HCC is a cancer with aggressive clinical course and high morbidity. Prognostic markers are widely used in clinical practice and have high clinical value as efficient treatment determinants . HSP90α has been previously reported to have high diagnostic value in patients with HCC [18, 19]. Our novel large-scale, multicenter study provided robust data on the suitability of HSP90α plasma usage as a prognostic biomarker for HCC. Our results suggested that patients with HSP90α < 143.5 ng/ml had longer mOS compared to patients with HSP90α ≥ 143.5 ng/ml (P < 0.001), implicating HSP90α ≥ 143.5 ng/ml as an independent poor prognostic factor for OS.
AFP is the most widely used biomarker in HCC to-date. Nevertheless, AFP-negative tumors account for about 30% cases of HCC, with several studies revealing AFP inability to evaluate this subset of HCC tumors [10, 11, 21]. Therefore, to eradicate this clinical decision gap, new prognostic markers are urgently needed. HSP90α is a master regulator and molecular chaperone regulating key cell signaling networks . The secretion of HSP90α in normal cells promotes tissue repair under stress, while the secretion in tumor cells can promote cancer cell proliferation and metastatic potential . Previous studies have confirmed increased expression HSP90α levels in several tumor types, including HCC [23, 24]. Furthermore, clinically, HSP90α can be used as a diagnostic biomarker for HCC, lung cancer, breast cancer, and gastric cancer [19, 24–26]. Despite its strong diagnostic value, few studies have elucidated the prognostic value of HSP90α in human cancer. Li et al. reported that lung cancer patients with high HSP90α level had poorer OS and PFS compared to low HSP90α patients . In addition, a study by Fu et al. found that HSP90α positively correlated with tumor volume after surgery or interventional therapy (P < 0.05) . However, the author did not explore the relationship between HSP90α levels with baseline characteristics and patient outcomes. Our study demonstrated that patients with high HSP90α level had shorter OS and HSP90α was an independent factor for OS in HCC.
Although the protein kinase inhibitor, sorafenib had been used in HCC for many years, its efficacy as a monotherapy is still poor, with a mOS of only 6.5 months . In recent years, the plethora of studies and drug development advancements of ICIs have expanded our therapeutic arsenal towards cancer. The combination of ICIs and targeted drugs has significantly improved the clinical outcomes of HCC patients [29–31]. To the same direction, the combination of TACE plus camrelizumab increased PFS of advanced HCC patients to 9 months . Nevertheless, predicting the efficacy of HCC patients receiving ICIs remains a clinical challenge with definite positive outcome in the quality of patient’s care. In our subgroup analysis (supportive care group, surgery group, TACE group, adjuvant TACE group, ICI plus targeted therapy group, and TACE plus ICI group), all the low HSP90α expressing patient groups demonstrated better OS than the high HSP90α ones. In the multivariate Cox analysis of the supportive care group, TACE group, TACE plus ICI group, and ICI plus targeted therapy group, the HSP90α ≥ 143.5 ng/ml cut-off was also an independent poor prognostic factor for OS. More importantly, in contrast to other more invasive diagnostic techniques, the liquid biopsy technique for determination of plasma HSP90α levels is characterized by low invasiveness and high convenience. Therefore, assessing HSP90α plasma levels is a robust approach to evaluate treatment efficacy and response of HCC patients.
In our current study, we further explored the relationship between plasma HSP90α level and baseline clinical characteristics. Strikingly, high HSP90α plasma levels were associated with multiple tumors co-occurrence, worse child grade and ALBI score, larger tumor diameter, and more aggressive BCLC staging. These results further implicate HSP90α as a prognostic factor in HCC. In accordance with our results, recent studies have also demonstrated that high HSP90α levels correlate with more aggressive clinical stage [18, 19, 24]. Furthermore, our data showed that patients with AFP ≥ 400 ng/ml had higher HSP90α level compared to patients with AFP < 400 ng/ml. Notably, a study by Xu et al. showed that HSP90α level detected by immunohistochemistry in HCC tissues did not associate with serum AFP levels . Nevertheless, we interpret these differences based on the fact that HSP90α plasma level determination is more sensitive method compared to tissue expression via immunohistochemistry.
To our knowledge, this is the first comprehensive study with a large sample size to elucidate the association between plasma HSP90α levels and prognosis in HCC patients. As far as the cut-off value is concerned, the value of 143.5 ng/mL was determined as the optimal value by the X-tile software. Subsequently, in our subgroup analysis, we also confirmed that this cut-off value can also be applied as a prognostic and predictive value in different treatment groups. These data have robust clinical significance implicating HSP90α as an important factor to evaluate the therapeutic response of HCC patients in various therapeutic interventions. Despite the advantages of our study, there are still some limitations. First, selection bias cannot be eliminated due to the nature of retrospective studies. Nevertheless, the large sample of our cohort significantly increased the power and robustness of our study. Second, although our study confirmed that HSP90α can predict the response of HCC patients to immunotherapy, our results may be affected by the underlying heterogeneity of different ICIs. Future studies with larger cohort samples and classes of ICI should be designed to safely assess these interesting preliminary findings.