PurposeThe primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses.Experimental designpCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes.ResultsThe numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34–66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24–54]) or neratinib (33% [95%CI 20–50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR−) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR.ConclusionsCombining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR− patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting.Trials registrationClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

3503 Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA (Colorectal Cancer Assigner) stem-like subtype were associated with a poor prognosis and no OX-benefit, but stage III patients with an enterocyte subtype did. We tested the association of CRCA and CMS molecular subtypes with prognosis and OX-benefit in stage III MOSAIC patients. Also, recombination proficiency scores (RPS) were tested for the same associations. RPS scores quantify the efficiency of DNA-damage repair. Low RPS have been associated with inferior overall survival (OS) in non-small cell lung carcinoma patients treated with surgery alone but better OS for patients who received surgery plus chemotherapy. Methods: Gene expression profiles from 590 stage III pts with follow up were successfully profiled by a custom designed nCounter code set. CRCA subtypes were determined by a locked down algorithm based on a re-estimated centroid using 72 genes (Song et al 2016). CMS subtypes were determined by modified single sample predictor (SSP) using 84 genes. RPS scores were determined as previously described by Pitroda et al (2014). Signature predictions were made while blinded to clinical outcome and signature performance was evaluated while blinded to gene expression. Results: The stem-like subtype was associated with a very poor prognosis (Stem-like vs others HR=1.56, p<0.01) and no OX-benefit. CRCA and CMS subtypes did not associate with OX-benefit. Using a median cut point, stage III patients with low RPS scores received significant OX-benefit (HR=0.67, p=0.033, N=290) and patients with high RPS scores did not (HR=1.2, p=0.32, N=300) with significant interaction p=0.025. Conclusions: The observation in C-07, that the stem-like subtype has the poorest prognosis and did not receive OX-benefit, was validated in MOSAIC, identifying patients who need new therapies. RPS scores may help to identify the subset of patients with OX-benefit in stage III CC, confirmation of this observation is currently being investigated in C-07. Support: PA DoH; NSABP; Sanofi.

Dr. Sama reports employment and stock options with Bristol Myers Squibb Ms. Piette reports commercial agreement to perform the statistical analyses, to participate in the writing of the statistical section of the manuscript, and the review. Dr. Pogue-Geile reports grants from the NCI and the Pennsylvania Dept of Health (PA DoH), during the conduct of the study*, and from Puma Biotechnology, Inc. (Puma). Mr. Lipchik reports grants to his institution from the PA DoH,* and Puma. Ms. Finnigan reports grants to her institution from the PA DoH,* and Puma. Dr. Beumer reports expert testimony from Pfizer, and grants from AbbVie, Spectrum, and NCI P30 CA47904 and R50 CA211241. Dr. Wolmark reports an institutional business contract with Puma. Dr. Lucas reports consulting fee paid to spouse from Bayer/Loxo, and stock/options with Amgen. Dr. Allegra reports fees and payments as an employee of NSABP Foundation. Dr. Srinivasan reports grants to his institution from the PA DoH, and Puma.

After the publication of this work [1] the authors have reported that in Table 3 The letter “T” in columns 5 and 7 should not be there.

Background: We previously described a predictive signature for trastuzumab benefit which was validated in the adjuvant setting in an independent cohort within NSABP B-31 (the 8-gene signature) (Pogue-Geile et al JNCI, 2013) and in Alliance/NCCTG N9831 (SABCs 2017). The 8-gene signature subtyped B-31 patients into three trastuzumab benefit groups: high HR=0.27, intermediate HR=0.56 and no benefit HR=1.56 based on disease free survival. The 8 gene signature was also predictive of trastuzumab benefit in N9831. HRs were 0.47, P&lt;0.001, 0.6, P=0.02, and 1.54, P=0.375 in the predicted-high, -intermediate and -no benefit groups, respectively based on recurrence free survival (SABCS 2017). The interaction P-value was significant at 0.019 in adjusted Cox models. The RFS at 10 years for trastuzumab-treated pts was 83%, 83% and 72% in the high, intermediate and no benefit groups, respectively. Now we have tested the association of the 8-gene signature groups with pCR in FB-7 which was a 3 arm neoadjuvant study testing the pCR rate of HER2+ breast cancer patients treated with paclitaxel in combination with trastuzumab (T) or neratinib (N) or the combination (T + N). Methods: RNA-Seq data from FB-7 pretreatment biopsies was used to predict the trastuzumab benefit groups (high, intermediate, and no) for each patient's tumor using the 8 gene signature using methods and cut-offs as previously described (Pogue-Geile et al 2013). The pCR rates (percentages) were tested for treatment interaction with a chi-square test. Results: The pCR rates were 75%, 53%, and 22%, in the high (N=12), intermediate (N=32) and no benefit groups (N=9), respectively, when analyzed without regard to treatment arm. The pCR rates for the no benefit group and the high benefit groups were significantly different (p=0.030) and there was a significant treatment interaction with the 8-gene benefit group (intp=0.0081). The predicted low and intermediate groups were combined to test whether the 8 gene signature could identify a group of patients whose pCR rates might improve by adding N to T, and referred to it as the low benefit group. This was necessary due to the small numbers of patients in each group. The pCR rate in the low benefit group was higher in patients treated with T+N (9/15, 60%) than in the T arm (6/11, 45%) but these differences were not significant. Conclusions: This is the first test of the 8-gene signature in the neoadjuvant setting and interpretations of these data should be interpreted cautiously due to the small numbers. However, if these results were validated in another neoadjuvant trial then the 8 gene signature could provide a rationale for selecting patients who would be appropriate for the addition of neratinib or other TKIs to trastuzumab and chemotherapy. SUPPORT: PUMA Biotechnology, NCI U10CA180868, -180822, UG1-189867, and U24-196067; The Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analysis,interpretations, or conclusions. Citation Format: Pogue-Geile KL, Wang Y, Srinivasan A, Gavin PG, Kim RS, Song N, Feng H, Lipchik C, Costantino JP, Wolmark N, Lucas PC, Paik S, Jacobs SA. The fully validated NSABP/NRG 8-gene signature which predicted the degree of benefit in the adjuvant setting (B-31 and NCCTG N9831) associates with pCR in the neoadjuvant setting in NSABP clinical trial FB-7 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-04.