Getting Under Your Skin with Tamoxifen Gel

What if there was a way to prevent breast cancer or help control very early disease — with few or no side effects?

That’s the goal of Dr. Seema Khan and other researchers who are testing anti-hormone drugs that are absorbed through the skin. Khan, the Bluhm Family Professor of Cancer Research at Northwestern University’s Feinberg School of Medicine in Chicago, is leading a trial of a gel formulation of the drug tamoxifen to determine if it will help prevent hormone-driven breast cancer or control the progression of stage 0 breast cancer, a non-invasive malignancy known as ductal carcinoma in situ (DCIS).

Tamoxifen prevents the hormone estrogen from binding to the estrogen receptor on breast cancer cells and relaying the message to grow and divide. It and other anti-hormone drugs are available to women facing a high risk of breast cancer that is driven by estrogen or progesterone, but many refuse to take the oral formulations because they cause hot flashes or joint pain and raise the risk of blood clots, uterine cancer and, in older patients, cataracts, Khan says.

If studies show that topical versions applied to the breasts work without causing such side effects, the findings could encourage more women to use the medicines and stick with them. That kind of data could also open the door to topical varieties of other kinds of drugs, such as those that treat breast cancers not driven by hormones, Khan says.

Khan talked with CURE® about clinical trials of topical drugs for breast cancer, including the study she’s leading.

CURE®: How well does the oral form of tamoxifen protect women against cancer?

Khan: An American trial published in the 1990s included 13,500 women at increased risk who were followed for five years — the P-1 trial. In the placebo group, 244 women got invasive breast cancer, or DCIS, and in the tamoxifen group, less than half that number developed the disease. These results have been nearly replicated in European trials, showing a 40% reduction in breast cancer in those who took tamoxifen.

Who is most likely to benefit from tamoxifen or aromatase inhibitors (which have shown similar effects) for breast cancer prevention?

This innovation of delivering drugs through the breast skin will apply to women who don’t need a systemic effect. Women who have a history of invasive cancer need drugs that travel through their bodies, because they may have cancer cells lurking in other organs. On the other hand, women who are at high risk of breast cancer or have DCIS (where cancer cells are inside the duct and unable to spread) need drugs delivered only to their breasts. Exposure to drugs in the rest of their bodies provides little benefit but presents the possibility of collateral damage.

The most common risk factors for the development of breast cancer are family history or a benign breast biopsy that shows atypical changes in cells. Others include high mammographic density, early age at first period and late age at first childbirth.

To identify women who would benefit from risk-reducing drugs, we use statistical models based on breast cancer risk factors. As a risk threshold, I use five-year risk of 3%, which is substantially higher than the general population. I have a very detailed discussion with women in this category about the risks and benefits of using one of these drugs.

Risk reduction in women with genetic susceptibility to breast cancer, such as those with BRCA1 gene mutations, is not well-proven enough with these drugs to make them the major way of preventing cancer. In those patients, surgery is more reliable and provides a larger reduction in risk.

Tell us about the clinical trial of tamoxifen gel that you’re leading.

Our trial is testing 4-OHT gel, which is an active form of tamoxifen, in women with DCIS. This study (TopTam2) is open at five sites around the country in addition to Northwestern; those interested in enrolling can find information by typing “TopTam2” into any browser or visiting the Northwestern University Lurie Cancer Center online.

When tamoxifen is taken by mouth, it goes through the gut and into the liver, where it’s broken down into two main active forms, 4-OHT and endoxifen. If we put any drug on the skin that goes directly into the breast, it has to be an active form like 4-OHT, because it won’t pass through the liver to be activated.

TopTam2 is a continuation and confirmation of an earlier study we opened almost 10 years ago. We enrolled 28 or 29 women with DCIS six weeks prior to surgery to either use the gel or take the pill to compare the results. We had very encouraging results, and in 2014 or so, we restarted the same study, with the goal of enrolling 100 women with DCIS. We are focusing on DCIS in these early studies because this is a condition where it’s easiest to measure a reduction in the growth rate of cancer cells with treatment for a few weeks.

