Abstract 1859: PI3KCA Mutations and Correlation With pCR in NeoALTTO Trial. (BIG 01-06) J. Baselga et al.
LBA 16: Evaluation of Everolimus in HER2+ Advanced Breast Cancer With Activated PI3K/mTOR Pathway: Exploratory Biomarker Observations From the BOLERO-3 G. Jerusalem et al.
Two correlative studies investigating prognostic and predictive biomarkers/pathways in HER2-positive breast cancer treated with anti-HER2 inhibitors were presented at the 17th ECCO / 38th ESMO meeting. The PI3K-Akt-mTOR pathway is one of the most commonly altered pathways in breast cancer, including HER2+ breast cancers, and is implicated as a means of resistance to HER2 inhibition (either trastuzumab or lapatinib). Prior correlatives studies have shown that PIK3CA mutations are associated with a poorer outcome in HER2+ MBC.
The Neo-ALTTO study was a randomized phase 2 study (n = 455) in the neoadjuvant setting of a six-week run in of lapatinib (L), trastuzumab (T) or the combination (LT) followed by combination with weekly paclitaxel x 12 weeks followed then by primary surgery. The primary end-point of the study, pCR (breast only), was significantly higher in the combination (LT) arm: 27.7%, 29.5% and 51.3% respectively (p = 0.001). In the correlative study, 355 patient samples (78%) were suitable for genotyping by mass spectrometry for PIK3CA, Akt, KRAS AND BRAF (V600E) mutations. In total, 23% of the correlative study population had a PIK3CA mutation, with no BRAF and very infrequent KRAS (1 patient) mutations were found.
BOLERO-3 was a randomized, double-blind, placebo-controlled phase 3 trial (n = 569) of trastuzumab and vinorelbine with everolimus (5 mg PO OD)/placebo in a prior taxane and trastuzumab treated HER2+ MBC population. The overall study demonstrated a statistically significant, but modest benefit in PFS in favor of the everolimus arm (HR = 0.78; 95% CI: 0.65–0.95). In this correlative study, 262 patient samples (46%) (predominantly archival from the primary tumor) with sufficiently available tumour for DNA sequencing for PIK3CA mutations and IHC assessment of pS6 and PTEN levels were available.