MYC amplification is detected in ∼15% of breast tumors and is associated with poor prognosis by mediating acquired resistance to anticancer therapies. This study aimed to determine the prevalence of MYC amplifications in Chinese women with breast cancer (BRCA) and investigate the correlation between MYC amplification and clinicopathological and molecular characteristics and its clinical implications. We analyzed MYC alterations in tissue specimens from 410 women diagnosed with BRCA in our hospital from June 1, 2017 to September 27, 2018. We compared our results with publicly available data from The Cancer Genome Atlas (TCGA) BRCA cohort (n = 1079). MYC amplification was identified in 12.4% (51/410) of our cohort, with mean copy number (CN) of 4.42 (range: 2.84-11.27). In TCGA cohort, MYC amplification was identified in 21.2% (229/1079) and was associated with age, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 (HER2) status, and molecular subtype, whereas in our cohort, MYC amplification was associated with smaller tumor size (T1-2, p = 0.023) and higher Ki-67 levels (≥20%; p = 0.031). Analysis of molecular profiles revealed that MYC-amplified breast tumors had significantly more concurrent CN variations compared with MYC nonamplified BRCA in both Guangdong Provincial People's Hospital (GDPH) and TCGA cohorts (p < 0.001). Pathway mapping analysis demonstrated that MYC-amplified tumors had more mutations involved in 15 different but interrelated pathways critical in DNA repair, cell cycle, and cell proliferation. Patients in TCGA cohort with MYC-amplified hormone receptor (HR)-positive/HER2-positive BRCA (p = 0.038) and MYC nonamplified triple-negative BRCA (p = 0.027) had significantly shorter overall survival. In conclusion, this study contributes to a better understanding that MYC-amplified breast tumors had distinct clinicopathological and molecular features compared with MYC nonamplified breast tumors. Further research with a larger sample size is necessary to further elucidate the clinical and survival implications of MYC amplifications.
543 Background: HER2 targeted therapy has revolutionized the survival outcomes of early and advanced HER2+ breast cancer (BC). However, among HER2+ patients, the therapeutic response to HER2 inhibitors vary. To understand the molecular mechanism of the variability in therapeutic efficacies, the mutational landscape of HER2+ tumors need to be elucidated. Methods: 107 HER2+ Chinese stage I-III BC patients were included in the study, including 64 HR+ and 43 HR- patients. A majority of the patients were diagnosed with infiltrating ductal carcinoma (99/107). Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes spanning 1.64 MB of the human genome. Results: 1,119 alterations were detected, including 478 single nucleotide variants (SNVs), 14 insertions or deletions, 29 fusions, 593 copy number amplifications (CNA), 2 large genomic rearrangements and 3 CN deletions in 267 genes. Alterations in 99 genes were shared between HR+/HER2+ and HR-/HER2+ tumors; while 123 and 45 genes were only detected in either HR+/HER2+ or HR-/HER2+ tumors, respectively. CNA, splice site and frameshift mutations were significantly more in HR+/HER2+ patients ( p= 0.017). Specifically, CNA in SPOP, CCND1, FGF19, FGF3, FGF4, RNF43, RAD51C, ADGRA4 and MDM4 and various alterations in GATA3 were significantly more among HR+/HER2+ tumors ( p< 0.05). In addition to HER2 amplifications, concurrent fusions in ERBB2 (67%, 4/6), SNVs in ERBB3 (100%, 3/3) and ERBB4 (100%, 1/1) were more likely to be detected in HR+/HER2+ tumors, while concurrent EGFR amplifications were exclusively detected in HR-/HER2+ tumors. The trend of concurrent mutations was consistent with mutation types detected in HER2- tumors based on HR status, wherein EGFR amplifications were more frequent in HR-/HER2- tumors, while SNVs in EGFR, ERBB2, ERBB3 and ERBB4 were more predominant in HR+/HER2- tumors. Based on KEGG pathway analysis, HR+/HER2+ tumors had more frequent alterations in TGFb ( p= 0.007), WNT ( p= 0.002) and homologous recombination ( p= 0.004) pathways than HR-/HER2+ tumors. Furthermore, our data revealed that HR+/HER2+ and HR-/HER2+ patients had comparable TMB ( p= 0.24), with a median TMB of 4.0 mutations/Mb for both. Conclusions: Our study revealed genetic heterogeneity between HR+ and HR- HER2+ tumors. The distinct genetic alterations are potentially relevant in the development of optimal treatment strategies for such patients.
