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.

Effect of the 2013 ASCO-CAP HER2 Testing Guideline on the Management of IHC/HER2 2+ Invasive Breast Cancer

“…Both cases categorized as Group 1 were positive with FISH; it has been reported that such cases have intense basolateral membrane staining and invasive micropapillary breast carcinoma (27). Our evaluation by NGS also confirmed amplification of the HER2 gene in such cases (26). Although the IHC method is still important in the era of genomic medicine, it may be possible to select more accurate anti-HER2 treatment indications by combining HER2 IHC with genomic diagnosis.…”

“…As we have reported previously, among HER2-negative cases in the clinical setting with IHC and ISH methods, there were three cases (2.8%) in which FoundationOne ® CDx (NGS) suggested the indication of anti-HER2 treatment (26). All five cases of Groups 0 and 1 were positive for hormone receptor, which suggested that tumour heterogeneity may also be linked to HER2-staining heterogeneity.…”

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

“…Of note, a significant portion of HR+ breast cancers shows dysregulation of the phosphoinositide 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, which is also the main contributor to ET resistance [43,44]. Furthermore, actionable co-alterations in PIK3CA and DNA repair genes might lead to the activation of the human leukocyte antigen (HLA) molecules due to increased TMB and subsequent neoantigens production, particularly in the metastatic setting [13,45,46]. This subset of patients represents a possible target for immunotherapy with ICB [47].…”

Differential Regulation of Lacto-/Neolacto- Glycosphingolipid Biosynthesis Pathway Reveals Transcription Factors as Potential Candidates in Triple-Negative Breast Cancer

“…GATA3 transcription factor has previously been associated with less aggressive ER+ BC [63], but recent studies reported the expression of GATA3 in a subset of TNBC, with a broad range of 31.4% to 83% of TNBCs reported in different studies [64][65][66]. Interestingly, GATA3 expression appears to correlate with TNBC metastasis [67], and GATA3 gene variants were detected in 11% of metastatic BCs in a 115 patient cohort [68]. However, there has been no established link between GATA3 expression and glycosylation regulation or GSL pathway.…”