Short abstract
This letter to the editor responds to comments by Hori et al. on the recently published study on intrahepatic cholangiocarcinoma and HER2 positivity rate.
We thank the authors for their comments on the subgroup of patients with intrahepatic cholangiocarcinoma (iHCC) described in our recently published paper. Through their Letter to the Editor [1], Hori et al. underlined that our HER2 positivity rate for iHCC is higher than described in most literature series and pointed out the surgical and staging peculiarities of this tumor location, which should have led us to analyze it separately from other sites.
Despite the known prognostic and molecular differences of biliary tract cancers (BTCs) according to primary site (mainly iHCC vs. extrahepatic cholangiocarcinomas [eHCCs]/gallbladder), we decided to comprehensively describe all our cases, since no differences in terms of therapeutic and surveillance strategies are at present supported by international guidelines [2, 3], except for ampullary cancers. Moreover, to our knowledge, no validated molecular prognostic determinants have been so far clearly identified to predict recurrence after resection, irrespective of anatomical site.
Firstly, with regard to HER2 overexpression proportion, we acknowledge that the percentage we found in patients with iHCC (as high as 11%) is greater than those reported by most meta‐analyses [4, 5, 6], indicating frequencies lower than 5%. Moreover, previous data showed primary site location as significantly related to different HER2 overexpression rates (higher in eHCC vs. iHCC) [5, 6], whereas we did not find such a correlation. In contrast, two remarkable series comprising 454 [7] and 194 [8] patients with BTCs did not present any formal statistical comparison for HER2 expression according to primary site. These observations support the hypothesis that the limited numbers of each primary tumor site in our sample could have affected HER2 site distribution, so it probably did in the 51‐patient series to which Hori et al. referred, where HER2 positivity rate among patients with iHCC was found to be 0%.
Another putative factor accounting for different HER2 overexpression according to primary site may be the heterogeneity of its expression, as explored by Hiraoka et al. [7]. All primary BTC sites showed a >75% heterogeneity, defined as the presence of ≥5% of cancer cells with a HER2 status different from those of other cancer cells in the same case: as clearly recognized in gastric cancer [9], this field warrants further exploration in future works.
Considering the poor prognosis of BTCs and the lack of druggable targets, we believe that our data support HER2 overexpression as a potential target in iHCC: although rare, this alteration may have a clinical impact on prognosis and deserves further evaluation as a predictive biomarker in iHCC, as for the recently identified IDH1 and FGFR alterations. Indeed, previous and ongoing phase II trials on anti‐HER2 agents in BTCs comprised all primary tumor sites [10].
To sum up, in our paper, the prognostic effect of HER2 overexpression/amplification was not investigated within different primary tumor locations since no difference in the rate of this condition was found with respect to the anatomical site of the malignancy (p = .901). However, we agree that exploring the specificity of HER2 as a prognostic factor for iHCC, eHCC and gallbladder carcinomas is of great interest: wider case series are warranted in which small numbers would not limit survival analyses' subgroup results.
Secondly, with regard to the iHCC surgical approach, we agree that lymphadenectomy in this BTC subtype is sometimes omitted because of the sole hepatic involvement; however, in our retrospective series, nodal status was known for the majority of patients (79%) and confirmed its independent strong prognostic role at Cox's multivariate analysis for disease‐free survival (DFS) and overall survival. Since HER2 retained its significant role at multivariate analysis for DFS, our results suggest that its value could be independent from other factors (such as intrahepatic location). Moreover, we did not test the prognostic effect of HER2 overexpression within each BTC subgroup because of their scarce numbers, which would have led to underpowered comparisons.
In conclusion, we think that the above‐discussed limitations of our work should not prevent further prospective investigations on the role of HER2 overexpression in BTCs, including iHCC, with particular reference to the different primary locations.
Disclosures
Lorenzo Fornaro: Eli Lilly & Co., Merck Sharp & Dohme (H). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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