Cancer Res Treat.  2023 Apr;55(2):531-541. 10.4143/crt.2022.221.

PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients

• Kim JW
• Lim AR
• You JY
• Lee JH
• Song SE
• Lee NK
• Jung SP
• Cho KR
• Kim CY
• Park KH

• KMID: 2541240
• DOI: http://doi.org/10.4143/crt.2022.221

Abstract

Purpose
Mutations in the PIK3CA gene occur frequently in breast cancer patients. Activating PIK3CA mutations confer resistance to human epidermal growth factor receptor 2 (HER2)-targeted treatments. In this study, we investigated whether PIK3CA mutations were correlated with treatment response or duration in patients with HER2-positive (HER2+) breast cancer.
Materials and Methods
We retrospectively reviewed the clinical information of patients with HER2+ breast cancer who received HER2-targeted therapy for early-stage or metastatic cancers. The pathologic complete response (pCR), progression-free survival (PFS), and overall survival were compared between patients with wild-type PIK3CA (PIK3CAw) and those with mutated PIK3CA (PIK3CAm). Next-generation sequencing was combined with examination of PFS associated with anti-HER2 monoclonal antibody (mAb) treatment.
Results
Data from 90 patients with HER2+ breast cancer were analyzed. Overall, 34 (37.8%) patients had pathogenic PIK3CA mutations. The pCR rate of the PIK3CAm group was lower than that of the PIK3CAw group among patients who received neoadjuvant chemotherapy for early-stage cancer. In the metastatic setting, the PIK3CAm group showed a significantly shorter mean PFS (mPFS) with first-line anti-HER2 mAb. The mPFS of second-line T-DM1 was lower in the PIK3CAm group than that in the PIK3CAw group. Sequencing revealed differences in the mutational landscape between PIK3CAm and PIK3CAw tumors.
Conclusion
Patients with HER2+ breast cancer with activating PIK3CA mutations had lower pCR rates and shorter PFS with palliative HER2-targeted therapy than those with wild-type PIK3CA. Precise targeted-therapy is needed to improve survival of patients with HER2+/PIK3CAm breast cancer.

Keyword

Breast neoplasms; HER2; Prognosis

Figure

• 

  Fig. 1 Comparison of treatment duration and clinical course of human epidermal growth factor receptor 2–positive (HER2+) breast cancer with or without PIK3CA mutation. Treatment response and duration of HER2-targeted therapy according to PIK3CA status. The pathologic complete response (pCR) rate after neoadjuvant anti-HER2 monoclonal antibody (mAb) was significantly lower in the mutated PIK3CA (PIK3CAm) group, while disease-free survival (DFS) after curative treatment was similar between the two groups. In palliative treatment for advanced-stage cancer, patients with PIK3CAm presented shorter mean progression-free survival (mPFS) with first-line anti-HER2 mAb and second-line T-DM1.

• 

  Fig. 2 Progression-free survival (PFS) in patients who received human epidermal growth factor receptor 2 (HER2)–targeted therapy according to PIK3CA status. (A) PFS of palliative first-line anti-HER2 monoclonal antibody (mAb). (B) PFS according to single/dual anti-HER2 mAb and PIK3CA status. (C) PFS of trastuzumab emtansine (T-DM1). (D) PFS of lapatinib and capecitabine; CI, confidence interval; HR, hazard ratio; PIK3CAm, mutated PIK3CA; PIK3CAw, wild-type PIK3CA; Tx, therapy.

• 

  Fig. 3 Tumor mutational landscape of breast cancer according to PIK3CA status. Heatmap visualization of gene alterations analyzed using next-generation sequencing. The 20 most frequently mutated genes are shown in each figure. (A) Tumor mutational landscape of breast cancer with the PIK3CA mutation. (B) Tumor mutational landscape of breast cancer with wild-type PIK3CA. ER, estrogen receptor; SNV, single-nucleotide variant.

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  Fig. 4 Tumor mutational landscape of breast cancer according to primary or recurrent status. Heatmap of somatic alterations analyzed using next-generation sequencing. The 20 most frequently mutated genes are shown in each figure. (A) Tumor mutational landscape of primary breast cancer. (B) Tumor mutational landscape of recurrent breast cancer. ER, estrogen receptor; SNV, single-nucleotide variant.

• 

  Fig. 5 Progression-free survival (PFS) with anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb) therapy according to the number of pathologic variants. PFS distribution with palliative first-line anti-HER2 mAb by subgroup according to the number of pathologic single-nucleotide variants (SNVs). Patients with fewer pathologic variants tended to show longer PFS than those with more pathologic SNVs. (A) PFS according to the number of SNVs. (B) PFS according to the number of pathologic SNVs.

Reference

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