Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer

Abstract

Background: The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers.

Materials and methods: Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses.

Results: A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR.

Conclusion: PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.

Implications for practice: HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more and more new anti-HER2 treatments are becoming available. There is a need to identify markers of sensitivity to different treatments to move in the direction of treatment personalization. This study identified PIK3CA mutations as a potential predictive marker of resistance to dual anti-HER2 treatment that should be further studied in breast cancer.

Trial registration: ClinicalTrials.gov NCT00429299.

Keywords: Breast neoplasms; Gene expression profiling; Molecular targeted therapy; Neoadjuvant therapy; PIK3CA; p95-HER2.

Figure 1.

Pathologic complete remission rates according to biomarkers in the CHER-LOB study. Pathologic complete remission rates (ypT0/is ypN0) according to hormone receptor (A), p95-HER2 (B), PIK3CA status (C), and PI3K pathway dysfunction (D). Abbreviations: −, negative; +, positive; CT, chemotherapy therapy; HR, hormone receptor; L, lapatinib; mut, mutated; neg, negative; pCR, pathologic complete response; PI3K, phosphoinositide 3-kinase; pos, positive; T, trastuzumab; wt, wild type.

Figure 2.

Copy number (CN) alteration and pathologic complete response (pCR). Results of the CN study obtained using the lokern smoothing copy number procedure. Each chromosome (y-axis) is represented along with its length (x-axis). CN loss is represented in the specific position as a blue bar, whereas CN gain is represented as a red bar. Panels refer to results for 68 breast cancer samples derived from 68 different patients who did not achieve a pCR (left column) (A, C, E) or who achieved a pCR (right column) (B, D, F) and were enrolled in arm B (23 samples; first row) (A, B), in arm A (18 samples; second row) (C, D), and in arm C (27 samples; third row) (E, F).