ECC 2013 Abstract#1859 NeoALTTO & LBA#16 BOLERO-3

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.

PIK3CA mutations are a poor prognostic factor in HER2-positive breast cancer (both early and advanced stage) and may be predictive of lack of substantial benefit from the combination of dual anti-HER2 therapy (trastuzumab and lapatinib).

Conversely, the PIK3CA wild-type HER2-positive breast cancers may be the subgroup that derives the greatest benefit from dual anti-HER2 therapies, and thus maximize the therapeutic efficacy and cost effectiveness ratio in favor of combination therapy in this cohort of patients.

Activation of the PI3K-Akt-mTOR pathway (as measured by low PTEN or high pS6) may possibly identify the subgroup that derives greater clinical benefit of everolimus in combination with vinorelbine and trastuzumab in BOLERO-3. Further validation however is required – both in additional studies with higher proportional collection of contemporary tissue and in determining the appropriate reproducible methodology and cut-points for measuring low PTEN and high pS6.

It is likely in the future, some HER2-positive breast cancers will require single upstream blockade, some will require dual upstream blockade, and others yet will require blocking both upstream and downstream of the activated HER2 pathway depending on the biomarker profile of the tumors.
— CARE Breast Cancer Faculty