NcXHF

RESISTANCE TO ANTI-HER2 THERAPIES IN BREAST CANCER
FIGURE 2. Reported PIK3CA Mutation Analyses in
Neoadjuvant Trials of HER2-Targeted Therapy 56-58
The percentage of patients who obtained a pathologic complete response (pCR) are
reported for each treatment arm (L, lapatinib; P, pertuzumab; T, trastuzumab). Orange bars
represent patients harboring phosphatidylinositol-3 kinase (PIK3CA) mutations; blue bars
represent patients with PIK3CA wild type (WT).
superiority compared with trastuzumab plus a taxane. Results
are expected to be presented at the 2015 ASCO Annual
Meeting. Close examination of these results is important but,
so far, it appears that T-DM1 will remain as a therapeutic
option for HER2-positive metastatic breast cancer that is resistant
to fırst-line chemotherapy plus trastuzumab and pertuzumab.
Further investigation into the mechanism of action
of T-DM1 and how best to combine it with other agents is
warranted.
ACTIVATION OF THE PI3K PATHWAY
The phosphoinositide 3-kinase (PI3K)/AKT pathway is a
powerful downstream signaling pathway activated by HER2
signaling. Constitutive activation of the PI3K/AKT pathway
by reduced levels of its tumor suppressor PTEN or by activating
mutations in PIK3CA results in resistance to trastuzumab
and other anti-HER2, according compelling preclinical evidence.
52,53 Activation of PI3K signaling by enrichment or
emergence of PIK3CA mutations may also contribute to acquired
resistance to lapatinib in experimental models. 54
Other studies, however, suggest that PTEN status may not
affect sensitivity of HER2-positive breast cancer cells to
lapatinib. 55
This mechanism of resistance has been explored in clinical
samples. Tumor tissue samples acquired at baseline from patients
who participated in neoadjuvant clinical trials with
anti-HER2 agents were studied for PIK3CA mutations, and
some trials also examined expression of PTEN. 56-58 As shown
in Fig. 2, these trials consistently showed that patients with
tumors that harbor an activating PIK3CA mutation have a
lower chance of achieving pCR after neoadjuvant therapy
with anti-HER2 agents. This difference seems to be more notable
in the group of patients who received dual anti-HER2
inhibitors compared with those who received a single anti-
HER2 agent. Although the majority of these studies coadministered
chemotherapy, which may confound their
results, there are concordant results from TBCRC006, 58 a
neoadjuvant clinical trial in which patients with HER2-
positive breast cancer received dual anti-HER2 therapy
alone, allowing for a purer biologic signal. This trial also
demonstrated that PIK3CA mutations or low PTEN levels are
associated with treatment resistance.
Conflicting results were reported, however, about the role
of PTEN in resistance to HER2-targeted therapies in other
clinical trials. Reasons for these conflicting results may po-
TABLE 4. Impact of Hormone Receptor Status on Pathological Complete Response Rate in Neoadjuvant Studies
with HER2-Targeted Therapies 42,43,45,49,67
No. of
Regimen
Overall pCR
pCR rate According
to HR (%)
Study
Patients Concurrent Therapy Anti-HER2 Therapy Rate (%) HR HR
NeoALTTO 455 Paclitaxel Trastuzumab 29.5 22.7 37.5
Lapatinib 24.7 16.1 33.7
Trastuzumab lapatinib 51.3 41.6 61.3
GEPARQUINTO 620 EC 3 docetaxel Trastuzumab 30.3 25.8 38.7
Lapatinib 22.7 16.2 28.3
NeoSphere 417 Docetaxel Trastuzumab 29.0 20 36.8
Pertuzumab 24 17.4 30
Trastuzumab pertuzumab 45.8 26 63.2
None Trastuzumab pertuzumab 16.8 5.9 29.1
TRYPHAENA 225 FEC 3 docetaxel Trastuzumab pertuzumab 61.6 49 65
Trastuzumab pertuzumab 57.3 46 79
Carboplatin docetaxel Trastuzumab pertuzumab 66.2 50 84
TBCRC 006 64 Letrozole* for ER-positive pts Trastuzumab lapatinib 27 21 36
Abbreviations: ER, estrogen receptor; HR, hormone receptor; NeoALTTO, Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization; EC, epirubicin/cyclophosphamide; NeoSphere,
Neoadjuvant Study of Pertuzumab and Herceptin in Early Regimen Evaluation; pCR, pathological complete response; TBCRC, Translational Breast Cancer Research Consortium; FEC; 5FU/epirubicin/
cyclophosphamide; Pts, patients.
*In combination with ovarian suppression in premenopausal patients.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e161