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