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Treatment Options for HER2-Positive Breast Cancer Expand and Evolve

Tuesday, October 16, 2012

(NCI Cancer Bulletin, Vol 9/No 20) New results from three clinical trials highlight the evolving treatment options for women who have HER2-positive breast cancer. These cancers, which produce too much HER2 receptor protein, are a particularly aggressive form of the disease and account for approximately 20 percent of all breast cancer diagnoses.

In one trial, researchers showed that the investigational drug T-DM1 improved overall survival in women with advanced HER2-positive disease who had been previously treated with the HER2-targeted drug trastuzumab (Herceptin) and taxane chemotherapy. These updated findings from the EMILIA trial appeared October 1 in the New England Journal of Medicine.

“Only a few studies in metastatic breast cancer have shown an improvement in overall survival. It’s tough to do,” said the trial’s lead investigator, Dr. Sunil Verma of the Sunnybrook Odette Cancer Centre in Toronto. “The gain that we saw in this trial, an incremental improvement of 5.8 months, is one of the largest seen of any trial reported to date [in this disease]. And we’re seeing that gain with less toxicity.”

In addition, findings from two other clinical trials, presented at the European Society for Medical Oncology Congress (ESMO), provided more evidence that the existing duration of adjuvant treatment with trastuzumab in women with early-stage breast cancer should remain 1 year.

The trials are part of what has become an increasingly dynamic area of research for HER2-positive breast cancer.

The Food and Drug Administration (FDA), for example, recently approved pertuzumab (Perjeta), which also targets the HER2 receptor, in combination with trastuzumab and docetaxel for women with metastatic HER2-positive breast cancer. And T-DM1 is already being tested in a phase III trial as a first-line therapy for these women.

Researchers are also testing several investigational drugs that disrupt signaling pathways thought to play an important role in tumor resistance to HER2-targeted agents, said Dr. Ingrid Mayer, clinical core director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Tennessee.

“It is possible that, with so many active drugs against HER2-positive disease, we may eventually see some patients with stage IV disease being cured,” Dr. Mayer said. But, she cautioned, much more research is needed before this would be possible.

In Advanced Disease, Improving Overall Survival

In the nearly 1,000-patient EMILIA trial, women who received T-DM1 had substantially better overall survival than women treated with the chemotherapy agent capecitabine (Xeloda) and another HER2-targeted drug, lapatinib (Tykerb): 30.9 months versus 25.1 months. (As previously reported, women who received T-DM1 also had better progression-free survival: 9.6 months versus 6.4 months.)

T-DM1 is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab and the chemotherapy drug DM1.

Trastuzumab has been linked to cardiovascular complications, but the two treatment groups had similar rates of cardiac events. Dr. Verma stressed, however, that clinicians should be cautious in interpreting the safety findings because patients who experienced cardiac toxicity with trastuzumab were not eligible for the trial, so those at increased risk for such complications were “selected out.”

“We still need to do more studies, but T-DM1 doesn’t appear to be any worse than capecitabine and lapatinib in terms of cardiac toxicity,” Dr. Verma said.

Genentech, which markets T-DM1 in the United States, has submitted a biologics license application to the FDA to market the drug for women with locally advanced or metastatic HER2-positive breast cancer that cannot be treated with surgery and who previously received trastuzumab and taxane chemotherapy.

In Early-Stage Disease, Finding the Optimal Treatment Duration

For now, at least, the standard of care for women with early-stage HER2-positive breast cancer should remain 1 year of adjuvant trastuzumab. That was the conclusion reached by the researchers who led the HERA and PHARE trials, which tested different durations of adjuvant treatment. Updated results from both trials were presented at ESMO earlier this month.

The 5,000-patient HERA trial had three treatment groups: 2 years of adjuvant treatment with trastuzumab, 1 year of trastuzumab, or observation. After a median follow-up of more than 8 years, progression-free and overall survival were nearly identical in the 1-year and 2-year treatment groups, Dr. Richard Gelber of the Dana-Farber Cancer Institute reported.

Over time, the difference in progression-free survival between participants who received trastuzumab for 1 year and those who underwent observation narrowed. Even with the longer follow-up, however, women who received 1 year of trastuzumab lived 24 percent longer without their disease progressing.

“We know that this…is an underestimate of the effect of the treatment, because more than half of patients in the placebo arm actually received trastuzumab later on,” Dr. Gelber said during a press briefing.

Although the rates of cardiac-related death and congestive heart failure were less than 1 percent in both treatment groups, women who received trastuzumab for 2 years had a statistically significantly higher incidence of reduced heart function (left ventricular ejection fraction), he reported.

The PHARE trial, meanwhile, compared 12 versus 6 months of adjuvant treatment with trastuzumab in the same patient population. The trial was smaller (3,380 patients), and it was a noninferiority trial. Noninferiority trials aim to demonstrate that the effectiveness of one treatment is not less than that of another treatment by more than a predetermined margin, suggesting that they are essentially equivalent.

Based on about 3.5 years of follow-up, the results “are inconclusive for noninferiority” between 6 and 12 months of adjuvant trastuzumab, explained the trial’s lead investigator, Dr. Xavier Pivot of Université de Franche-Comté, at an ESMO press briefing. There was, however, “a strong trend in favor of 12 months of treatment,” Dr. Pivot said.

The shorter treatment duration appeared to be safer, Dr. Pivot noted, with the percentage of women experiencing cardiac events nearly three times as high in women who received trastuzumab for 1 year (5.7 percent versus 1.9 percent). In the trial, however, “‘cardiac event’ was a composite variable” encompassing several heart-related problems, he explained, “so interpreting these data is not so easy.”

Based on the results thus far, Dr. Mayer agreed, the standard of care for adjuvant treatment with trastuzumab in women with early-stage HER2-positive breast cancer should remain 1 year.

Although he concurred, Dr. Gelber stressed that the follow-up was not long enough to draw any definitive conclusions.

“There are some patients who may do just as well with the shorter duration,” Dr. Gelber said.

The most recent analysis of patient subgroups in the PHARE trial will be presented in December at the San Antonio Breast Cancer Symposium. These findings may begin to identify women who need only 6 months of adjuvant trastuzumab, Dr. Pivot said.

Several other international clinical trials are testing shorter durations of adjuvant trastuzumab treatment in women with early-stage HER2-positive breast cancer.

Carmen Phillips

Further reading: “For Some Breast Cancers, New Drug May Be Treatment Option” and “Pertuzumab Approved to Treat Some Metastatic Breast Cancers

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