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SABCS HER2 low expression Breast cancer hotspot summary.
The 45th San Antonio Breast Cancer Symposium (SABCS) in 2022 has been held from December 6th to 10th, Central Time in the United States! Breast cancer with low HER2 expression accounts for approximately 40 to 50% of all breast cancer subtypes. The new ADC drug breaks the traditional belief that only HER2-positive breast cancer can benefit from anti-HER2 treatment, and ends the era of dichotomy between HER2-positive and -negative breast cancer since the discovery of HER2. The emergence of ADC drugs has also triggered widespread interest among scholars in studying the prognostic and molecular characteristics of breast cancer with low HER2 expression. As the largest and most influential breast cancer conference in the world, the results of multiple HER2 low expression studies were presented at the conference. Professor Yuan Peng took stock of posters and abstracts related to low HER2 expression in SABCS, providing inspiration for future research directions!
HER2-04 Prevalence of HER2-low among Metastatic Breast Cancer Patients and Their Outcomes Compared to HER2 IHC 0
The study included a total of 3053 breast cancer patients who were initially diagnosed as early-stage and then relapsed, and 1203 female breast cancer patients who were initially diagnosed as late-stage. The proportion of HER2-low in patients who were initially diagnosed as early stage and then relapsed was 59.3% (1811/3053), and the proportion of patients who were initially diagnosed in late stage was 59.3% (713/1203). Among patients with breast cancer who were first diagnosed in early stages and then relapsed, multivariate logistic regression showed that pCR rate was significantly related to ER, PR status, and lymphovascular invasion. In multivariate Cox regression, HER2-low was significantly associated with longer OS (HR=0.878, p=0.009). Among patients who received neoadjuvant chemotherapy , HER2-low was significantly associated with longer OS (HR=0.867, p=0.044). Among patients with advanced disease at initial diagnosis, nuclear grade and ER-positive status were associated with HER2-low. By multivariate Cox regression, HER2-low status was significantly associated with longer OS (HR=0.834, p=0.026). Conclusions: In patients with metastatic breast cancer, HER2-low was significantly associated with longer OS compared with HER2-0.
HER2-05: Comprehensive genomic characterization of HER2-low breast cancer
This study conducted NGS testing on HER2-negative metastatic breast cancer patients, including HER2-low (n=487) and HER2-0 samples (n=552). In HER2-low tumors, ER expression was enriched (76.0% vs. 60.9%). After adjusting for ER status, no major differences were observed in genetic mutations and CNV in HER2-low and HER2-0 tumors. After adjusting for ER status, any mutation in MPL, CYLD, and MAP3K and oncogenic mutations in TP53 and NF1 were more common in HER2-0 patients, whereas MTOR, RAD21, DNMT3A, and PDGFRA were enriched in HER2-low patients; however, none of the TMB, mutation, or CNV differences reached statistical significance. Compared with HER2-0, HER2-low tumors had a significantly higher number of ERBB2 alleles. Conclusions: In metastatic breast cancer, the genetic landscape of HER2-low and HER2-zero does not differ significantly after correction for ER status.
HER2-08: Molecular characterization of HER-2 low patients identifies basal-enriched subset with poor clinical outcomes in real-world data
The study retrospectively analyzed 1,545 breast cancer samples, with HER2-low accounting for 920 cases. Use the Tempus xT assay, which includes DNA sequencing and whole-exome capture RNA sequencing. The HER2 RNA gene signature was used to identify genes associated with HER2 overexpression by comparing HER2-0 (n=464, IHC 0) and HER2-positive (n=161, IHC 3+ or IHC 2+ and FISH+) patients. The HER2 gene signature was used to perform hierarchical clustering of HER2-low samples. HER2-low patients can be clustered into three categories. Different population stages and population distributions (race, ethnicity, age) are similar. Cluster 3 is mainly basal-like subtype, while cluster 1 and cluster 2 are dominated by luminal type and have internal heterogeneity. In addition, the median real-world progression-free survival (rwPFS) of stage 4 patients in group 3 was significantly shorter than that of stage 4 patients in groups 1 and 2. Conclusion: HER2-low breast cancer consists of distinct molecular subtypes. In a preliminary analysis, the basal-like subtype showed worse prognosis in HER2-low breast cancer. These data further emphasize the importance of using RNA expression to fully characterize the clinical characteristics of the relevant subpopulation .
