PTEN Expression Does Not Diminish Trastuzumab Effectiveness

Phosphatase and tensin homolog (PTEN)-positive breast cancer can be treated with trastuzumab (Herceptin) as effectively as PTEN-negative breast cancer, according to study data unveiled on Monday at the ASCO conference in Chicago.

“We detected that patients who had PTEN expression or patients who had no PTEN expression benefited to the same degree [with] trastuzumab,” said the study’s lead investigator, Edith A. Perez, MD, director of the Breast Clinicat the Mayo Clinic in Jacksonville, Florida, in an interview with OncLive.com. “This is a very important finding, as many investigators have been trying to get at that type of information. Our results provide the data so that other researchers can look for other potential reasons for sensitivity or resistance to trastuzumab.”

Perez and her colleagues looked at tumors from 1802 patients enrolled in the North Central Cancer Research Group (NCCTG) N9831 clinical trial, and found that patients with HER2-positive breast cancer who had either a loss of PTEN functioning or normal PTEN activity did equally well when trastuzumab was added to chemotherapy to prevent breast cancer recurrence. They reported that 1341 (75%) of the patients were PTEN-positive and that this was associated with a lower percentage of hormone receptor positivity (45% vs 55%; P <.001) and higher nodal positivity (87% vs 83%; P = .04) but not associated with age, race, tumor histology, grade, or size.

According to the researchers, PTEN prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) were evaluated. They examined the percentage of cells with PTEN staining and assigned an intensity score from 0 (none) to 3 (strong) using either tissue microarray sections or whole-tissue sections; this data was then linked with DFS.

Their analysis determined that PTEN status did not significantly impact DFS. Perez and her associates noted, “In contrast to preclinical and limited clinical studies that suggest a decrease in trastuzumab sensitivity in PTEN-negative tumors, our adjuvant data show benefit of adding trastuzumab for both PTEN-positive and PTEN-negative groups (with slightly greater benefit for [the] PTEN-negative group).”

Perez said that preclinical studies and some small patient studies had suggested that tumors with loss of PTEN expression would not benefit from trastuzumab. As a result, investigators were considering using PTEN biomarkers in clinical studies as a test of trastuzumab resistance, and patients who tested positive for PTEN loss might then be offered other therapies or be invited to participate in clinical trials.

“We have all been interested in biomarkers that predict for benefit to anti-HER2 therapy,” Perez said, “but PTEN is not one that we should pursue further, based on our rigorous analysis.”

Perez EA, Dueck AC, Reinholz MM, et al. Effect of PTEN protein expression on benefit to adjuvant trastuzumab in early-stage HER2+ breast cancer in NCCTG adjuvant trial N9831. J Clin Oncol. 29:2011 (suppl; abstract 10504).