In this study, we retrospectively analyzed treatment duration and clinical response to HER2-directed treatment based on PIK3CA mutations in patients with HER2+ breast cancer. Patients with pathogenic PIK3CA mutations had lower pCR rates after neoadjuvant therapy and significantly shorter PFS with anti-HER2 monoclonal antibody therapy or ADC than those with wild-type PIK3CA in a palliative setting. The PFS with lapatinib was similar in both the groups. In addition, clinically targeted sequencing revealed that TP53 was the most frequently co-occurring mutation in HER2+/PIK3CAm breast cancer tissues. Patients whose tumor tissues had a higher number of pathological SNVs tended to show shorter PFS with palliative anti-HER2 mAb treatment.
Anti-HER2 mAbs, including trastuzumab and pertuzumab, have several antitumor effects, including inhibition of signal transduction through HER, induction of antibody-dependent cellular cytotoxicity in tumor cells with HER2 amplification [16], and inhibition of HER2 extracellular domain cleavage [17]. Most importantly, downregulation of intracellular signaling through the PI3K/AKT/mTOR pathway [18] is the main cellular event after the binding of trastuzumab to domain IV or pertuzumab to domain II of HER2. However, constitutive activation of the PI3K/AKT/mTOR pathway is known to drive resistance to HER2-directed therapy, and pathologic mutations in PIK3CA are found in approximately 23–30% of HER2+ breast-cancer patients [19].
The significance of PIK3CAm in primary tumors of early stage breast cancer has been addressed in several prospective clinical trials. In a pooled analysis of 967 patients who were undergoing chemotherapy and received neoadjuvant treatment with either trastuzumab, or lapatinib, or both [13], the pCR rate was significantly lower in the PIK3CAm group than in the wild-type group (16.2% vs. 29.6%; P < 0.001). In the NeoALTTO trial, which compared the efficacy of dual therapy with trastuzumab and lapatinib to lapatinib alone, patients with PIK3CAm had poorer outcomes in all treatment groups (pCR rate, 28.6% vs. 53.1%, p = 0.012) [20]. Similar results were reported in the TBCRC006 trial, which evaluated neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy, and the pCR rate was significantly lower in patients with PIK3CA mutations or low PTEN levels (4% vs. 39%, p=0.006) [21]. In the era of dual blockade using trastuzumab and pertuzumab, a retrospective analysis from the NeoSphere study showed an inferior pCR rate in patients with HER2+/PIK3CAm tumors [22]. Our data from Korean patients support these previous findings, suggesting that patients with PIK3CAm have significant unmet needs despite receiving dual HER2-directed neoadjuvant treatment as the standard of care.
In a retrospective analysis of adjuvant trastuzumab treatment in combination with chemotherapy, the presence of PIK3CAm did not change the prognosis of the patients who participated in the ShortHER or FinHER trials [23, 24], with a 5-year DFS rate of 90.6% for PIK3CAm and 86.2% for PIK3CAw, p = 0.417 [23]. However, a previous study reported that patients who retained the initial PIK3CAm after neoadjuvant therapy had worse DFS after surgical resection, implying a possible role of PI3KCAm in predicting worse clinical outcomes in early breast cancer [25].
Substantial efforts have been made to identify biomarkers for resistance to anti-HER2 treatment in metastatic HER2+ breast cancer. In preclinical studies, breast cancer cell lines with BRAF, KRAS, and PIK3CA mutations were less sensitive to trastuzumab than the wild-type [26], and drug susceptibility also differed depending on the mutation site in PIK3CA [27]. Genome-wide loss-of-function genetic screens have also identified that reduced ARID1A expression confers resistance to HER2-targeted therapy [19]. Nevertheless, treatment for patients with HER2+ breast cancer is still a “one-size-fits-all” approach based on positive results from key trials. In a retrospective analysis of the CLEOPATRA study, PIK3CA mutation status had the greatest prognostic impact on PFS in palliative first-line therapy (docetaxel, trastuzumab, and pertuzumab) [28]. Biomarker analysis from clinical trials assessing T-DM1 and lapatinib in the later lines of treatment had similar consequences [29, 30].
Our study has several limitations, including its retrospective nature. First, the use of HER2 antibodies was switched from single to dual initial trastuzumab therapy combined with pertuzumab in both the early and metastatic settings. Thus, the number of patients in each treatment group was divided according to the genotype, resulting in a small sample size. Second, due to the retrospective nature of our study, we could not control for other potential prognostic factors, such as the levels of HER2 protein, HER2 and HER3 mRNA, soluble HER2, or the PIK3CA genotype. In addition, access to tissue biopsies is limited in some patients with metastatic cancers. Considering that 8–10% of patients are known to acquire PIK3CA mutations in a metastatic setting [31], our data should be interpreted with caution.
In our study, patients with PIK3CA mutations showed weakened responses to single or dual HER2 antibodies combined with taxane and subsequent T-DM1. Different genomic landscapes were identified according to the PIK3CA status. Thus, there is a significant unmet need for these patients, which may be addressed by targeting the aberrantly activated PI3K/AKT/mTOR pathway. Given the promise of the FDA-approved α-specific PI3K inhibitor alpelisib for the treatment of HR+/HER2- advanced stage cancers, studies examining the clinical utility of targeting PIK3CA as well as HER2 are warranted.