Analyzing the Nuances of Trastuzumab Therapy for HER2-Positive Breast Cancer

Beth Fand Incollingo
Published Online: Tuesday, September 3, 2013
Dr. Debu Tripathy

Debu Tripathy,MD

Trastuzumab is the clear standard of care for firstline therapy for nearly all HER2-positive breast cancers, and the oncology community has come a long way toward understanding how best to use the drug.

But there are still questions clouding the use of the humanized monoclonal antibody that was initially approved in 1998. These include whether the benefit of treatment with anthracyclines exceeds its risks, and in the adjuvant setting, whether it can be given for less than a year without a loss of efficacy; how to predict which patients will benefit or encounter cardiac toxicities; and establishing its value in the smallest and lowest-risk HER2-positive tumors, said Debu Tripathy, MD, during a presentation at the 12th International Congress on the Future of Breast Cancer.

Tripathy, professor of Medicine and co-leader of the Women’s Cancers Program at Norris Comprehensive Cancer Center at the University of Southern California, addressed best practices in adjuvant and neoadjuvant HER2-targeted therapy during the conference, held July 17-19 in Huntington Beach, California.

Before choosing trastuzumab, he cautioned, practitioners must navigate the sometimes tricky task of establishing a patient’s HER2 status in the first place.

A guideline issued by the American Society of Clinical Oncology and the College of American Pathologists in 2006 recommended diagnosing HER2-positive breast cancer when a tumor scores ≥3+ on an immunohistochemistry (IHC) assay, or is fluorescence in situ hybridization (FISH)-positive with an amplification rate ≥2.2. However, the guideline included a gray area, defining an IHC between 2+ and 3+ as equivocal, with diagnosis to then be determined by a FISH test. A FISH amplification rate between 1.8 and 2.2, meanwhile, was also considered “equivocal,” or not a definitive means of diagnosing the disease.

“This 1.8 to 2.2 equivocal range has confused some people, but a 2011 clarification said that, for all adjuvant clinical trials, the criteria was FISH of 2 or greater, and that’s what we’re using in our practice, rather than letting people remain in limbo with an equivocal number,” Tripathy said.1

Questioning Anthracyclines

While pairing trastuzumab with chemotherapy is preferred in adjuvant treatment, it’s not clear whether that chemotherapy needs to contain an anthracycline, Tripathy said. Investigators want to understand the relative value of anthracyclines for patients in this population, he said, because the drugs raise the risk of cardiac complications, compounding the already higher risk that comes with trastuzumab use.

Tripathy pointed to half a dozen adjuvant trials— including the HERA, NSABP B-31/NCCTG 9891, and BCIRG 006 studies—that were launched when trastuzumab was experimental to determine whether adding the agent to anthracycline-based chemotherapy would improve outcomes for patients with early-stage HER2-positive breast cancer. Consistently, Tripathy said, the trials demonstrated that adding trastuzumab reduced disease recurrence by 30% to 50% and mortality by 20% to 30%.

However, he said, they left open the question of whether anthracyclines are a critical component of adjuvant chemotherapy regimens for this population, since the nonanthracycline arms included in some of the trials demonstrated similar benefits to the anthracycline arms.

“Study BCIRG 0062 looked at docetaxel and carboplatin with trastuzumab [TCH regimen] and compared that to anthracycline therapy followed by docetaxel as the control arm, and to the same therapy with trastuzumab overlapping docetaxel,” Tripathy said. “Both trastuzumab regimens showed an improvement in outcome, so there’s still a controversy as to how important anthracyclines are.

Can we get away with a TCH regimen? The jury is still out, because the study was not designed to compare the two trastuzumab arms, but to compare the control to each of the trastuzumab arms.” Tripathy noted that numerically more deaths and recurrences were recorded in the anthracycline arm; however, he said, that difference was not statistically significant.

The value of overlapping anthracycline with trastuzumab was explored in the neoadjuvant setting in study ACOSOG Z1041 (NCT00513292), which showed no difference in complete pathological response rate with sequential versus overlapping anthracycline and trastuzumab, Tripathy said.

While “there’s a lingering sense that maybe anthracyclines are a better partner” for trastuzumab in terms of outcome, he said, “I feel comfortable that a nonanthracycline therapy with less cardiac risk is still a reasonable way to go, even in highrisk disease.”

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