Introduction: Previous studies have shown that HER2+ breast cancer is biologically heterogenous and intrinsic subtypes can be identified (luminal A, luminal B, HER2-enriched [HER2-E] and basal-like). HER2-E predominates and is associated with higher response rates following anti-HER2-based chemotherapy or dual HER2 blockade (only with lapatinib and trastuzumab). We explored the ability of intrinsic subtypes to predict pCR in pts treated with anti-HER2 neoadjuvant therapy.

Methods: KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC. Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 and hormone receptor (HR) status were centrally assessed. Gene expression (RNA) was assessed by a custom 800-gene codeset on the nCounter platform. Intrinsic subtypes were assessed with the research-based PAM50 classifier.

Results: KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P, n=221; T-DM1+P, n=223). PAM50 results were available for 354 pts (79.7% of the intent-to-treat [ITT] population). Baseline characteristics and efficacy in the PAM50 population were similar to that of the ITT population. The HER2-E subtype represented 54.8% of the samples (Table 1). Differences were observed by HR status. Almost all luminal tumors (131/132) were identified within HR+ disease. Of HR+ tumors, 32% were identified as HER2-E. In the TCH+P arm, the pCR rate was 72.1% for HER2-E vs 32.8% in the other subtypes combined (Table 2.) In the T-DM1+P arm, the pCR rate was 62.2% for HER2-E vs 26.9% in the other subtypes combined. No major differences were observed in pCR rates within the HER2-E subtype according to HR status. Further multivariable analyses assessing differences between treatment arms and treatment benefit across subtypes is ongoing.

Table 1. Intrinsic subtypes

n (%) ITT (n=354) HR- (n=143)* HR+ (%) (n=200)* 
HER2-E 194 (54.8) 123 (86.0) 64 (32.0) 
Luminal A 60 (16.9) 1 (0.7) 57 (28.5) 
Luminal B 74 (20.9) 74 (37.0) 
Basal-like 26 (7.3) 19 (13.3) 5 (2.5) 
n (%) ITT (n=354) HR- (n=143)* HR+ (%) (n=200)* 
HER2-E 194 (54.8) 123 (86.0) 64 (32.0) 
Luminal A 60 (16.9) 1 (0.7) 57 (28.5) 
Luminal B 74 (20.9) 74 (37.0) 
Basal-like 26 (7.3) 19 (13.3) 5 (2.5) 

*Central HR status unknown for n=11

Table 2. pCR by intrinsic subtype

    TCH+P T-DM1+P 
  pCR, n (%) pCR, n (%) pCR difference (95% CI) 
HER2-E 104 75 (72.1) 90 56 (62.2) -9.89 (-23.11, 3.32) 
HER2-E and HR+ * 37 24 (64.9) 27 15 (55.6) -9.31 (-33.56, 14.94) 
HER2-E and HR- * 64 48 (75.0) 59 37(62.7) -12.29 (-28.56, 3.98) 
Other subtypes combined 67 22 (32.8) 93 25 (26.9) -5.9 (-20.36, 8.45) 
Luminal A 25 4 (16.0) 35 10 (28.6) 12.57 (-8.18, 33.32) 
Luminal B 32 11 (34.4) 42 12 (28.6) -5.80 (-27.19, 15.58) 
Basal-like 10 7 (70.0) 16 3 (18.8) -51.25 (-85.49, -17.01) 
    TCH+P T-DM1+P 
  pCR, n (%) pCR, n (%) pCR difference (95% CI) 
HER2-E 104 75 (72.1) 90 56 (62.2) -9.89 (-23.11, 3.32) 
HER2-E and HR+ * 37 24 (64.9) 27 15 (55.6) -9.31 (-33.56, 14.94) 
HER2-E and HR- * 64 48 (75.0) 59 37(62.7) -12.29 (-28.56, 3.98) 
Other subtypes combined 67 22 (32.8) 93 25 (26.9) -5.9 (-20.36, 8.45) 
Luminal A 25 4 (16.0) 35 10 (28.6) 12.57 (-8.18, 33.32) 
Luminal B 32 11 (34.4) 42 12 (28.6) -5.80 (-27.19, 15.58) 
Basal-like 10 7 (70.0) 16 3 (18.8) -51.25 (-85.49, -17.01) 

*Central HR status unknown for n=7

Conclusions: In this analysis from the KRISTINE study, HER2-E was the most common intrinsic subtype and was associated with the highest pCR rate with both regimens. Results are consistent with previous findings. The luminal A and B subtypes were well associated with HR+ status. A sizeable subgroup of the HER2-E subtype was HR+ (32%), and pCR rates within the HER2-E subtype seemed independent of HR status.

Citation Format: Prat A, Slamon D, Hurvitz SA, Press MF, Lewis Phillips G, Lopez Valverde V, Kiermaier A, Helms H-J, Martin M, de Haas SL. Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-06.