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Background <p>HER2-positive (HER2+) breast cancer (BC) accounts for 15–20% of all BC. Mutations in the <i>PIK3CA</i> gene are found in 25–30% of HER2 + BC cases and have been implicated in tumor progression and endocrine therapy resistance. Recent evidence suggests that a somatic <i>PIK3CA</i> mutation (<i>PIK3CA</i>m) may serve as a marker of early progression in HER2 + metastatic BC. However, its precise prognostic significance across various lines of therapy and disease stages is not fully understood. We therefore aimed to evaluate the impact of <i>PIK3CA</i>m status on clinical outcomes in HER2 + BC patients.</p> Methods <p>We conducted a retrospective cohort study using data from the American Association for Cancer Research (AACR) Project GENIE Biopharma Collaborative (BPC). Overall survival (OS), Distant Recurrence-Free Survival (DRFS), and progression-free survival (PFS) were the primary outcomes. We compared patients with and without <i>PIK3CA</i>m and performed survival analysis using Kaplan-Meier methods and Cox proportional hazards models.</p> Results <p>We identified 212 HER2 + patients (150 early-stage and 62 Stage IV), of which 58 had a <i>PIK3CA</i>m. The median OS for the overall cohort was 125.1 months from treatment. Among early-stage patients, <i>PIK3CA</i>m was associated with a longer DRFS from diagnosis (37.7 months [95% CI 28.6–62.6] vs. 22 months [95% CI 16.8–32.8], <i>p</i> = 0.04). In contrast, among patients with Stage IV disease receiving first-line therapy, <i>PIK3CA</i>m was associated with a shorter median PFS (5.5 [95% CI 1.6–32.2] vs. 14.9 months [95% CI 7.2–22.0], <i>p</i> = 0.04). <i>PIK3CA</i>m was not identified as an independent predictor of OS, DRFS, or PFS in univariable or multivariable regression analyses. Within the <i>PIK3CA</i>m subgroup, not having received hormone therapy was the only factor associated with worse survival on multivariable analysis (aHR = 4.51, 95% CI 1.77–11.5).</p> Conclusion <p><i>PIK3CA</i>m was not found to be associated with worse OS, however it was associated with a shorter PFS among patients receiving first-line therapy, suggesting <i>PIK3CA</i>m could be explored as a predictive biomarker for identifying HER2 + Stage IV patients at higher risk of disease progression. These findings underscore the need for enhanced surveillance and personalized treatment strategies to manage disease progression in this patient subgroup.</p>

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Impact of somatic PIK3CA mutations on clinical outcomes in HER2-positive breast cancer

  • 期刊论文

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  • 发表日期：

    2026年6月20日

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  • Nickolas Stabellini,
  • Sonia D. de Oliveira,
  • Takae Mizukami,
  • Shawn M. Sweeney,
  • Nikolaus Schultz,
  • Ken Kehl,
  • Gregory Riely,
  • Katherine Panageas,
  • Deborah Schrag,
  • Philippe Bedard,
  • Christine Micheel,
  • Xindi Guo,
  • Alberto J. Montero

摘要

Background

HER2-positive (HER2+) breast cancer (BC) accounts for 15–20% of all BC. Mutations in the PIK3CA gene are found in 25–30% of HER2 + BC cases and have been implicated in tumor progression and endocrine therapy resistance. Recent evidence suggests that a somatic PIK3CA mutation (PIK3CAm) may serve as a marker of early progression in HER2 + metastatic BC. However, its precise prognostic significance across various lines of therapy and disease stages is not fully understood. We therefore aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2 + BC patients.

Methods

We conducted a retrospective cohort study using data from the American Association for Cancer Research (AACR) Project GENIE Biopharma Collaborative (BPC). Overall survival (OS), Distant Recurrence-Free Survival (DRFS), and progression-free survival (PFS) were the primary outcomes. We compared patients with and without PIK3CAm and performed survival analysis using Kaplan-Meier methods and Cox proportional hazards models.

Results

We identified 212 HER2 + patients (150 early-stage and 62 Stage IV), of which 58 had a PIK3CAm. The median OS for the overall cohort was 125.1 months from treatment. Among early-stage patients, PIK3CAm was associated with a longer DRFS from diagnosis (37.7 months [95% CI 28.6–62.6] vs. 22 months [95% CI 16.8–32.8], p = 0.04). In contrast, among patients with Stage IV disease receiving first-line therapy, PIK3CAm was associated with a shorter median PFS (5.5 [95% CI 1.6–32.2] vs. 14.9 months [95% CI 7.2–22.0], p = 0.04). PIK3CAm was not identified as an independent predictor of OS, DRFS, or PFS in univariable or multivariable regression analyses. Within the PIK3CAm subgroup, not having received hormone therapy was the only factor associated with worse survival on multivariable analysis (aHR = 4.51, 95% CI 1.77–11.5).

Conclusion

PIK3CAm was not found to be associated with worse OS, however it was associated with a shorter PFS among patients receiving first-line therapy, suggesting PIK3CAm could be explored as a predictive biomarker for identifying HER2 + Stage IV patients at higher risk of disease progression. These findings underscore the need for enhanced surveillance and personalized treatment strategies to manage disease progression in this patient subgroup.