PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications

Background: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role. Methods: RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (n = 140) included in a prospective study (NCT01322893). Gene expression analyses were performed using the Breast Cancer 360 (BC360) assay from Nano-String. The subtype shifts were evaluated using McNemar and symmetry tests, and clinical outcomes were evaluated with log-rank tests and Cox regression. Results: The PAM50 subtype changed in 25/59 of paired samples between PTs and LNMs (Psymmetry = 0.002), in 31/61 between PTs and DMs (Psymmetry < 0.001), and in 16/38 between LNMs and DMs (Psymmetry = 0.004). Shifts toward subtypes with worse outcomes were the most common. Patients with shifts from the luminal PT to non-luminal DM subtypes had worse progression-free survival compared to patients with a stable subtype (hazard ratio (HR): 2.3; 95% confidence interval (CI): 1.14–4.68, p = 0.02). Conclusion: Strong evidence of PAM50 subtype shifts toward unfavorable subtypes were seen between PTs and metastatic samples. For patients with a shift in subtype from luminal PT to non-luminal DM, a worse prognosis was noted.

PAM50 HER2-enriched subtype as an independent prognostic factor in early-stage HER2+ breast cancer following adjuvant chemotherapy plus trastuzumab in the ShortHER trial.

544 Background: We investigated the prognostic role of the PAM50 HER2-enriched (HER2-E) subtype in HER2+ early breast cancer enrolled in the randomized Phase III ShortHER trial. Methods: The ShortHER study randomized 1254 HER2+ early breast cancer patients to receive 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy. Gene expression measured using nCounter platform was available for 438 surgical samples. Intrinsic subtyping was determined using the research-based PAM50 predictor. Metastasis-free survival (MFS) was calculated from randomization to distant disease recurrence or death (median follow up 72 months). Uni- and multi-variable analysis were performed using Cox models. Results: PAM50 subtype distribution was: HER2-E 53% (N = 233), Luminal A 20% (N = 87), Luminal B 10% (N = 43), Normal-like 11% (N = 48) and Basal-like 6% (N = 27). HER2-E subtype was associated with hormone receptor-negative status (p < 0.001) and TILs ≥20% (p < 0.001), but not with stage and age ( < or ≥60 yrs). HER2-E subtype was associated with worse MFS vs other PAM50 subtypes overall (HR 2.78, p = 0.001), in the short (HR 2.24, p = 0.046), and in the long arm (HR 4.04, p = 0.011). Multivariable Cox model confirmed the independent prognostic value of HER2-E subtype (Table). HER2-E subtype added significant prognostic value on top of clinicopathological variables (Likelihood ratio test p < 0.001). Conclusions: HER2-E intrinsic subtype is an independent prognostic factor for HER2+ early breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Integration of PAM50 subtype in prognostic algorithms can help refine risk stratification. These findings warrant independent validation. Clinical trial information: NCT00629278. [Table: see text]