Correlation of PIK3CA Mutation and Neoadjuvant Lapatinib/Letrozole Response in Hormone Receptor–Positive, HER2-Negative Breast Cancer
In a phase IIB study reported in the Journal of Clinical Oncology, Guarneri et al compared neoadjuvant letrozole plus lapatinib (Tykerb) or placebo in postmenopausal women with hormone receptor–positive, HER2-negative breast cancer. Response rates were similar in the two groups, but a significantly higher response rate was observed in letrozole/lapatinib patients with vs without PIK3CA mutation.
Study Details
In this double-blind study, 92 women with stage II to IIIA hormone receptor–positive, HER2-negative primary breast cancer were randomly assigned to receive neoadjuvant letrozole at 2.5 mg/d plus either lapatinib at 1,500 mg/d (n = 43) or placebo (n = 49) for 6 months. Surgery was performed within 2 weeks from the last dose of study medication. Clinical response was assessed by ultrasonography, and genomic analysis was performed in fresh-frozen tissue samples. The primary endpoint was objective response rate.
For the lapatinib and placebo groups, median age was 70 years in both, 95% and 92% had Eastern Cooperative Oncology Group performance status of 0, clinical disease stage was IIA in 49% and 53% and IIB in 40% and 43%, 67% and 78% had ductal histology, and histologic grade was 2 in 37% and 39% and 3 in 30% and 39%.
Response Rates
Objective response rates were 70% in the lapatinib group, including complete response in 12%, and 63% in the placebo group, including complete response in 2%. The conversion rate from mastectomy to breast-conserving surgery was 46% in the lapatinib group and 59% in the placebo group. No pathologic complete responses were observed in patients undergoing surgery.
Response in PIK3CA-Mutant Tumors
Ki-67 and pAKT expression were significantly reduced in both groups during treatment. A total of 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. The clinical objective response rate was significantly higher in patients with vs without PIK3CA mutation in the lapatinib group (93% vs 63%, P = .037) but not in the placebo group (63% vs 66%, P = .79).
Toxicity
Adverse events of any grade were more common in the lapatinib group, including diarrhea (60% vs 10%), skin disorders (58% vs 6%), and liver function test abnormalities (26% vs 4%). One grade 4 skin reaction (2%) was observed in the lapatinib group. Grade 3 adverse events were more common in the lapatinib group, including diarrhea (14%), skin disorders (9%), and nail toxicity, increased transaminases, and increased gamma-glutamyltransferase (5% each); only one grade 3 adverse event (increased transaminases, 2%) was observed in the placebo group.
The investigators concluded: “The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor–positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in [hormone receptor–]positive/HER2-negative early breast cancer must now be independently confirmed.”
Pierfranco Conte, MD, of University of Padova, Italy, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by GlaxoSmithKline. For full disclosures of the study authors, visit jco.ascopubs.org.
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