Low HER2 Expression Research Articles

HER2 in Gastric Cancer: A Comprehensive Analysis Combining Meta-Analysis and DCE-MRI Radiomics.

Advanced gastric cancer (AGC) is a severe malignant tumor, and overexpression of HER2/ERBB2 may play a crucial role in its development. The purpose of this study is to investigate the overexpression of HER2/ERBB2 in gastric cancer through a meta-analysis and examine its relationship with perfusion parameters using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) technology. We conducted an extensive literature search and collected relevant studies for the meta-analysis. We used a random-effects model and assigned weights using the "inverse variance" method. Additionally, we included 95 AGC patients diagnosed pathologically between April 2018 and October 2021. They all underwent DCE-MRI scans, and the data were subsequently analyzed using the Omni kinetic software. HER2 expression was assessed using immunohistochemistry. The meta-analysis revealed an overall odds ratio (OR) of .21 for HER2/ERBB2 overexpression in gastric cancer, with a 95% confidence interval of [.14, .30]. DCE-MRI results showed a significant association between high HER2 expression and poor tumor differentiation (P < .005). The extracellular volume fraction (Ecv) quantile, mean, relative deviation, median intensity, and difference entropy were significantly higher in the low HER2 expression group compared to the high HER2 expression group. Receiver operating characteristic (ROC) curve analysis demonstrated that the area under the curve (AUC) values of DCE-MRI radiomic parameters with significant differences were close to .7. Overexpression of HER2/ERBB2 in gastric cancer is significantly associated with certain radiomic parameters of DCE-MRI, providing a valuable diagnostic tool for clinical practice. Furthermore, the meta-analysis further confirmed the critical role of HER2/ERBB2 in the development of gastric cancer.

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer.

Breast cancer continues to have a high incidence rate among female malignancies. Despite significant advancements in treatment modalities, the heterogeneous nature of breast cancer and its resistance to various therapeutic approaches pose considerable challenges. Antibody-drug conjugates (ADCs) effectively merge the specificity of antibodies with the cytotoxicity of chemotherapeutic agents, offering a novel strategy for precision treatment of breast cancer. Notably, trastuzumab emtansine (T-DM1) has provided a new therapeutic option for HER2-positive breast cancer patients globally, especially those resistant to conventional treatments. The development of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) has further broadened the applicability of ADCs in breast cancer therapy, presenting new hopes for patients with low HER2 expression and triple-negative breast cancer. However, the application of ADCs presents certain challenges. For instance, their treatment may lead to adverse reactions such as interstitial lung disease, thrombocytopenia, and diarrhea. Moreover, prolonged treatment could result in ADCs resistance, complicating the therapeutic process. Economically, the high costs of ADCs might hinder their accessibility in low-income regions. This article reviews the structure, mechanism of action, and clinical trials of commercially available ADCs for breast cancer treatment, with a focus on the clinical trials of the three drugs, aiming to provide insights for clinical applications and future research.

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody–drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.

Antibody-drug conjugates transform the outcome of individuals with low-HER2-expression advanced breast cancer.

Antibody-drug conjugates (ADCs)-a groundbreaking class of agents for targeted oncological therapies-consist of monoclonal antibodies with strong antigenic specificity coupled with highly active cytotoxic agents (also referred to as "payloads"). Over the past 2 decades, breast cancer research has evolved into a focal point for the research and development of ADCs, leading to several recent landmark publications. These advancements are ushering in a transformative era in breast cancer treatment and redefining conventional classifications by introducing a prospective subtype termed "HER2-low." The latest iterations of ADCs have demonstrated enhanced efficacy in disease management through the optimization of various factors, notably the incorporation of the bystander effect. These conjugates are no longer limited to the oncogenic driver human epidermal growth factor receptor 2 (HER2). Other antigens, including human epidermal growth factor receptor 3 (HER3), trophoblast cell surface antigen 2 (Trop-2), zinc transporter ZIP6 (LIV-1), and folate receptor α (FRα), have recently emerged as intriguing tumor cell surface nondriver gene targets for ADCs, each with one or more specific ADCs that showed encouraging results in the breast cancer field. This article reviews recent advances in the application of ADCs in the treatment of HER2-low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.

Phase 2 study of trastuzumab deruxtecan as neoadjuvant treatment for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).

