Song, Nan

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Abstract Our objective was to validate the NSABP 8-gene trastuzumab-benefit signature, developed and initially validated in NRG Oncology/NSABP B-31 in Alliance/NCCTG N9831. The B-31 and N9831 trials demonstrated the benefit of adding trastuzumab to chemotherapy in the adjuvant setting for HER2+ breast cancer patients. NSABP investigators utilized gene expression profiles of N9831 patients (N = 892) to blindly assign patients to large-, moderate-, or no-trastuzumab benefit groups and then NCCTG investigators assessed the degree of trastuzumab benefit using Cox models adjusted for age, nodes, estrogen receptor/progesterone receptor status, tumor size, and grade. Hazard ratios and 2-sided P values for recurrence-free survival of the predicted large- (n = 387), moderate- (n = 401), and no-benefit (n = 104) groups, based on the 8-gene signature were 0.47 (95% CI = 0.31 to 0.73, P < .001), 0.60 (95% CI = 0.39 to 0.92, P = .02), and 1.54 (95% CI = 0.59 to 4.02, P = .38), respectively (Pinteraction = .02), providing validation of the 8-gene signature in an independent study.

PURPOSE Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor receptor 2–negative (HER2−) breast cancer. Although risk of late relapse in HR+ HER2− breast cancer is fairly well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based chemotherapy remains largely unknown. METHODS We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier: NCT00005970 ) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier: NCT00004067 ) trials. RESULTS Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS) during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P < .001). Among patients treated with trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P < .001). However, there was no significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88; P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR− breast cancers ( P for interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one to three lymph nodes (N1). CONCLUSION The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was observed between HR+ and HR− HER2+ disease but with similar degree of benefit from adjuvant trastuzumab. RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.

Abstract BACKGROUND Clinical trials NRG/NSABP B-31 and Alliance/NCCTG N9831 demonstrated that trastuzumab added to chemotherapy extended disease-free survival (DFS) in breast cancer patients (pts) in the adjuvant setting (Romond et al). However, the degree of trastuzumab benefit varies among pts. We previously described an 8-gene model that was predictive for trastuzumab benefit, which was validated in an independent cohort of B-31 patients (Pogue-Geile 2013). The 8-gene signature subtyped B-31 pts in an independent validation cohort into three trastuzumab benefit groups: one with large benefit HR=0.27, one with medium benefit HR=0.56, and one with little to no benefit HR=1.56. The purpose of this study was to validate the 8-gene model in pts enrolled into N9831, which tested the efficacy of adding trastuzumab to doxorubicin plus cyclophosphamide → paclitaxel by randomizing pts into one of three arms: chemotherapy only (Arm A), trastuzumab given after chemotherapy (Arm B), or trastuzumab given concurrently with chemotherapy (Arm C). METHODS NCounter data, consisting of 8 predictive genes and 4 house-keeping genes, for 1,379 patients enrolled into N9831 were used to assign each patient to one of the three benefit groups. Assignments to one of the three trastuzumab benefit groups based on the 8-gene model were made by the NSABP/NRG Pathology Laboratory Biostatistician, who was blinded to outcome data. Predictions were sent to N9831 investigators and accuracy of predictions were tested in pts enrolled into arms A and C (N=892) using Cox models adjusted for age, nodes, ER/PR status, tumor size, and grade. Recurrence-free survival (RFS) and DFS were used as endpoints. RESULTS Tumors from N9831were placed into one of the three trastuzumab benefit groups based on the 8-gene signature. The N9831 pts in the predicted-large benefit group had a hazard ratio (HR) of 0.47, P=0.0006, pts in the predicted-medium benefit group had an HR of 0.6, P=0.02, and the predicted-low benefit group had an HR of 1.54, P=0.375. The interaction P value was significant at 0.019 in adjusted Cox models. The RFS at 10 years for trastuzumab-treated pts was 72%, 83%, and 83% in the low, medium, and large benefit groups, respectively. CONCLUSIONS The 8-gene signature developed in a discovery cohort and validated in an independent cohort of B-31 pts has now been validated in N9831. Many anti-HER2 therapies such as lapatinib, afatinib, neratinib, pertuzumab, and TDM-1 have been approved for treatment in metastatic breast cancer pts and although these agents have shown responses, the actual improvements in outcomes in pts is variable and it is not known which pts actually receive benefit. Thus this signature may be clinically useful in identifying pts who may benefit from additional treatment beyond trastuzumab or for stratification of pts enrolled into clinical trials testing new anti-HER2 therapies. SUPPORT U10CA180868, -180822, UG1CA189867, U24CA196067, the PA DOH, which disclaims certain responsibilities, Genentech, Inc., and the Breast Cancer Research Foundation. Citation Format: Pogue-Geile KL, Song N, Serie DJ, Thompson EA. The NSABP/NRG 8-gene signature accurately predicts degree of benefit from trastuzumab in Alliance/NCCTG N9831: Validation of the 8-gene signature in an independent clinical trial [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 PD3-18.