TROP2 as Patient-Tailoring but Not Prognostic Biomarker for Breast Cancer

Abstract

Purpose Trophoblast cell surface antigen 2 (TROP2) has emerged as a promising target of antibody-drug conjugates (ADCs) for triple-negative breast cancer (TNBC), as well as other breast cancers (BCs). This study aims to investigate the biomarker value of TROP2 for patient-tailoring and prognostic for BC patients, including TNBC. Methods The levels of TROP2 expression in 404 Chinese BC tissues on tissue microarrays (TMAs) were quantified by immunohistochemistry and their correlations to the clinicopathological factors and the overall survival rate were analyzed. Also, BC cell lines and patient-derived organoids (PDOs) with different TROP2 expression levels were employed to investigate the correlation between TROP2 expression levels and the therapeutic responses to DS001, a TROP2-directed ADC molecule with stable linker and potent payload. Results TROP2 overexpression was identified in significantly more ( P = 0.046) tumor tissues (41.08%, 99/241) than normal adjacent tissues (31.29%, 51/163) from Chinese BC patients, and in significantly more ( P = 0.024) TNBC patients (59.38%, 19/32) than in other BC types (38.28%, 80/209). BC cell line with the lowest TROP2 expression level failed to respond to DS001 treatment. The levels of TROP2 expression were determined to be significantly correlated with the potencies of DS001 treatment, but not with the overall survival rates of the patients. Conclusion Our results demonstrated that TROP2 could serve as a patient-tailoring and predictive biomarker for ADC therapeutics but not as a general prognostic biomarker to predicate patient survival.

Emerging Intrinsic Therapeutic Targets for Metastatic Breast Cancer

“…A phase III study of SKB264 in metastatic TNBC was also initiated [102]. Of note, two TROP-2-directed ADCs, namely, PF-06664178 (RN927C) from Pfizer and BAT8003 from Bio-Thera failed to achieve a sufficient therapeutic window in phase I clinical trials [103].…”

Update Breast Cancer 2022 Part 4 – Advanced-Stage Breast Cancer

“…Trop-2 is an antigen which is overexpressed in some cancers such as breast cancer, some thyroid carcinomas, pancreatic carcinoma, colon carcinoma, urothelial carcinoma and other tumors 24 – 26 . Even if participations in signaling pathways are postulated, which play a role in the development of cancer or progression, it has not yet been possible to prove that Trop-2 is a prognosis marker for patients with breast cancer 27 . However, as already described above, the activity of the addressed signaling pathway does not necessarily appear to be of great importance for an efficacy of some ADCs, but rather the pure presence of the target molecule, in the case of Trop-2.…”

“…Trop-2 ist ein Antigen, das bei einigen Krebsarten wie dem Mammakarzinom, einigen Schilddrüsenkarzinomen, dem Pankreaskarzinom, dem Kolonkarzinom, dem Urothelkarzinom und anderen Tumoren überexprimiert ist 24 , 25 , 26 . Auch wenn Beteiligungen an Signalwegen postuliert werden, die bei der Krebsentstehung oder Progression eine Rolle spielen, konnte bislang nicht nachgewiesen werden, dass Trop-2 ein Prognosemarker für Patientinnen mit Mammakarzinom ist 27 . Wie oben bereits beschrieben, scheint für eine Wirksamkeit von einigen ADCs jedoch nicht unbedingt die Aktivität des adressierten Signalweges von großer Bedeutung zu sein, sondern eher das pure Vorhandensein des Zielmoleküls, in dem Fall Trop-2.…”