stopping a P13K inhibitor, which would turn the pathway to back on, could give cancer cells the chance to start growing again. Miller says that's unlikely.

"When you switch it off for a number of hours or days the cancer cells will die. When you switch it back on, the cancer cells are dead, so now only your normal cells are being reactivated." Allowing your normal cells to "turn back on" can potentially help alleviate side effects.

"In a perfect world you would take this drug for a week and never take it again but that's not reality. The reality is, or what we hope to achieve, is that you would take it for a few days or once a month, and then take a couple of weeks off."

Getting a Drug Company to Listen

Miller's team has submitted a research paper detailing their findings that he hopes to publish soon. The next step, he says, is "to get a drug company to listen to me" and launch a phase 1 clinical trial with a different dosing schedule that could maximize beneficial effects while minimizing toxic ones.

Ultimately, he hopes his findings will help identify when and how to best incorporate P13K inhibitors in the care of women with breast cancer.

"For women with early stage breast cancer, these drugs are too experimental to put into routine use for patients who might be cured with surgery," Miller says. "However, for patients with metastatic ER-positive breast cancer, there is good data to suggest these drugs have the potential to help control the cancer in combinations with anti-estrogens."

American Cancer Society news stories are copyrighted material and are not intended to be used as press releases. For reprint requests, please see our Content Usage Policy.