New Guidelines for HER2+ Breast Cancer

Due to the evolving treatment landscape for HER2-positive breast cancer, the American Society of Clinical Oncology has released new evidence-based guidelines for the use of systemic therapy in metastatic disease, and consensus-based recommendations for managing patients whose disease has spread to the brain.

The HER2 gene is amplified in almost 20% of breast cancers. Since the 1998 FDA approval of trastuzumab (Herceptin; Roche), three additional therapies have emerged: lapatinib (Tykerb; GlaxoSmithKline) plus capecitabine; ado-trastuzumab emtansine (Kadcyla; Roche), commonly called T-DM1; and pertuzumab (Perjeta; Roche). Both pertuzumab and T-DM1 were approved in 2013.

After examining key outcomes from 16 trials—including overall survival (OS), progression-free survival (PFS), and adverse events—a panel concluded that trastuzumab and pertuzumab, in combination with a taxane, is the optimal first-line regimen for metastatic disease. If the disease progresses, T-DM1 should be used as a second- or even third-line therapy, due to its OS and PFS benefits and more favorable toxicity profile than lapatinib plus capecitabine.

“T-DM1 may ultimately have a first-line role,” says Eric Winer, MD, panel co-chair and director of Dana-Farber Cancer Institute's Breast Oncology Center in Boston, MA. “We're waiting for the results of a study evaluating it alone and with pertuzumab in this setting.”

Up to half of patients with advanced HER2-positive breast cancer develop brain metastases. The panel recommended resecting a single lesion or the largest of a limited number of lesions, followed by radiotherapy. They advised stereotactic radiosurgery for additional smaller lesions, and whole-brain radiotherapy for extensive metastases.

Otherwise, “we don't have effective therapies, and no really interesting new options at this point,” says Kent Osborne, MD, director of Baylor College of Medicine's Cancer Center in Houston, TX. “It's a problem, because patients whose extracranial disease is now controllable end up dying from brain metastases.”

Winer and Osborne believe understanding why resistance to HER2-targeted therapies happens, and how to prevent it, are key unsolved questions. Osborne was an author on a recent study, first reported at the 2013 San Antonio Breast Cancer Symposium, showing that patients with low PTEN protein levels or PI3KCA gene mutations—both activating the PI3K pathway—are much less responsive to lapatinib combined with trastuzumab. “That's one clue,” Osborne says of the resistance puzzle. “They obviously also require a PI3K or AKT inhibitor.”

Winer also thinks the field's numerous individual studies generally “underestimate the dramatic progress” made in treating metastatic HER2-positive breast cancer; with new treatments, the big picture is not as bleak as one might otherwise surmise. “Women are living years longer than was once the case,” he says, “and with a much better quality of life.”