Should Adjuvant Pertuzumab Be Used for Patients With HER2-Positive Breast Cancer?

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While APHINITY showed a small improvement with adjuvant pertuzumab, it is unclear whether the benefits are worth the cost, time, and toxicity associated with the drug.
While APHINITY showed a small improvement with adjuvant pertuzumab, it is unclear whether the benefits are worth the cost, time, and toxicity associated with the drug.

In December 2017, the US Food and Drug Administration (FDA) granted regular approval to pertuzumab, a monoclonal antibody targeting HER2, in combination with trastuzumab and chemotherapy for the adjuvant treatment of HER2-positive breast cancer at high risk of recurrence.1 This full approval followed the FDA's 2013 accelerated approval of the drug as a neoadjuvant treatment in this patient population.

About 1 in 5 breast cancers will have a gene amplification or overexpression of HER2. Almost 20 years ago, in 1998, trastuzumab became the first HER2-targeting therapy approved by the FDA for patients with breast cancer. Trastuzumab was designed to target HER2 proteins overexpressed on HER-positive tumor cells. In combination with chemotherapy, it significantly improved progression-free and overall survival in HER2-positive metastatic breast cancer.2

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Pertuzumab is also a HER2-targeting monoclonal antibody therapy, but it binds to the HER2 receptor at different regions; it blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4.

“HER2-positive cancer cells have an excess of HER receptors on their surface and when these proteins ‘knock into each other' — called dimerization — they send a signal to the cell to grow,” explained Angela DeMichele, MD, MSCE, Alan and Jill Miller professor in breast cancer excellence at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia. “These antibodies can embed themselves between the HER2 receptors in order to prevent this dimerization. They are complementary because trastuzumab binds to one receptor at one spot, and pertuzumab does it at a different place.”

Metastatic Disease

The first regulatory approval for pertuzumab was in combination with trastuzumab and docetaxel to treat HER2-positive metastatic breast cancer.3

The 2012 approval was based on results from the CLEOPATRA study, which compared pertuzumab/trastuzumab/docetaxel with trastuzumab/docetaxel/placebo in 808 patients with HER2-positive metastatic breast cancer.4

Adding pertuzumab resulted in a 6-month improvement in median progression-free survival (18.5 vs 12.4 months; hazard ratio [HR], 0.62; 95% CI, 0.51-0.75; P < .001). An interim analysis also showed a significant improvement in overall survival with pertuzumab. The final overall survival analysis confirmed this improvement, showing a median of 56.5 months with pertuzumab compared with 40.8 months with placebo (HR, 0.68; 95% CI, 0.56-0.84; P < .001).5

In an editorial published with the initial results of CLEOPATRA, William J. Gradishar, MD, of Northwestern University's Feinberg School of Medicine in Chicago, Illinois, wrote, “Although HER2-positive breast cancer accounts for only 25 to 30% of breast cancers, the increasing therapeutic options provide hope to patients and considerable challenges for clinicians.”6

Dr Gradishar added that “given the success of the pivotal trials of adjuvant trastuzumab therapy, clinical trials of adjuvant therapies, which are already large and expensive, will by necessity require even more subjects to detect small differences with a new agent.”

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