Abstract PS09-07: SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs)

Abstract Background: SPAG5 is a novel oncogene that is amplified in 40% of HER2+BC. Herein, we evaluated the prognostic and predictive significance of SPAG5 in HER2+ BC Methods: This retrospective cohort study included 2454 patients with HER2+BC derived from 6 cohorts in adjuvant (Adj) and neoadjuvant (NACT) settings. Adj cohorts: The association between SPAG5 and survivals were evaluated in 1354 HER2+ BC who received Adj therapy: 1) HER2+ Adj transcript cohort (n=448): 31% (137/448) did not receive Anthracycline (AC), Taxane (TX), Trastuzumab (TZ) or Pertuzuman (PZ) whereas 20% (89/448) had received AC alone and 35% (155/448) received TZ + AC +/- TX (Median follow- up (MFU): 60 months (m). 2) HER2+ Adj Molecular Taxonomy of BC International Consortium cohort (n=240): patients with ER- and lymph node (LN) + received Adj chemotherapy but none received TZ (MFU: 109 m). 3) HER2+ Adj Historical cohort (n=206): no TZ, AC or TX was received (MFU: 143 m). 4) HER2+/ER- cohort (n=101): AC alone was received; MFU: 62 m. 5) HER+ Adj TZ cohort (n=359): patients received TZ +TX+/-AC (MFU: 90 m). Neo-Adjuvant cohort: the associations of SPAG5 protein expression with pathological complete response (pCR) was evaluated in 1100 BCs (MFUT: 67 m) including 200 local cases participated in ROSCO trial. In this cohort; 73% (803/1100) received AC+TX. AC alone was given to 187/1100 (17%) whereas 88/1100 (8%) received TX alone. Of HER2+ BC, 14% (54/399) received AC +/- TX and 63% received TZ + TX +/-AC and 23% (92/399) received TZ + PZ + TX +/- AC. Sections were IHC profiled for HER2, ER, PR, Ki67 and SPAG5 and stained for Fluorescent in situ hybridisation (FISH) using a novel triple colour probe (HER2/SPAG5/Ch17). ASCO guidelines recommendations were followed. Results: In univariate survival analysis, High SPAG5 (+) transcript was associated with shorter 5- year distant metastases free survival (5-y DRFS); p< 0.0001, compared to SPAG5 low (-) in HER2+ patients who did not receive TZ or AC whereas in those who received AC alone, SPAG5+ was associated with lower risk of 5-y DRFS than SPAG5- (p < 0.001). Multivariable Cox regression analysis showed that SPAG5+ transcript ; as well as LN status, was independently associated with poor prognosis (HR (95% CI): 4.9 (2.0-12.0), p< 0.001). The interaction term between SPAG5 and AC was significantly associated with lower risk of DR. Multivariable Cox regression analysis for 10-year relapse free survival (10y-RFS) in HER2+ patients who did not receive AC or TZ confirmed that SPAG5+ protein expression ; as well as LN status and tumour size, were independently associated with poor prognosis (HR (95% CI): 2.1 (1.3, 3.5), p=0.002). SPAG5+ predicted response for NACT +/- HER2 targeting agents. For instance; None of HER2 IHC 2+ with SPAG5- expression/(0/191) either with HER2 FISH- (0/121) or HER2 FISH+ (0/70) achieved pCR whereas 51% (48/95) of those of HER2 IHC 2+/SPAG5+ achieved pCR (p < 0.0001). Similarly patients with HER2+ IHC 3+/SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [73% (107/146) vs., 10% (14/135); respectively]; p< 0.0001. Noteworthy, after receiving TZ+ PZ +Texans +/- AC, patients with SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [85% (50/59) vs., 0% (0/51); respectively, p< 0.001]. Similarly in HER2 + BC patients who received TZ + TX +/- AC, SPAG5+ expression was associated with higher pCR [67% (67/101)] compared to those with SPAG5- [10% (11/107)]; p< 0.001. In HER2+ who received AC alone, SPAG5+ cases achieved higher pCR compared to those with SPAG5- [56% (20/36) vs., 6% (3/47); p< 0.001; respectively]. Multivariable logistic regression analysis showed that SPAG5+ expression as well as ER, HER2 IHC, grade, clinical TNM and HER2 targeting agents were independent predictors for pCR (OR (95% CI: 13.74 (5.76-32.79; p< 0.001). Conclusions SPAG5 is an independent poor prognostic factor in HER2+ BC and could help in distinguishing those who would and would not benefit from NACT and HER2 targeting agents. Citation Format: TAREK ABDEL-Fatah, Graham Ball, Daniel Yeo, Graham Hickman, Arlene Chan, Ian Ellis, Stephen Chan. SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-07.