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.
Background: Classifying breast cancer into molecular subtypes (Luminal A/B, Her2-enriched, and Basal-like) has proven to be biologically and clinically informative. Recently, we developed a gene expression based protocol (PAM50) that provides reliable subtype classification as well as independent prognostic utility (Parker et al, J Clin Oncol 2009). In this study, we evaluated the ability of the PAM50 subtypes to predict pathological complete response (pCR) to anthracycline/taxane-based chemotherapy in the neoadjuvant setting.Methods: Gene expression data were combined from three independent neoadjuvant studies totaling 361 subjects. Complete clinical data (hormone receptor levels, tumor size, node status, and grade) were available for 186 subjects. The I-SPY cohort (n=129; fresh-frozen, Agilent) was treated with doxorubicin/cyclophosphamide (ACx4) followed by paclitaxel (Tx4). The NSABP B-27 cohort (n=103; FFPE, Affymetrix) was treated with ACx4 followed by docetaxel (4 cycles). The third cohort from MD Anderson Cancer Center (MDACC) (n=129; fresh-frozen tissue, Affymetrix) was treated with paclitaxel/T followed by sequential fluorouracil-AC (FAC). Subtype assignments and prognosis scores were generated as previously described (Parker et al., 2009). Univariate and multivariate testing for pCR was performed with Fisher's exact test and logistic regression. Statistical learning methods were also implemented in order to identify an improved predictor of pCR.Results: There was no difference between the cohorts/studies with respect to estrogen receptor (ER) status (p=0.23), subtype distribution (p=0.77), or pCR rate (p=0.95). ER, PR, HER2, grade, node status, and subtype were all associated with pCR in univariate analyses. Multivariable logistic regression indicated that molecular subtype is an independent predictor of pCR (p<0.01). We found that molecular subtype contains additional pCR-predictive information beyond that of ER status, and that adding ER status to models containing molecular subtype did not significantly improve the model's performance. This indicates that the information predictive of pCR represented by ER status is largely also present in molecular subtype. Among the subtypes, Basal-like and Her2-enriched tumors demonstrated the highest rate of pCR relative to Luminal A tumors (OR 7.4; 2.2-24.8; OR 6.4; 2.0-20.7). The Risk of Relapse based on the subtype (ROR-S) was also a strong predictor of pCR (auROC=0.74), but was improved when using a novel ridge regression model (auROC=0.77; p<0.01). ROR-S and the different pCR predictors evaluated were generally correlated, however, Luminal B samples were consistently classified as having a poor prognosis and a low likelihood of pCR.Conclusions: In this combined analysis, using ER, PR, HER2, node status, tumor size, and subtype, the intrinsic molecular subtype classification is the most significant predictor of pCR across three anthracycline/taxane-based neoadjuvant cohorts.Interestingly, hormone receptor status is no longer significant when subtype is included in the model. These results indicate robust predictive information provided by the subtype classification, and highlights the chemotherapy insensitivity of the poor prognosis luminal B breast cancer subtype. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2019.
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