Topic:
 
Issue Section:
 Biomarkers, translational research and precision medicine
Background: The PI3K signaling pathway is frequently dysregulated in breast cancer (BC), effected through mutations in PIK3CA, which encodes for the catalytically subunit p110-alpha. An influence of PIK3CA mutations in therapy response resistance associated with a worse clinical outcome has previously been shown in HER2+ BC. Mutations in exon 9 or 20 may play a role in cell proliferation and therapy response.
Methods: We investigated PIK3CA mutation status in 484 BC patients, randomized in three clinical multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880). Classical Sanger sequencing in exon 9 and 20 was performed on formalin-fixed paraffin embedded pretherapeutical core biopsies with a tumor content > =20%.
Results: Mutation analysis of exon 9 and 20 were successful in 431 cases: PIK3CA was mutated in 21.6%, exon 9 in 8.8% and exon 20 in 13.9% of cases. Detection of a PIK3CA mutation was not significantly associated with a higher proliferation rate (Ki67 >20%: 76.3% mut. vs. 75.0% WT, p = 0.878). TN tumors were more often Ki67 low (38.5%) when exon 20 was mutated compared to wildtype (6.5%) (p = 0.005). There were no significant differences in proliferation in hormone receptor positive or HER2 positive tumors. Lower stromal lymphocyte infiltration was seen when exon 9 was mutated compared to wildtype in HER2+/HR- (Infiltration >60%: 28.5% mut. vs. 5.6% WT, p = 0.012), but not overall or in other subtypes. Detection of any PIK3CA mutation was significantly associated with lower pathologic complete response (pCR, ypT0ypN0) (24.7% in PIK3CA mutated vs. 38.2% in wildtype; p = 0.020). However, patients with mutation in exon 9 (21.1% mutated vs. 36.6% wildtype; p = 0.074) or 20 (25% mutated vs. 36.9% wildtype; p = 0.081) did not reach statistical significance for pCR.
Conclusions: PIK3CA mutation is not linked with a higher tumor proliferation, but in HER2+/HR- tumors associated with a lower stromal lymphocyte infiltration. However, PIK3CA could be used as a biomarker for a worse outcome in terms of a lower rate of pCR after neoadjuvant anthracycline-taxane–based chemotherapy.
Clinical trial identification: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880).
Legal entity responsible for the study: GBG Forschungs GmbH.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
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