We’re at 56 patients now and expect to close enrollment within the year and shortly thereafter have results. Hopefully, it will be the same as the earlier study, showing equivalence between the two approaches. If that happens, we want to work with the National Cancer Institute to launch a big trial using this gel approach.

If this trial meets its goals, will women with DCIS someday be able to use tamoxifen gel to avoid or delay surgery?

I would be very interested in exploring that. A trial ongoing in the U.S. and a couple of others in Europe are testing the idea that not all women with DCIS need surgery, because not all DCIS progresses to invasive cancer. The problem is that there’s no good way to identify the women who will or will not have progression to invasive cancer.

Standard treatment for women with DCIS, even when it’s low-grade, is surgery, then radiation, then oral tamoxifen if the DCIS is positive for estrogen or progesterone receptors. On the COMET trial (listed under the number NCT 02926911 on clinicaltrials.gov), women with low-grade DCIS are being randomized to either standard care or avoidance of surgery and radiation with encouragement to take the tamoxifen pill. If we are able to identify women who could be safely offered the option of observation instead of surgical and radiation treatment by using an agent like this, doing so would make a lot of sense.

What are the details of the other ongoing trial of 4-OHT?

The NCI Prevention Consortium based at The University of Texas MD Anderson Cancer Center in Houston is conducting a study we’re participating in that is testing the possibility of reducing breast density with 4-OHT gel. One of the things that increases breast cancer risk is breast density, and tamoxifen reduces that in a proportion of women. We know from past research that those who experienced a reduction in density with tamoxifen also experienced a very good reduction of breast cancer risk.

The current trial is looking at density reduction. It has enrolled 90 women so far who have the two highest of four categories of breast density, and they’re being randomized to either medicated gel or placebo gel for a year. The endpoint is to measure their density after that, with the hope that we’ll see a reduction.

There are two benefits to reducing density. Density is associated with an increased risk of developing breast cancer, and it reduces the accuracy of mammography: Cancers can hide in dense breast tissue. We can expect that women whose breast density is reduced with 4-OHT gel will see a reduction in breast cancer risk and also that mammograms will be more accurate.

Those interested in enrolling can learn more by visiting MD Anderson’s website.

What are the side effects of tamoxifen gel?

In our study, the participants are in their mid-40s and older, and many women in this age group experience some early hot flashes anyway — it’s a fact of life after a certain age. We don’t know yet what the frequency of hot flashes is in women who get the medicated gel versus placebo. We don’t expect the other health risks I mentioned, but the studies are not large enough to evaluate those because they are rare events. I can say that the circulating gel levels in the body are extremely low compared with oral tamoxifen.

Other trials are testing different types of breast cancer drugs in the form of topical gels. Please tell us about those. Targretin (bexarotene) is a retinoid that might protect against non-hormone sensitive breast cancer. A phase 1 trial at MD Anderson is testing the toxicity of that drug (listed under the number NCT 03323658 on clinicaltrials.gov). If it passes and goes to phase 2, they’ll start looking at its effectiveness. As an oral drug, this was too toxic to use in healthy women.

What other breast cancer drugs would you like to test that might be too toxic to take orally?

We tested an anti-progesterone drug, but it didn’t penetrate the skin, so we have to go back to the drawing board and develop an agent that’s differently formulated.

The other possibility is aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) like ibuprofen. These could help prevent breast cancer, but one drug in that class, Vioxx (rofecoxib), was taken off the market because it increased the risk of heart attacks. This group of drugs potentially has other side effects, too, such as stomach upset and peptic ulcers. So, that’s the next group of agents that is likely to be useful for prevention but not used at the moment and is available as a gel and a patch.

Some other agents work against HER2-positive breast cancer (which is driven by the HER2 protein, not by hormones) and are good candidates because they are small- molecule drugs, but we’d have to make sure they could get through the skin.

At the moment, our focus is proving that the concept holds. If it does so without the same side effects that come with oral versions, there would be a lot of space for developing alternative drugs.