Breast cancer is highly heterogenous with temporal and spatial heterogeneity making it necessary for rebiopsy. DS-8201a, a new potential therapy for human epidermal growth factor receptor 2 (HER2) low expression breast cancer, had been proved that it could overcome heterogenous HER2 expression in a preclinical setting. In January 2014, a 23-year-old woman was presented with a lump in the right breast with bone metastasis, diagnosed as infiltrating ductal carcinoma, estrogen receptor (ER)+, progesterone receptor (PR)+, HER2 immunohistochemistry (IHC) 2+, and fluorescence in situ hybridization negative. The patient received a series of therapies including surgery, radiotherapy, endocrine therapy, target therapy, and chemotherapy. The longest progression-free survival was 17 months after surgery. Biopsy of liver metastasis in February 2020 showed triple negative (HER2-, ER-, PR-), which was quite different from the initial diagnosis in 2014, so retesting was performed and the results showed ER-, PR+ by 10%, HER2 IHC score of 1+, indicating heterogeneity of HER2 expression. In May 2020, DS-8201a treatment was initiated and continued for 10 cycles until November 2020. Remarkable relief in symptoms was observed after the first dose. A reduction in the metastatic lesion size (liver and brain) and improved liver function was observed during the therapy. This case indicated the heterogeneity of breast cancer, and impressive efficacy of DS-8201a in a heavily treated patient with HER2-low and HER2 heterogeneity.
Abstract Backgroud There were limitations existing in programmed cell‐death ligand 1 (PD‐L1) as predictive biomarkers for breast cancer (BC), hence exploring the correlation between PD‐L1 levels and other biomarkers in BC may become a very useful therapeutic clinical tool. Methods A total of 301 Chinese patients with different BC subtypes including 47 HR+/HER2+, 185 HR+/HER2−, 38 HR−/HER2+, and 31 triple‐negative breast cancer (TNBC) were enrolled in our study. Next‐generation sequencing based Yuansu450 gene panel was used for genomic alteration identification and PD‐L1 expression was tested using immunohistochemistry. Results The most prevalent BC‐related mutations were TP53 mutations, followed by mutations in PIK3CA , ERBB2 , CDK12 , and GATA3 in our Chinese cohort. We found that mutations DDR2 and MYCL were only mutated in HR−/HER2+ subtype, whereas H3‐3A and NRAS mutations were only occurred in HR−/HER2− subtype. The percentage of patients with PD‐L1‐positive expression was higher in patients with HR‐/HER2− mainly due to the percentage of PD‐L1‐high level. Mutational frequencies of TP53 , MYC , FAT4 , PBRM1 , PREX2 were observed to have significant differences among patients with different BC subtypes based on PD‐L1 levels. Moreover, a positive correlation was observed between TMB and PD‐L1 level in HR+/HER2− subtype, and showed that the proportion of patients with high PD‐L1 expression was higher than that of patients with low PD‐L1 expression in the HR+/HER2− and HR+/HER2+ cohorts with high Ki67 expression. Conclusions The genomic alterations based on PD‐L1 and other biomarkers of different cohorts may provide more possibilities for the treatment of BC with different subtypes.
Abstract Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear. Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations. Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1). Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy. Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-06.
Abstract Background: Next generation sequencing (NGS) and the according target-based precision therapy has shown promising efficacy in many tumors. Here we report the genomic characteristics of Chinese breast cancer to support the development of more precise treatment strategy. Methods: Formalin fixed, paraffin embedded (FFPE) tumor samples and matched peripheral blood samples of 220 Chinese cancer patients including 218 females and 2 males were collected for NGS-based 450-genes panel assay. Pathological subtypes included 104 HR+/HER2-, 30 HR-/HER2+, 44 HR+/HER2+ and 42 triple negative breast cancers (TNBC). Assessed genomic alterations included single base substitution, short and long insertions/deletion, copy number variation, gene fusion and rearrangement. MSK breast cancer data was obtained from cBioPortal for comparing the difference between Chinese and Western patients. Results: The top mutated genes were TP53 (88.1%), PIK3CA (26.2%) and PTEN (21.4%) in TNBC; ERBB2 (86.7%), TP53 (86.7%), CDK12 (80.0%) and PIK3CA (23.3%) in HR-/HER2+ patients; ERBB2 (75%), TP53 (61.4%), CDK12 (54.5%) and PIK3CA (45.5%) in HR+/HER2+ patients. In HR+/HER2- patients, the most frequently mutated genes was PIK3CA (49.0%), followed by TP53 (30.8%) and GATA3 (27.9%), whereas the frequency of PIK3CA and GATA3 mutation were lower (41.6% and 19%, respectively) in Western patients. Although Alpelisib was approved by FDA in PIK3CA mutated HR+/HER2- patients, we observed PIK3CA mutation frequency had no difference among four subtypes. In this cohort, patients with PIK3CA mutation were significantly elder than patient without PIK3CA mutation (50 vs 47 years old, p=0.006). The hotspot mutations of PIK3CA (E542X, E545X and H1047X) accounted for 79.8% of PIK3CA mutations (71/89). Gene fusion/rearrangement was observed in 26% patients, in which 4 patients had gene fusions. Gene variations in homologous recombination pathway were found in 27.7% of patients. Among the 11.4% of patients with BRCA1/2 mutations, 11 patients harbored germline mutations and 19 patients had somatic mutations. Rearrangement accounted for 35% in somatic BRCA1/2 mutations. In the patients with germline BRCA1/2 mutation, 6 were HR+/HER2- patients who have been approved to use Olaparib. Based on the usage of CDK4/6 inhibitor in HR+/HER2- patients, this 450-genes panel enabled us to find that 41.3% HR+/HER2- patients had genes variations are related to CDK4/6 inhibitor resistance (CCND1, 18.3%; FGFR1 17.3%; NF1, 7.7%; MDM2, 6.7%; ESR1, 6.7% and RB1, 1.9%). The median TMB was 4.3 Muts/Mb in the whole cohort and patients with KMT2C mutations had significantly higher TMB (5.5 vs 3.8 Muts/Mb, p=0.004). In addition, Chinese breast cancer patients had a significantly higher frequency of KMT2C mutations compared to western patients (11.4% vs 1.4%, p<0.001). Conclusions: Our study revealed the genomic variation characteristics in Chinese breast cancer patients and the value of NGS-based panel analysis in identifying potential benefit and resistance mechanisms of precision therapy. Integrating genomic features into the diagnosis and treatment of breast cancer patients is necessary to maximize the clinical benefits for each patient. Citation Format: Ning Liao, Guochun Zhang, Bo Chen, Yulei Wang, Kai Li, Chongyang Ren, Hsiaopei Mok, Li Cao, Lingzhu Wen, Minghan Jia, Cheukfai Li, Liping Guo, Guangnan Wei, Jiali Lin, Jiangguo Lai, Honglin Guo, Wenjing Wang, Shiyue Zhang, Zhijian Song, Jian Wang, Hui Chen, Jinwei Hu, Weifeng Wang, Weiwei Shi, Kai Wang. Comprehensive genomic analysis of Chinese breast cancer and clinical application [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-03.
e15120 Background: Trop2 has been confirmed to enhance tumor proliferation, metastasis and invasion in various epithelial tumors. Breast cancer (BC) patients with high Trop2 protein expression have better prognosis and objective response rates. Thus, this study aimed to explore potential biomarker associated with Trop2 protein expression in BC. Methods: BC patients with complete clinical parameters were enrolled, including age, estrogen receptor (ER) status, progesterone receptor (PR) status, human epithelial growth factor receptor 2 (HER2 status), molecular subtype, Ki67 status, T stage, N stage, TNM stage, PD-L1 and Trop2 protein expression level. Univariate and multivariate ordinal logistic regression analyses were performed to identify the independent factor for Trop2 protein expression level. Immunohistochemical analysis was conducted to detect the protein expression level of Trop2 in BC. Kaplan–Meier analysis and the log-rank test were executed to assess the survival difference between low- and high- gene expression level of Trop2. Results: A total of 65 BC patients from the Guangdong Provincial People’s Hospital were included. Based on the univariate and multivariate ordinal logistic regression analyses, Ki67 status was the only independent factor for Trop2 protein expression level (P < 0.05). This finding revealed that BC patients with higher Ki67 status may harbor higher Trop2 protein expression level. According to cBioPortal database, the mutation rate of Trop2 was 2.1% and mutation type was amplification. BC patients with low Trop2 gene expression level had significantly greater survival prognosis (P < 0.05). Conclusions: We performed the comprehensive analysis of the Trop2 in BC patients. It has the potential to guide individualized targeted treatment in BC patients.
