Discussion
Trastuzumab and Lapatinib have been the mainstays of anti-HER2 treatment
in breast cancer. While they showed superior efficacy in subsets of
primary and metastatic HER2-positive breast cancers, therapeutic
resistance to HER2-targeted therapy remains an important clinical
problem. Expression of mutant PIK3R1 in endometrial cancer8, 9,
malignant
glioma 10 and breast cancer cell lines6, 11, 12 is associated with activation of PI3K
downstream signaling. However, the clinical significance of PIK3R1
mutations in HER2-positive breast cancer patients is less well
understood and needs further investigation. For the first time, we
reported a case of a 52-year-old HER2-positive breast cancer patient
with a novel
PIK3R1EY451delinsDwho developed resistance to HER2-targeted therapies.
Strikingly,
the
combined use of trastuzumab and
everolimus
overcame the resistance in this case harboring
PIK3R1EY451delinsD.
The precise knowledge of the genomic alterations present in cancer is
critical to select the optimal treatment for each patient, so monitoring
the impact of individual oncogenic alterations on lesion specific
responses is indispensable. Cheung et al. and Urick et al. reported that
thePIK3R1 indels
(E439del, H450-E451del, Y463-L466del, R574fs, T576del, R574-T576del)
have shown to be oncogenic and led to increased levels of p-AKT in
endometrial cancer 8, 9. Quayle et al. demonstrated
that three PIK3R1 indels (DKRMNS560del, R574fs, T576del) with the
strongest activities increased P110α kinase activity in the in
vitro kinase assay in malignant glioma 10. Cheung et
al. uncovered that the PIK3R1 R348* and L370fs truncations were
localized to the nucleus, where they facilitated abnormal pathway
activation 11. Thorpe et al. and their colleagues
found that the genetic ablation of PIK3R1 accelerated a mouse model of
HER2/neu-driven breast cancer 12. Chen et al.6 provided a landscape of PIK3R1 mutations
in 149
Chinese
breast cancer patients, and reported that
PIK3R1
mutations were prevalent (25 tumors, 17%) in this Chinese cohort. They
also confirmed when normal mammary epithelial cell line MCF10A
overexpressing exogenous
PIK3R1
mutations were grown in the absence of EGF, the levels of
pAKTSer473 were slightly higher 6.
Together, there is
an
increasing number of evidence that
PIK3R1
mutations activate the PI3K signaling
pathway
and display oncogenic properties 3, 4, 6, 8-13.
By analyzing the cBioPortal database, there is a huge difference of
frequency range of PIK3R1 alterations among types of cancer from
more than 30% to less than 2% (Figure 2A). It is also worth noting
that there are about 31% PIK3R1 mutations (Uterine_TCGA PanCan, Figure
2A) that frequently occur in uterine corpus endometrial carcinoma.
Future
PIK3R1
mutational location analysis that covers all mutations is shown as
Figure 2B, including 65939 cancer patients and 1690 mutations. In
addition, we also summary characteristics of eleven patients with the
same
E541_Y542del
from cBioPortal (Figure 2C), but
PIK3R1EY451delinsDis a rare mutant form with little prior
knowledge
in breast cancer patients. To better display the result of PIK3R1
mutations, we showed that genomic characterization of PIK3R1 in breast
cancer cohorts (Figure 2D and 2E).
PIK3R1
mutations are only found in a small subset (1.8%,87/4602,
www.cbioportal.org) of breast cancers including HER2 positive subtype
(Figure 2E). In contrast, PIK3R1 mutations (not including
PIK3R1EY451delinsD) are prevalent (25 tumors, 17%) in
Chinese breast cancer patients 6. This is the first
report representing
PIK3R1EY451delinsDin breast
cancer.
This novel PIK3R1EY451delinsD confers resistance to
trastuzumab and lapatinib in HER2-positive breast cancer. Fortunately,
this case supports the combined use of trastuzumab and everolimus after
failure of previous targeted therapies in
HER2-positive
breast cancer patient harboring PIK3R1EY451delinsD.
However, brain metastasis was very tricky to treat
in
clinical, and we needed more effective drugs to cross the blood-brain
barrier. We believe that
PIK3R1
alterations can be clinically useful to predict the treatment response
for HER2-targeted treatment. In the future, functional PIK3R1
alterations should be incorporated in clinical trials to evaluate
treatment response of targeted therapies in HER2-positive breast cancer.
Preclinical studies have demonstrated that breast cancer cell lines
harboring PIK3R1 mutants or loss of p85α (encoded by PIK3R1 gene)
activate the PI3K/AKT signaling pathway 6, 12.
However, whether PIK3R1 mutation status confers resistance to
HER2-targeted therapies still awaits testing in HER2 positive breast
cancer patients. Our case validated PIK3R1EY451delinsDas a potential mechanism of resistance to HER2-targeted inhibition, and
suggested that PIK3R1 alterations may also be clinically useful to
stratify the treatment option for HER2-targeted therapies or in
combination with everolimus treatment.
Abbreviations
ctDNA: circulating tumor DNA
AF: allele frequency.
AC: doxorubicin/cyclophosphamide
TH: paclitaxel/trastuzumab
DT: radiotherapy
G+X+H: gemcitabine/xeloda/trastuzumab
L+Cap: Lapatinib/capecitabine
WBRT: whole brain radiation therapy
NVB: navelbine
EVE: everolimus
CBP:
Carboplatin
FUSCC: Fudan University Shanghai Cancer Center
PI3K: phosphatidylinositol-3-kinase