Abstract PD3-06: 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

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 subtypesn (%)ITT (n=354)HR- (n=143)*HR+ (%) (n=200)*HER2-E194 (54.8)123 (86.0)64 (32.0)Luminal A60 (16.9)1 (0.7)57 (28.5)Luminal B74 (20.9)074 (37.0)Basal-like26 (7.3)19 (13.3)5 (2.5)*Central HR status unknown for n=11 Table 2. pCR by intrinsic subtype TCH+PT-DM1+P npCR, n (%)npCR, n (%)pCR difference (95% CI)HER2-E10475 (72.1)9056 (62.2)-9.89 (-23.11, 3.32)HER2-E and HR+ *3724 (64.9)2715 (55.6)-9.31 (-33.56, 14.94)HER2-E and HR- *6448 (75.0)5937(62.7)-12.29 (-28.56, 3.98)Other subtypes combined6722 (32.8)9325 (26.9)-5.9 (-20.36, 8.45)Luminal A254 (16.0)3510 (28.6)12.57 (-8.18, 33.32)Luminal B3211 (34.4)4212 (28.6)-5.80 (-27.19, 15.58)Basal-like107 (70.0)163 (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.

Different Pathological Complete Response Rates According to PAM50 Subtype in HER2+ Breast Cancer Patients Treated With Neoadjuvant Pertuzumab/Trastuzumab vs. Trastuzumab Plus Standard Chemotherapy: An Analysis of Real-World Data

“…Our study provides valuable information from the real world about neoadjuvant anti-HER2 treatment in early breast cancer, showing that the rate of pCR obtained by double blockade with pertuzumab plus trastuzumab exceeds by 20% that obtained with trastuzumab alone. The pCR rate observed in our series with pertuzumab and trastuzumab treatment (60.6%) is in the range of responses observed in the published phase II-III trials (45.8–69.8%) (8, 13–15, 17, 22). Moreover, the pCR rate found in patients treated with trastuzumab alone (39.4%) is in agreement with previous data (31–46%) (7–12).…”

“…Neoadjuvant trastuzumab with or without lapatinib shows pCR rates of 50–70% in HER2-enriched tumors, 9–34% in luminal A, 17–36% in luminal B, and 25–38% in basal-like cases (12, 25, 27). Similarly, pCR rates by intrinsic subtype in patients treated with neoadjuvant pertuzumab plus trastuzumab were 70–83% in the HER2-enriched subtype, 16–45% in luminal A, 16–52% in luminal B, and 20–85% in basal-like tumors (13, 17, 22, 23). In a series of patients with BluePrint-defined subtypes, the pCR rate was 76% in the HER2+ type, 31% in the luminal type, and 43% in the basal type (28).…”

“…This distribution may vary depending on the hormone receptor status. In the hormone-receptor-negative subset, the main intrinsic subtype was HER2 enriched (51–85%), with fewer cases of luminal (luminal A 0.7–24%; luminal B 3–11%), and basal-like subtypes (9–28%) (12, 19, 20, 22, 24, 25). In contrast, in hormone-receptor-positive tumors, luminal subtypes were more frequent (luminal A 28–44%; luminal B 24–48%) than HER2-enriched (8–32%) or basal-like (0.5–2.5%) ones (12, 20, 22, 25, 26).…”

Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

“…The clinical value of the HER2-E subtype in HER2+ breast cancer is starting to be elucidated. From a therapeutic perspective, the HER2-E subtype has shown, across 14 clinical trials and ∼2,000 patients, higher sensitivity to anti-HER2-based therapies than the non-HER2-E subtypes [7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, not all HER2-E tumors achieve a complete response following anti-HER2-based therapies.…”

Dual targeting of HER2-positive breast cancer with trastuzumab emtansine and pertuzumab: understanding clinical trial results

“…Hence T-DM1 is only effective against cells expressing HER2; there is no bystander effect from release of maitansine against cells that do not express HER2. Thus the lack of improved outcomes of T-DM1 and T-DM1-P compared with trastuzumab plus chemotherapy in the MARIANNE and KRISTINE studies could be explained partially by lack of effect of T-DM1 on cells that do not overexpress HER2 but coexist with the HER2 overexpressing cells in a heterogeneous tumour [ 18 ]. Selective pressure from treatment in a tumor with heterogeneous HER2 expression, may result in the dominance of clones with limited or no expression of HER2 [ 19 , 20 ].…”