Comprehensive molecular profiling broadens treatment options for breast cancer patients

Abstract

Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne^® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

Keywords: ERBB2; breast cancer; next generation sequencing; precision oncology; tumor mutational burden.

FIGURE 1

Study flow chart. A total of 120 samples from patients with breast cancer were enrolled; 11 were initially excluded because of insufficient tissue quantity, but additional samples were obtained for 6 of them. Finally, 115 samples were analyzed and sequenced, and genome profiling data were available for 109 of the samples (success rate =94.8%). TIFA, tissue insufficient for analysis.

FIGURE 2

Potentially actionable alterations in patient samples. Frequency of short variants (SNV/InDel) (A) and structural variants (CNA/fusion/loss/splicing/rearrangement) (B) in most commonly altered genes. C, Proportion of clinically actionable alterations.

FIGURE 3

Proportion of alterations annotated on the basis of their clinical actionability according to OncoKB and the consensus of three major Japanese cancer‐related societies. The outer pie chart demonstrates the proportion of the levels of evidence according to OncoKB (A) and JCRSs/C‐CAT (B). The inner pie chart indicates the proportion of accessibility to treatments in Japan according to JCRSs/C‐CAT. Figures show distribution (%). JCRSs, three major Japanese cancer‐related societies; C‐CAT, Center for Genomics and Advanced Therapeutics

FIGURE 4

Tumor mutation burden (TMB). Dots represent the TMB of samples; red horizontal bars represent the mean and error bars show ±standard error of the mean (SEM). The vertical axis (log‐scaled) shows the TMB (mut/Mb) in all samples (A), by subtype (B), and by tumor type (C). mut/Mb, mutations/megabase.