Abstract 5P
Background
Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial.
Methods
Tumor tissue were collected before neoadjuvant chemotherapy from all enrolled patients and at surgery in patients who did not achieve pathologic complete response (pCR). Targeted sequencing using FoundationOne CDxTM and whole transcriptome sequencing (WTS) were performed. The association between genomic features and pCR achievement was analyzed by Fisher's exact test for the enrichment test by mutations and by differential gene expression analysis using edgeR package. A p-value or false discovery rate (FDR) less than 0.05 were considered as statistically significant.
Results
Targeted sequencing result were obtained from 63 patients(T1) and 15 patients(T3), respectively. Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687). When genomic mutations were compared before and after neoadjuvant chemotherapy, ERBB2 amplification (p= 0.0026) and CDK12 amplification (p=0.0006) were enriched in pre-treatment tumors and PTPRO mutation (p=0.0229) was enriched in residual tumor tissue. WTS result were obtained from 62 patients(T1) and 10 patients(T3), respectively. Luminal subtypes were enriched in non-pCR group (p = 0.0558). In patients with non-pCR, LRP1B (FDR=4.04e-04), ESR1 (FDR=1.07e-4) and RAD21 (FDR=2.05e-03) were highly expressed and ESR1, luminal and MYC related genesets showed higher expression (FDR<0.05).
Conclusions
Luminal subtype and MYC amplification were associated with non-pCR in patients with HER2-positive EBC who were treated with immunotherapy and anti-HER2 treatment combination. Further evaluation of the predictive role of these mutations are warranted.
Clinical trial identification
NCT03881878.
Legal entity responsible for the study
Yeon Hee Park.
Funding
This work was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). The study drugs were provided by Roche (trastuzumab, pertuzumab, and atezolizumab), Sanofi (docetaxel), and Dong-A ST (tripegfilgrastim).
Disclosure
H.K. Ahn: Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Boehringer Ingelheim, MSD, Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: MSD Boehringer Ingelheim. S. Im: Financial Interests, Personal, Invited Speaker: Merck, AstraZeneca, Eisai, GSK, Hanmi, Eli Lilly, MSD, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pfizer, Dae Woong; K.H. Jung: Non-Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Novartis, BiXink, Takeda. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. All other authors have declared no conflicts of interest.