HER2-09: Multiomics Profiling Characterizes Distinct HER2-low Breast Cancer Subgroups in the East Asian Population
This study examined a HER2-low breast cancer cohort (n=441) and additionally HER2-0 (n=114) and HER2-positive (n=181) tumors served as auxiliary cohorts, using multi-omics approaches including genomics, transcriptomics, and proteomics. The results showed that in the HR-negative subgroup, HER2-low breast cancers were composed of more non-basal-like types compared with HER2-0. Furthermore, HR-negative HER2-low breast cancers exhibit significant internal heterogeneity, with basal-like tumors closely resembling HER2-0 and non-basal-like tumors resembling HER2-positive breast cancers. These non-basal-like tumors are mainly divided into HER2-enriched and luminal androgen receptor (LAR). In contrast, in the HR-positive subgroup, the multi-omics data of HER2-low breast cancer and HER2-0 breast cancer were similar, and no obvious internal heterogeneity occurred. Conclusions: Compared with HR-positive disease, HER2-low breast cancers in the HR-negative subgroup are more likely to be molecularly distinct entities from HER2-0 tumors. In addition, HR-negative HER2-low breast cancer also has higher internal heterogeneity.
HER2-12: Genomic and transcriptomic landscape of HER2-low breast cancer
The study detected mutations by DNA next-generation sequencing (NextSeq 592 genome or NovaSeq whole-exome panel) and included 4349 cases of HER2-low, including 3403 HR-positive HER2-low and 946 HR-negative HER2-low. Among HR-negative tumors, compared with TNBC, there were differences in the PIK3CA mutation rate (33.5% vs 16.7%) and the tumor suppressor gene TP53 mutation rate (74% vs 86%). With some exceptions, HER2-low and HER2-0 breast cancers generally share the same genomic signature. In addition, the study also analyzed immune indicators and found that in HR-negative breast cancer, there was no significant difference between HER2-low and TNBC immune indicators (PD-L1, TMB, dMMR). Conclusion: HER2-low breast cancer may not be an independent molecular subtype.
Expert comments
Low HER2 expression was previously classified as HER2-negative breast cancer. However, with its excellent efficacy, new ADC drugs provide a new treatment option for patients with HER2 low-expression breast cancer and bring good news to clinical patients. In recent years, as breakthroughs have been made in the field of HER2 low-expression breast cancer, more and more experts and scholars have paid attention to this patient group with low HER2 expression.
The prognostic value of low HER2 expression is a matter of great concern in clinical practice. Although current research results on the prognostic value of low HER2 expression are inconsistent, more articles currently tend to support that low HER2 expression is associated with better prognosis. In addition, many studies have shown that among traditionally defined HER2-negative tumors, HR-positive breast cancers have a higher proportion of low HER2 expression than HR-negative breast cancers. HR receptor status is an important biological driver of prognosis, and HER2 expression is related to HR expression. Therefore, HR status needs to be corrected in the prognostic analysis of low HER2 expression to avoid confounding factors of HR status.
In addition, there has been controversy as to whether breast cancer with low HER2 expression is an independent molecular subtype due to the lack of sufficient research data. Several posters and abstracts at this SABCS conference studied this issue, and further provided research data for the genetic landscape of low HER2 expression through genome, transcriptome, and other methods. Although the current research conclusions are not exactly the same, more research conclusions tend to believe that HER2 low-expression breast cancer is not an independent molecular subtype. This issue still needs further research. Further clarification of the genetic landscape of HER2 low expression will help to better provide precise treatment for this subtype of HER2 low expression, which is expected to bring further survival benefits.
Expert profile
Yuan Peng Professor
National Cancer Center Chinese Academy of Medical Sciences Cancer Hospital
Chief physician, professor, doctoral supervisor
Chinese Anti-Cancer Association Director
Chinese Anti-Cancer Association International Medical and Exchange Branch Chairman Member
Chinese Anti-Cancer Association Breast Cancer Professional Committee Standing Committee member
Chinese Society of Clinical Oncology Breast Cancer Expert Committee Standing Committee member
Chinese Medical Doctor Association Oncology Branch Breast Cancer Research Group Chairman
Beijing Cancer Prevention and Control Society Chairman
National Natural Science Foundation Review expert
National March 8th Red Flag Bearer
Reference:
[1].2022 SABCS poster HER2-04
[2].2022 SABCS poster HER2-05
[3].2022 SABCS poster HER2-08
[4].2022 SABCS poster HER2-09
[5].2022 SABCS poster HER2-12
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
