Background: Lapatinib (L), a HER2 signaling, tyrosine kinase inhibitor, demonstrated numerically higher pCR in NSABP B-41 when added to paclitaxel (AC→P) and trastuzumab (T) following doxorubicin + cyclophosphamide (62% v 52.5%). We previously validated an 8-gene signature that predicted the degree of T benefit in NSABP B-31 and NCCTG9831. The purpose of this study is to determine the association of pCR with the 8- gene T-benefit groups, enabling the possibility of stratifying patients (pts) who do or do not receive benefit from L.

Methods: Normalized B-41 nCounter® Breast Cancer 360 gene expression data was used to define the three T-benefit groups: large-, moderate-, and no-. The 8-gene signature was modified to use only 7 genes because one of the 8 genes was not included in the nCounter code set. The ability of the 7-gene signature to predict T benefit was equivalent to the 8-gene signature when tested in B-31. Comparisons within each treatment arm were made with Fisher's exact test.

Results: The pCR rates were significantly different among the three groups in the AC→P+T arm: Large: 24/28 (86%); Moderate: 13/32 (41%); and No: 1/9 (11%); p<0.001, but were not significantly different in the other two arms; a trend for significance was seen in the AC→P+T+L arm (Table 1). We also tested if L would improve pCR when added to AC→P+T in any of the 7-gene benefit groups compared to T. There was a non-significant, numerical increase in pCR in the no-benefit group in the AC→P+T+L arm (44%) v the AC→P+T arm (11%) (p=0.29).

Conclusions: The significant association of the modified 8-gene benefit groups with pCR in the AC→P+T arm suggests this signature could identify pts who may benefit from dual HER2-targeted neoadjuvant therapy. This could be tested in a meta-analysis including other neoadjuvant trials.

Support: Lombardi CCC; BCRF; GSK; P30CA051008; Genentech; NSABP

Table 1.

pCR rates in trastuzumab benefit groups in NSABP B-41

pCR rates in Breast and Nodes
TreatmentNo BenefitIntermediateLarge BenefitEntire Cohortp value
AC→P+T 1/9 (11.1%) 13/32(40.6%) 24/28 (85.7%) 38/69 (55.1%) <0.001 
AC→P+L 2/7 (28.6%) 11/26 (42.3%) 14/31 (45.2%) 27/64 (42.2%) 0.82 
AC→P+T+L 4/9 (44.4%) 11/25 (44.0%) 20/27 (74.1%) 35/61 (57.4%) 0.051 
pCR rates in Breast and Nodes
TreatmentNo BenefitIntermediateLarge BenefitEntire Cohortp value
AC→P+T 1/9 (11.1%) 13/32(40.6%) 24/28 (85.7%) 38/69 (55.1%) <0.001 
AC→P+L 2/7 (28.6%) 11/26 (42.3%) 14/31 (45.2%) 27/64 (42.2%) 0.82 
AC→P+T+L 4/9 (44.4%) 11/25 (44.0%) 20/27 (74.1%) 35/61 (57.4%) 0.051 

Citation Format: Nan Song, Xiaoqing E. Tan, Ying Wang, Rim S. Kim, Hanna Bandos, Gong Tang, Eleftherios Mamounas, Charles E. Geyer, Priya Rastogi, Samuel A. Jacobs, Ashok Srinivasan, Peter C. Lucas, Soonmyung Paik, Norman Wolmark, Sandra M. Swain, Katherine L. Pogue-Geile. Association of pCR and the 8-gene signature: NRG Oncology/NSABP B-41 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 532.