In Reply

Short abstract

This letter to the editor responds to remarks on the authors' recently published article on the role of HER2 as a negative prognostic factor in completely resected biliary tract cancer.

We thank Rizzo and colleagues for their interest in our work [1, 2]. As they properly underline, biliary tract cancer (BTC) represents a rare and heterogenic entity as regards both anatomical and molecular features, and this certainly represents a limitation in many clinical and translational studies that have been conducted so far. Even though we agree with them about this issue and the lack of standardized criteria for human epidermal growth receptor 2 (HER2) assessment in BTC, we decided not to exclude any type of BTC (because of the rarity of the disease) and to use gastric cancer criteria (to account for potential heterogeneity in HER2 expression) to comprehensively explore the role of HER2.

As reported in Table 1, we found no difference in baseline characteristics according to HER2 status by chi‐square test. We decided to compare the two groups of patients using absolute values and not percentages as reported by Rizzo at al. because percentages in small groups can be misleading.

Although in our experience the prognostic role of Eastern Cooperative Oncology Group (ECOG) performance status (PS) was confirmed in multivariate analysis for overall survival (OS), that was not formally proved for HER2 positivity (p = .073). On the contrary, unlike that of ECOG PS, the impact of HER2 status in the disease‐free survival was maintained in multivariate analysis, suggesting a likely independent poor prognostic role in terms of recurrence. Moreover, the impact on OS of different postprogression treatments in the two groups should be recognized and cannot be completely ruled out in our retrospective study.

The role of adjuvant treatment in resected BTC is still controversial [3]. Only in the last years, data from the phase III BILCAP trial have shown a potential benefit from postoperative treatment with capecitabine [4]. In our cohort, the role of adjuvant treatment appears not significant in univariate analysis for both disease‐free survival and OS, but the small number of treated patients does not allow us to draw a definitive conclusion about its efficacy. We agree with the authors that the adjuvant treatment with gemcitabine does not have a high level of evidence, but it is still considered in guidelines [3] and was accepted as an adjuvant treatment when our study was conducted [5].

Moreover, the proportion of patients receiving adjuvant gemcitabine was not significantly different in HER2‐negative and HER2‐positive patients (41/47 vs. 3/3, Fisher's exact test p = 1.000), and based on the trial by Ebata and colleagues [6], we would rule out a detrimental role of this regimen in resected BTC.

To conclude, the main messages of our work are represented by the confirmation of HER2 as a potential therapeutic target in an important percentage of BTC cases and by the suggestion of a poor prognostic relevance of HER2 status in resected BTC. Furthermore, HER2 status can be easily assessed in routine practice with conventional laboratory methods such as immunohistochemistry and fluorescence in situ hybridization by using already available scoring criteria. In our opinion, these considerations support further exploration of the role of HER2 (and potentially anti‐HER2 agents) in BTC.

Disclosures

The authors indicated no financial relationships.