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. 2024 Apr;204(3):453-463.
doi: 10.1007/s10549-023-07209-2. Epub 2024 Jan 5.

Potential role of Fbxo22 in resistance to endocrine therapy in breast cancer with invasive lobular carcinoma

Saki Nakagawa  1   2 , Minoru Miyashita  3 , Ichiro Maeda  4   5   6 , Atsushi Goda  6 , Hiroshi Tada  1 , Masakazu Amari  7 , Yasuyuki Kojima  8 , Koichiro Tsugawa  8 , Yasuyo Ohi  9 , Yasuaki Sagara  10 , Miku Sato  1 , Akiko Ebata  1 , Narumi Harada-Shoji  1 , Takashi Suzuki  11 , Makoto Nakanishi  12 , Tomohiko Ohta  13 , Takanori Ishida  1
Affiliations

Potential role of Fbxo22 in resistance to endocrine therapy in breast cancer with invasive lobular carcinoma

Saki Nakagawa et al. Breast Cancer Res Treat. 2024 Apr.

Abstract

Background: Invasive lobular carcinoma (ILC) is distinct from invasive ductal carcinoma (IDC) in terms of their hormonal microenvironments that may require different therapeutic strategies. We previously reported that selective estrogen receptor modulator (SERM) function requires F-box protein 22 (Fbxo22). Here, we investigated the role of Fbxo22 as a potential biomarker contributing to the resistance to endocrine therapy in ILC.

Methods: A total of 302 breast cancer (BC) patients including 150 ILC were recruited in the study. Fbxo22 expression and clinical information were analyzed to elucidate whether Fbxo22 negativity could be a prognostic factor or there were any correlations among clinical variables and SERM efficacy.

Results: Fbxo22 negativity was significantly higher in ILC compared with IDC (58.0% vs. 27.0%, P < 0.001) and higher in postmenopausal patients than premenopausal patients (64.1% vs. 48.2%, P = 0.041). In the ILC cohort, Fbxo22-negative patients had poorer overall survival (OS) than Fbxo22-positive patients, with 10-year OS rates of 77.4% vs. 93.6% (P = 0.055). All patients treated with SERMs, Fbxo22 negativity resulted in a poorer outcome, with 10-year OS rates of 81.3% vs. 92.3% (P = 0.032). In multivariate analysis regarding recurrence-free survival (RFS) in ILC patients, Fbxo22 status was independently predictive of survival as well as lymph node metastasis.

Conclusion: Fbxo22 negativity significantly impacts on survival in BC patients with IDC and ILC, and the disadvantage was enhanced among ILC postmenopausal women or patients treated with SERMs. The findings suggest that different therapeutic strategies might be needed according to the different histopathological types when considering adjuvant endocrine therapy.

Keywords: Breast cancer (BC); Endocrine therapy; F-box protein 22 (Fbxo22); Invasive lobular carcinoma (ILC); Resistance; Tamoxifen.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Representative immunohistochemical images of Fbxo22. Tumor cells showing moderate to strong nuclear staining are determined positive for Fbxo22. In ILC, discohesive tumor cells arrange in single file linear cords and invade the stroma. (A) Fbxo22-positive cells in ILC, (B) Fbxo22-negative cells in ILC. In IDC, tumor cells arrange in clusters with tubular structures. (C) Fbxo22-positive cells in IDC, (D) Fbxo22-negative cells in IDC
Fig. 2
Fig. 2
The proportion of Fbxo22-positive tumor (IDC vs. ILC, or premenopausal vs. postmenopausal among ILC). Sixty-three (42.0%) patients were determined to be positive for Fbxo22 expression in the ILC cohort (N = 150), which is significantly lower than that of the IDC cohort (the positivity rate: 73.0%, 95/130). In the ILC cohort, Fbxo22 positivity was lower in postmenopausal ILC patients (35.9%, 33/92) than in premenopausal ILC patients (51.8%, 30/58)
Fig. 3
Fig. 3
Kaplan‒Meier curves stratified by Fbxo22 protein expression in ER-positive/HER2-negative cases. (A) OS and (B) RFS in the entire cohort, (C) OS and (D) RFS in the ILC cohort. P values were calculated using the log-rank test. P values of less than 0.05 were considered statistically significant
Fig. 4
Fig. 4
Kaplan‒Meier curves stratified by Fbxo22 protein expression in ER-positive/HER2-negative cases. (A) OS and (B) RFS in SERM-treated cases, (C) OS and (D) RFS in TAM-treated ILC cases. P values were calculated using the log-rank test. P values of less than 0.05 were considered statistically significant
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