Drug Combo May Fight a Tough Form of Breast Cancer

• December 15, 2021

An experimental drug, added to chemotherapy, may benefit women with an aggressive form of breast cancer, suggests an early study offering much-needed good news.

The study involved women with "triple-negative" breast cancer, which accounts for about 15% to 20% of breast cancers among U.S. women. It is so called because the cancers lack receptors for the hormones estrogen and progesterone, and for the protein HER-2.

That means women with triple-negative cancer cannot benefit from two key breast cancer treatments: hormonal therapies and drugs that target HER-2.

Traditionally, surgery and chemotherapy have been the mainstays of treatment for triple-negative breast cancer. Unfortunately, the disease often resists, or becomes resistant to, chemotherapy -- and that was the case for women in the new study.

So the researchers tried a new approach. They added an experimental agent, dubbed L-NMMA, to the standard chemotherapy drug docetaxel. Twenty-four patients received up to six three-week cycles of the combo.

By the end of treatment, 11 patients had responded, showing a regression in their cancer. For two women, there were no more signs of cancer in the breast.

The study group included both women with metastatic cancer, which means it had spread to distant sites in the body, and those with locally advanced cancer. Those are advanced tumors that have not yet spread throughout the body.

Women with locally advanced cancer responded better to the experimental treatment combo: nine out of 11 had at least a partial response. That was true for two of 13 women with metastatic cancer, according to the report.

The findings, reported Dec. 15 in Science Translational Medicine, lay the foundation for larger trials, the researchers said.

One next step is a larger study of women with advanced triple-negative cancer, said study author Dr. Jenny Chang, director of Houston Methodist Cancer Center in Texas.

The researchers also want to test the approach against metaplastic breast cancer, a rare form of the disease that is often triple-negative.

L-NMMA works by inhibiting so-called nitric oxide signaling. That refers to a group of enzymes in the body that are needed for normal health. But in triple-negative breast cancer, increased nitric oxide signaling is linked to a poorer prognosis, Chang explained.

In lab research, her team has found that L-NMMA can curb tumor growth and spread.

However, experts who reviewed the new study said much more research is needed to know how L-NMMA might fit into triple-negative breast cancer treatment.

"I applaud the idea," said Dr. Julie Gralow, chief medical officer of the American Society of Clinical Oncology. Essentially, she noted, the approach is about improving patients' responses to chemotherapy.

Larger studies are required to further test the treatment's efficacy and safety, said Gralow, who was not involved in the research.

She also emphasized the recent strides that have been made against triple-negative breast cancer. While chemo was once the only option, several new treatments have been approved or are currently under study.

Earlier this year, the U.S. Food and Drug Administration approved the immunotherapy Keytruda (pembrolizumab) for women with early-stage triple-negative cancer, as well as some women whose cancer has spread to other sites in the body. The drug frees a "brake" on the immune system, allowing it to find and attack cancer cells.

For women with early-stage triple-negative cancer, Keytruda is used along with chemo before surgery, and then on its own afterward. And that, Gralow said, is now the standard of therapy.

Another drug, called sacituzumab (Trodelvy) also became available this year. It's an antibody that delivers chemo directly to cancer cells. The FDA approved it for patients who've already received standard treatments for locally advanced or metastatic triple-negative breast cancer.

Meanwhile, Gralow said, research has shown that some triple-negative cancers do have receptors for androgens ("male" hormones like testosterone). And studies are now testing anti-androgen drugs in those patients.

"We've traditionally defined triple-negative disease by what it isn't," Gralow noted. "We're learning more about what it is."

Dr. Charles Shapiro, a professor and oncologist at Mount Sinai's Icahn School of Medicine, in New York City, made similar points.

He said the treatment of women with advanced triple-negative cancer has gone from "dismal," when chemo was the sole weapon, to more encouraging, with the newer options.

Blocking nitric oxide signaling in the disease is a "novel therapeutic approach," Shapiro said, and should be studied further.

According to Chang, one question for the future is whether L-NMMA can also boost the response to immunotherapy.

More information

The American Cancer Society has more on treating triple-negative breast cancer.

SOURCES: Jenny C. Chang, MD, director, Houston Methodist Cancer Center, Houston; Julie Gralow, MD, chief medical officer, American Society of Clinical Oncology, Alexandria, Va.; Charles Shapiro, MD, professor, medicine, hematology and medical oncology, Icahn School of Medicine at Mount Sinai, New York City; Science Translational Medicine, Dec. 15, 2021, online

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