PTEN status did not alter benefit of adjuvant trastuzumab in HER-2 breast cancer
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Adjuvant trastuzumab conferred a benefit in patients regardless of tumor phosphatase and tensin homolog status, according to phase 3 results from the North Central Cancer Treatment Group trial.
PTEN may be involved in tumor sensitivity to trastuzumab (Herceptin, Genentech), according to background information in the study.
For this reason, Edith A. Perez, MD, director of the breast cancer program at Mayo Clinic in Jacksonville, Fla., and a HemOnc Today Editorial Board member, and colleagues examined the association between tumor PTEN protein expression and DFS in 1,802 patients with HER-2-positive breast cancer.
Edith A. Perez
The researchers randomly assigned patients to one of three arms: chemotherapy alone, chemotherapy plus sequential trastuzumab, or chemotherapy plus concurrent trastuzumab.
The researchers determined the percentage and intensity of invasive cells with cytoplasmic PTEN staining by either tissue microarray sections containing three cores per block (n=1,286) or in whole tissue sections (n=516) with standard immunohistochemistry.
Median follow-up was 6 years.
A total of 1,342 women had PTEN-positive tumors. Having these types of tumors was associated with nodal positivity (P=.04) and hormone receptor negativity (P<.001).
PTEN did not affect DFS in any of the three study arms. When the researchers compared DFS between patients assigned to chemotherapy plus concurrent trastuzumab arm vs. patients assigned to chemotherapy alone, they found that PTEN-positive and PTEN-negative tumors had HRs of 0.65 (P=.003) and 0.47 (P=.005), respectively (interaction P=.16).
When the researchers compared patients assigned chemotherapy plus sequential trastuzumab vs. patients assigned chemotherapy alone, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P= .009) and 0.85 (P=.44), respectively (interaction P=.47).
“Our study answered a hypothesis that had been proposed by a wide range of investigators and clinicians,” Perez told HemOnc Today. “It specifically tested whether the PTEN protein in tumors correlated with benefit to the adjuvant anti-HER–2 therapy trastuzumab. Based on our findings, patients with either no, low or normal PTEN clearly benefitted from therapy.”
The next steps include evaluation and validation of genomic signatures and other tumor and circulating blood markers to better predict who might or might not significantly benefit from targeted trastuzumab treatment, Perez said.
“Inconsistent with this report, several smaller retrospective clinical studies have shown that loss or low levels of PTEN are associated with a reduced clinical benefit from trastuzumab,” Brent N. Rexer, MD, Yu Shyr, MD, and Carlos L. Arteaga, MD, all from Vanderbilt-Ingram Cancer Center and the Vanderbilt University School of Medicine, wrote in an accompanying editorial. “Several possibilities to explain these differences should be considered.”
The study by Perez and colleagues “is an important step in defining, in a large group of patients, the impact of PTEN expression/function and other mutations in the PI3K pathway on the outcome of patients with HER-2-positive breast cancer,” Rexer, Shyr and Arteaga added.
For more information:
Perez EA. J Clin Oncol. 2013;doi:10.1200/JCO.2012.42.2642.
Rexer BN. J Clin Oncol. 2013;doi:10.1200/JCO.2012.48.5243.
Edith A. Perez, MD, can be reached at: perez.edith@mayo.edu.
Disclosure: Perez reports research funding from Genentech and GlaxoSmithKline.