Why does Herceptin stop working?

Since the FDA’s approval of Herceptin in 1998, it has been used to treat about 420,000 women with early-stage or metastatic breast cancer. But Herceptin can lose its effect over time, and some cancers are resistant to it from the start.

In one study designed to learn why, researchers looked at 143 HER2-positive women who had been treated before surgery with chemotherapy plus Herceptin. Seventy-two still had signs of cancer at the time of surgery. When researchers looked more closely at the 23 patients for whom they had sufficient tumor tissue to conduct more HER2 tests, they saw that seven women whose tumors had previously been HER2 positive were now HER2 negative.

“What this is suggesting is that in patients who don’t achieve a significant response, about a third of them may be converting to HER2-negative disease,” says Elizabeth A. Mittendorf, MD, an assistant professor of surgical oncology at the University of Texas M.D. Anderson Cancer Center in Houston and lead author of the study presented at ASCO’s 2008 Breast Cancer Symposium. Why? There are two hypotheses: First, some HER2-positive cells may have become negative as a result of treatment. It’s also possible that the patients’ tumors contained both HER2-positive and HER2-negative cells, and the drugs wiped out only the positive ones, leaving the negative cancer cells to grow. Researchers are looking further into these positive-to-negative tumors to see if they have other characteristics typical of Herceptin-resistant cancer. Until more is known, however, Mittendorf says this won’t change the way doctors treat women with HER2-positive disease.

Eric Winer, MD, chief of the division of women’s cancers at the Dana-Farber Cancer Institute in Boston and chief scientific advisor to Susan G. Komen for the Cure, agrees. He adds that even after Herceptin seems to stop working, some patients can still benefit from it or another anti-HER2 drug. He likens Herceptin to a roadblock on a highway. In this case, cancer cells may be smart enough to find ways around the roadblock, but Herceptin is still slowing down their trip. “By understanding what’s allowing the cancer cell to escape Herceptin, we’ll be able to come up with drugs to block that escape mechanism,” he says.

Researchers are also comparing chemotherapy drugs administered alone or in combination with anti-HER2 drugs to see which does the better job of keeping the cancer under control when Herceptin fails. In one 2006 study, researchers from Allegheny General Hospital in Pittsburgh studied two groups of women with locally advanced (stage III) or metastatic (stage IV) breast cancer whose disease had progressed despite receiving chemotherapy and Herceptin. One group was given the anti-HER2 drug Tykerb (lapatinib) plus Xeloda (capecitabine), while the other received Xeloda alone. The women on the Tykerb/Xeloda combination stayed stable longer before their illness progressed again than the women on Xeloda only.

Similarly, in a study conducted by researchers in Germany, women whose metastatic disease stopped responding to Herceptin fared better when they were given a Xeloda/Herceptin regimen than women who took only Xeloda. The group reported an updated form of its findings at the 2008 ASCO annual meeting.

The response rate (percentage of patients whose cancer stopped progressing) went from 27 percent on Xeloda to about 48 percent with the combination. “It’s a little surprising,” Hudis says. “I always thought all the activity was from changing the chemo. Changing the chemo got you benefit, but changing chemo and continuing the [Herceptin] gave you more benefit.”

Hudis recently reflected on the ways oncologists have changed their thinking about HER2-positive breast cancer. “When [my med school classmates and I] began our careers [20 years ago], HER2-positive wasn’t described in the clinic. In the middle of our careers, HER2-positive meant a bad prognosis and a worse outcome. And in the last five years, HER2-positive means, on average, a better outcome than the average breast cancer. The drugs have flipped the results.”

Coming in Part II: New HER2 drugs, the possibility of a HER2 vaccine and stories from HER2-positive women.