Makoto Urano1, Hideaki Hirai2, Yuichiro Tada3, Daisuke Kawakita4, Tomotaka Shimura2, Kiyoaki Tsukahara5, Satoshi Kano6, Hiroyuki Ozawa7, Kenji Okami8, Yuichiro Sato9, Chihiro Fushimi3, Akira Shimizu5, Soichiro Takase5, Takuro Okada3, Hiroki Sato5, Yorihisa Imanishi7, Kuninori Otsuka7, Yoshihiro Watanabe7, Akihiro Sakai8, Koji Ebisumoto8, Takafumi Togashi9, Yushi Ueki9, Hisayuki Ota9, Yukiko Sato10, Natsuki Saigusa2, Masato Nakaguro11, Toyoyuki Hanazawa12, Toshitaka Nagao2. 1. Department of Diagnostic Pathology, School of Medicine, Fujita Health University, Toyoake, Japan. 2. Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan. 3. Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan. 4. Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan. 5. Department of Otolaryngology, Tokyo Medical University School of Medicine, Tokyo, Japan. 6. Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 7. Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan. 8. Department of Otolaryngology-Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan. 9. Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan. 10. Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. 11. Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan. 12. Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Abstract
AIMS: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). CONCLUSIONS: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.
AIMS: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). CONCLUSIONS: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.
Authors: Masato Nakaguro; Yuichiro Tada; William C Faquin; Peter M Sadow; Lori J Wirth; Toshitaka Nagao Journal: Cancer Cytopathol Date: 2020-05-18 Impact factor: 5.284