J Breast Cancer.  2018 Dec;21(4):382-390. 10.4048/jbc.2018.21.e48.

PIK3CA Mutations and Neoadjuvant Therapy Outcome in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: A Sequential Analysis

• Seo Y
• Park YH
• Ahn JS
• Im YH
• Nam SJ
• Cho SY
• Cho EY

• KMID: 2429816
• DOI: http://doi.org/10.4048/jbc.2018.21.e48

Abstract

PURPOSE
PIK3CA mutation is considered to be a possible cause for resistance to neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the association between PIK3CA mutations and the outcome of NAC in HER2-positive breast cancers.
METHODS
A total of 100 HER2-positive breast cancer patients who had undergone NAC and surgery between 2004 and 2016 were examined. Mutation status was sequentially assessed in pre-NAC, post-NAC, and recurrent specimens taken from these patients.
RESULTS
PIK3CA mutations were identified in the sequential specimens of 17 patients (17.0%). These 17 patients experienced shorter disease-free survival (DFS) than the rest of the patients (58.3 months vs. 119.3 months, p=0.020); however, there was no significant difference in pathologic complete response (pCR) and overall survival (OS) (pCR, 17.6% vs. 33.7%, p=0.191; OS, 84.5 months vs. 118.0 months, p=0.984). While there was no difference in pCR between the wild-type and mutant PIK3CA groups in pre-NAC specimens (25.0% vs. 31.8%, p=0.199), PIK3CA mutations correlated with lower pCR in post-NAC specimens (0.0% vs. 24.3%, p < 0.001). Multivariate analysis revealed significantly worse DFS in the mutant PIK3CA group than in the wild-type group (hazard ratio, 3.540; 95% confidence interval, 1.001-12.589; p=0.050). Moreover, the DFS curves of the change of PIK3CA mutation status in sequential specimens were significantly different (p=0.016).
CONCLUSION
PIK3CA mutation in HER2-positive breast cancer was correlated with a lower pCR rate and shorter DFS. These results suggest that PIK3CA mutation is a prognostic marker for NAC in HER2-positive breast cancer, especially in post-NAC specimens.

Keyword

Breast neoplasms; ErbB-2 receptor; Mutation; Neoadjuvant therapy; Phosphatidylinositol 3-kinases

MeSH Terms

Breast
Breast Neoplasms
Disease-Free Survival
Drug Therapy
Epidermal Growth Factor*
Humans
Humans*
Multivariate Analysis
Neoadjuvant Therapy*
Phosphatidylinositol 3-Kinases
Polymerase Chain Reaction
Receptor, Epidermal Growth Factor*
Receptor, ErbB-2
Epidermal Growth Factor
Phosphatidylinositol 3-Kinases
Receptor, Epidermal Growth Factor
Receptor, ErbB-2

Figure

• 

  Figure 1 Survival curves for disease-free survival (DFS) and overall survival (OS). (A) PIK3CA mutant group (MT) in any sequential specimen had a shorter median DFS than the purely wild-type group (WT) in sequential specimens (58.3 months vs. 119.3 months, p=0.020). (B) In post-neoadjuvant chemotherapy (NAC) specimens, MT showed a shorter median DFS tendency than WT (60.2 months vs. 113.5 months, p=0.148). (C) Median DFS was not significantly different in pre-NAC WT and pre-NAC MT (51.8 months vs. 103.9 months, p=0.477). (D) There was no difference in median DFS depending on mutation site in sequential analysis (119.3 months vs. 47.2 months vs. 59.8 months, p=0.063). (E) Mutation site was associated with different median DFS in post-NAC specimens (post-NAC WT: 113.5 months vs. post-NAC exon 9: 41.8 months vs. post-NAC exon 20: 74.0 months, p=0.039). In subgroup analysis, post-NAC exon 9 mutation was found to have significantly shorter DFS than other groups (vs. post-NAC WT: p=0.017 vs. post-NAC exon 20: p=0.048). (F) OS was not correlated with PIK3CA mutation status (84.5 months vs. 118.0 months, p=0.984).

• 

  Figure 2 Survival curve for disease-free survival (DFS) according to mutation change status. There are four groups of mutation change status in sequential analysis. Due to lack of recurrence in the mutant-wild (MT-WT) group, Kaplan-Meier methods could not be utilized. The log-rank test was used to reveal significantly different survival curves for DFS (p=0.016). Subgroup analysis determined a significant DFS difference between the WT-WT group and WT-MT groups (p=0.005).*MT-WT: PIK3CA mutation lost after neoadjuvant chemotherapy; †WT-WT: purely PIK3CA wild-type in all of the sequential specimens;‡MT-MT: purely PIK3CA mutant type in all of the sequential specimens; §WT-MT: gained PIK3CA mutation after neoadjuvant chemotherapy.

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