Cancer Res Treat.  2025 Jan;57(1):126-139. 10.4143/crt.2023.1251.

A Single-Arm Phase II Clinical Trial of Fulvestrant Combined with Neoadjuvant Chemotherapy of ER+/HER2– Locally Advanced Breast Cancer: Integrated Analysis of ¹⁸F-FES PET-CT and Metabolites with Treatment Response

• Shao Q
• Zhang N
• Pan X
• Zhou W
• Wang Y
• Chen X
• Wu J
• Zeng X

• KMID: 2564587
• DOI: http://doi.org/10.4143/crt.2023.1251

Abstract

Purpose
This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to neoadjuvant chemotherapy in patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 16α-18F-fluoro-17β-fluoroestradiol (¹⁸F-FES) positron emission tomography (PET)–computed tomography (CT) and metabolites with efficacy.
Materials and Methods
Fulvestrant and EC-T regimen were given to ER+/HER2– LABC patients before surgery. At baseline, patients received ¹⁸F-FES PET-CT scan, and plasma samples were taken for liquid chromatography–mass spectrometry analysis. The primary endpoint was objective response rate (ORR). Secondary endpoints included total pathologic complete response (tpCR) and safety.
Results
Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥ 3 treatment-emergent adverse events was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p < 0.05). The maximum standardized uptake value, mean standardized uptake values, total lesion ER expression of ¹⁸F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p < 0.05). Moreover, these parameters were significantly correlated with Miller and Payne grade and the change in ER expression before and after treatment (p < 0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways.
Conclusion
This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. ¹⁸F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.

Keyword

Breast neoplasms; ER+/HER2?; Fulvestrant; Neoadjuvant therapy; F-FES PET-CT; Metabolites

Figure

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  Fig. 1. Correlation analysis of estrogen receptor (ER), partial response (PR), Ki-67, and therapeutic efficacy. (A-C) ER, PR, and Ki-67 expression at baseline and postoperative (n=36). (D) The change in ER expression between sensitive and non-sensitive group. (E) The correlation between the change in ER expression and Miller and Payne (MP) grading. (F) Receiver operating characteristic (ROC) curves of the change in ER expression distinguishing the sensitive and non-sensitive breast cancer patients. (G) The change in Ki-67 expression between sensitive and non-sensitive group. (H) The correlation between the change in Ki-67 expression and MP grading. (I) ROC curves of the change in Ki-67 expression distinguishing the sensitive and non-sensitive breast cancer patients.

• 

  Fig. 2. Correlation analysis of 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) positron emission tomography (PET)–computed tomography (CT) and therapeutic efficacy. (A-C) The maximum standardized uptake value (SUVmax), mean standardized uptake values (SUVmean), total lesion estrogen receptor (TL-ER) expression of 18F-FES PET-CT in breast lesions between sensitive and non-sensitive group. (D-F) The correlation between the SUVmax, SUVmean, TL-ER of 18F-FES PET-CT in breast lesions and Miller and Payne (MP) grading. (G-I) The correlation between the SUVmax, SUVmean, TL-ER of 18F-FES PET-CT in breast lesions and the change in ER expression. (J-L) Receiver operating characteristic curves of the SUVmax, SUVmean, TL-ER of 18F-FES PET-CT in breast lesions distinguishing the sensitive and non-sensitive breast cancer patients. AUC, area under curve; CI, confidence interval.

• 

  Fig. 3. Analysis of serum metabolomics of patients with ER+/HER2– breast cancer patients from liquid chromatography–mass spectrometry data. (A) Partial least squares discriminant analysis (PLS-DA) score plot for discriminating non-sensitive and sensitive to neoadjuvant therapy (NAT) in the electrospray ionization negative (ESI–) mode. (B) PLS-DA score plot for discriminating non-sensitive and sensitive to NAT in the ESI+ mode. (C) The volcano diagram depicting the differentially expressed metabolites in the non-sensitive and sensitive groups. ER, estro gen receptor; FC, fold change; HER2, human epidermal growth factor receptor 2; ns, not significant; VIP, variable importance in the projection. (D) Heatmap depicting the differences in metabolites between non-sensitive and sensitive patients depending on metabolite class. Each column represents a subject and each row represents a metabolite. (E) The scatter plot of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched for differential expression metabolites. (F) The network of metabolites and their enriched pathways.

Reference

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