Background:

Previously we found that SPAG5 gene was amplified/gained in 20-35% of HER2+BC. Herein, we investigated the prognostic and predictive significance of SPAG5 (mRNA, protein) expression in 1726 HER+BC patients with median follow-up >5 years.

Methods:

Analysis of SPAG5 mRNA (cDNA array expression) and protein (immunohistochemistry) and their association with distant relapse risk (DRR) were determined in 446 and 642 cases of HER+2 early stage BC in which 36% and 40% of them had received adjuvant Herceptin (H) + Anthracycline based (AC) + Taxane (T); respectively. In 33% and 31% of SPAG5 mRNA cohort and 21% and 38% of SPAG5 protein cohort had received adjuvant (Adj) AC+T or chemotherapy (CT) naïve; respectively. The association between SPAG5 expression (mRNA, protein) and both pCR and DRR after receiving neoadjuvant chemotherapy (Neo-Adj-CT) were evaluated in 476 and 162 patients with HER2+ locally advanced BC; respectively. Neo-Adj AC+T+HER2 targeting (Herceptin, Herceptin+ Lapatinib or Lapatinib) and AC+/-T has been prescribed to 51% and 49% of mRNA cohort whereas the 45% and 55% of the protein expression cohort has received Neo-Adj AC+T+H and AC+/-T; respectively.

Findings:

In patients with SPAG5 mRNA overexpression (+;> median), those who had received AC+/-T Neo-Adj-CT alone achieved similar pCR to those who had received AC+T+HER2 targeting Neo-Adj (38% vs., 37%; OR (95% CI): 1.0 (0.6–1.6), p=0.923) in either ER- (46% vs., 52%; OR (95% CI): 1.3 (0.5–3.0), p=0.58) or ER+ subgroups (25% vs., 26%; OR (95% CI): 1.1 (0.4–3.4), p=0.88). Whereas in patients with low SPAG5 mRNA (-), those who had received AC+T+HER2 targeting Neo-Adj had achieved 2.5 fold increased in pCR compared to those who received AC+/-T alone (47% vs., 26%; OR (95% CI): 2.5 (1.4–4.4), p=0.001) in either ER- (60% vs., 31%; OR (95% CI): 3.4 (1.7–6.7), p<0.001) or ER+ subgroups (42% vs., 16%; OR (95% CI): 4.0 (1.2–12.9), p=0.018). Similarly in patients with SPAG5- protein expression; receiving AC+T+HER2 targeting Neo-Adj was associated with higher pCR compared to AC+/-T (21% vs., 4%; OR (95% CI): 6.6 (1.4–32.6), p=0.01). Whereas receiving AC+/-T was associated with similar pCR to AC+T+HER2 targeting Neo-Adj in patients with SPAG5+ protein (49% vs., 53%; OR (95% CI): 1.2 (0.5–3.2), p=0.702). Receiving AC+T+HER2 targeting Neo-Adj was associated with lower DRR compared to AC+/-T [HR (95% CI): 0.82 (0.08-0.97); p=0.045] in patients with SPAG5- protein expression but not in those with SPAG5+ protein [HR (95% CI): 1.08 (0.34-3.36); p=0.901]. Similarly, receiving Adj Herceptin+AC+T was associated with lower DRR compared to AC+/-T alone in those with SPAG5- (mRNA, protein) expression [HR (95% CI): 0.48 (0.25-0.93); p=0.029 and 0.82 (0.08-0.97); p=0.045; respectively] but not in those with high SPAG5+ (mRNA, protein) [HR (95% CI): 1.04 (0.48-2.26); p=0.924 and 1.00 (0.82-1.22); p=1.00; respectively.

Conclusion: SPAG5 expression could help in selecting patients who would benefit from both HER2-targeting agents and or AC-CT. Therefore patients with SPAG5- expression could avoid unnecessary AC-CT whereas those with SPAG5+ could receive a shorter Herceptin course.

Citation Format: Abdel-Fatah TM, Ball GR, Ellis IO, Chan A, Chan SY. Sperm associated antigen 5 (SPAG5) predicts pathological complete response (pCR) and distant relapse risk to HER2 targeting agents and anthracycline based chemotherapy in HER2 positive (HER2+) breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-08.