Triple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population.We recruited 89 patients with TNBC at Guangdong Provincial People's Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies.Cases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p<0.05; Ki-67 ≥30%: 83.3% vs. 58.8%, p<0.05), while androgen receptor (AR) and PD-L1 positive (combined positive score≥10) rates were lower than of STs cases (AR: 11.1% vs. 47.1%; PD-L1: 9.6% vs. 33.3%, p<0.05). The most commonly altered genes were TP53 (88.7%), PIK3CA (26.8%), MYC (18.3%) in NSTs, and TP53 (68.8%), PIK3CA (50%), JAK3 (18.8%), KMT2C (18.8%) in STs respectively. Compared with NSTs, PIK3CA and TP53 mutation frequency showed difference in STs (47.1% vs 19.4%, p=0.039; 64.7% vs 87.5%, p=0.035).In TNBC patients with STs, decrease in histologic grade and ki-67 index, as well as increase in PD-L1 and AR expression were observed when compared to those with NSTs, suggesting that TNBC patients with STs may better benefit from immune checkpoint inhibitors and/or AR inhibitors. Additionally, lower TP53 and higher PIK3CA mutation rates were also found in STs patients, providing genetic evidence for deciphering at least partly potential mechanism of action.
Abstract Background Immunotherapies such as PD-L1 inhibitors have shown promising efficiency in breast cancer (BC) patients. However, treatment responses for immunotherapies are diverse since the immunogenicity of breast cancer is heterogeneous. Specific subtypes such as hormone receptor (HR)-positive, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown heterogeneity in immunogenicity. Therefore, precisely identification of patients potentially benefit from immunotherapy is important. Previous studies have proved PD-L1 expression and tumor mutational burden (TMB) as predictive biomarkers for immunotherapy. Here, we report the PD-L1 expression and TMB status in Chinese BC patients with different subtypes. Using comprehensive molecular analysis, we also characterized the genomic features related to these biomarkers. Methods Tumor samples from 112 Chinese patients with BC were collected and subjected to next-generation sequencing (NGS) and immunohistochemical (IHC) analysis. NGS were performed in a laboratory accredited by College of American Pathologists (CAP) and certified by Clinical Laboratory Improvement Amendments (CLIA) using validated panel targeting 450 cancer genes. Genomic alterations, included including single base substitution, short and long insertions/deletion (Indel), copy number variation, gene fusion, and rearrangement, were assessed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Tumor tissues were analyzed for PD-L1 expression by IHC with 22C3 or 28-8 antibodies, respectively. Results The 112 Chinese BC patients consisted of 87 HR+ (77.7%), 19 TNBC (17.0%) and 6 HR-/ HER2 + (5.3%), with a median age of 47.5 years old (range 24-81). Of all patients, 42.0% were positive for PD-L1 expression (CPS≥1), including 30.4% PD-L1 (1≥CPS>10) and 11.6% PD-L1 (CPS≥10). PD-L1 expression were observed in HR+ BCs (41.4%) as well as in TNBC (47.4%) and HR-/ HER2+ (33.3%) subtypes, no significant difference were observed among the three subtypes. 8.9% patients were TMB-High (≥10 muts/Mb) with median TMB of 3.4 muts/Mb (range 0-80.8). TMB was slightly correlated with PD-L1 expression (Kendall tau = 0.241; P =0.01). 17.0% of PD-L1 positive patients and 3.1% of PD-L1 negative patients were TMB-High (p=0.016). Patients with PD-L1 CPS≥10 had significantly higher median TMB (7.1 vs. 3.1 muts/Mb, p<0.001). Moreover, patients with TMB-High were significantly elder than TMB-Low (median age, 57.5 vs. 47, p=0.012). In PD-L1 positive patients, the most frequently mutated genes were TP53 (66%), PIK3CA (36%) and ERBB2 (30%); In TMB-High patients, the most frequently mutated genes was PIK3CA (80%), followed by TP53 (60%) and ERBB2 (40%). Conclusion Our data shows that the PD-L1 expression has no significant difference among HR+, TNBC and HR-/ HER2+ subtypes. These data provide the hypothesis that PD-L1 expression positive in different subtype breast cancers may benefit from immune treatment, including HER2 and Luminal subtypes. Otherwise, there was a correlation between PD-L1 expression and TMB, High TMB was also observed in PD-L1 negative patients, which may enrich the subgroup of patients who could benefit from immunotherapy. The verification of integrated predictive biomarkers for immunotherapy in BC is further needed. Citation Format: Ning Liao, Cao Li, Jundong Wu, Bo Chen, Guochun Zhang, Xueri Li, Liping Guo, Guangnan Wei, Jiali Lin, Yingzi Li, Yuchen Zhang, Hsiaopei Mok, Chongyang Ren, Yulei Wang, Kai Li, Cheukfai Li, Lingzhu Wen, Minghan Jia, Tengjiao Lin, Chunyan Cheng. Pd-l1 expression among different subtypes of chinese breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-44.
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