309 Background: Currently no HER2 directed therapy is available in the perioperative setting for gastric and gastroesophageal junction (GEJ) cancer. Trastuzumab deruxtecan (T-DXd) received regulatory approval based on the encouraging efficacy demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 studies in pretreated patients (pts) with metastatic gastric and GEJ cancer. This multicenter phase 2 study aimed to evaluate the clinical activity and safety of neoadjuvant T-DXd for locally advanced gastric and GEJ cancer. Methods: Eligible pts possessed previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort enrolled pts exhibiting HER2-positivity, defined as IHC 3+ or IHC 2+ with ISH+ by local assessment. An exploratory cohort included patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with serum HER2-ECD exceeded 11.6 ng/ml. Treatment included three cycles of T-DXd administered every 3 weeks, followed by surgery. The primary endpoint was the major pathological response (MPR) rate by central assessment, with an expected rate of 45% and a futility threshold of 20%. The planned sample size in the main cohort was 27 pts with one-sided alpha of 10% and power of 90%, while an additional 10 pts would be enrolled into the exploratory cohort. Pre- and post-treatment samples were subjected to biomarker analyses. Clinical trial identification: NCT05034887. Results: Between November 2021 and November 2022, 27 pts were enrolled into the main cohort from seven Japanese sites. The majority of the pts had IHC3+ (24pts). The primary sites were gastric (16 pts) and GEJ (11 pts). Clinical stages ranged from II/III/IVa: 2/21/4 pts. Of the cohort, 26 pts completed planned 3 courses of T-DXd and one pt discontinued because of toxicity. R0 resection was achieved in 25 pts, with one undergoing R1 resection. The MPR rate as the primary endpoint was 14.8% (80% CI 6.6 % - 27.5 %) which did not surpass the predefined 20%. The pCR rate was 3.7% (95% CI 0.1 % - 19.0 %). There were no new safety signals during T-DXd treatment and during the post-surgery phase. Biomarker analyses remain ongoing. Conclusions: T-DXd monotherapy showed modest single agent activity for locally advanced HER2-positive gastric or GEJ adenocarcinoma in this phase 2 study. An additional cohort combining perioperative T-DXd with capecitabine and durvalumab is planned, to assess whether treatment efficacy and outcomes can be enhanced. Clinical trial information: NCT05034887 .

Novel quantitative immunohistochemistry method using histone H3, family 3B as the internal reference standard for measuring human epidermal growth factor receptor 2 expression in breast cancer.

Immunohistochemistry (IHC) is an essential technique in surgical and clinical pathology for detecting diagnostic, prognostic, and predictive biomarkers for personalized cancer therapy. However, the lack of standardization and reference controls results in poor reproducibility, and a reliable tool for IHC quantification is urgently required. The objective of this study was to describe a novel approach in which H3F3B (histone H3, family 3B) can be used as an internal reference standard to quantify protein expression levels using IHC. The authors enrolled 89 patients who had human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). They used a novel IHC-based assay to measure protein expression using H3F3B as the internal reference standard. H3F3B was uniformly expressed at the protein level in all tumor regions in cancer tissues. HER2 expression levels were measured with the H-score using HALO software. Kaplan-Meier analysis indicated that, among patients who had HER2-positive BC in The Cancer Genome Atlas data set and the authors' data set, the subgroup with low HER2 expression had a significantly better prognosis than the subgroup with high HER2 expression. Furthermore, the authors observed that HER2 expression levels were precisely evaluated using the proposed method, which can classify patients who are at higher risk of HER2-positive BC to receive trastuzumab-based adjuvant therapy. Dual-color IHC with H3F3B is an excellent tool for internal and external quality control of HER2 expression assays. The proposed IHC-based quantification method accurately assesses HER2 expression levels and provides insights for predicting clinical prognosis in patients with HER2-positive BC who receive trastuzumab-based adjuvant therapy.

New insights into HER2-low breast cancer brain metastasis: A retrospective analysis

BackgroundA considerable number of patients with breast cancer will suffer from brain metastasis in the advanced setting. The HER2 status serves as a significant prognostic factor and the reference of applying treatment for patients with breast cancer brain metastasis (BCBM). MethodsBetween January 2010 and July 2021, patients with BCBM who had available HER2 status were identified. The patients with HER2 1+ in immunohistochemistry (IHC) or IHC 2+ and fluorescence in situ hybridization (FISH) negative were categorized as HER2-low. Comparisons were conducted between the HER2-low and HER2-zero population. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. Survival outcomes were assessed using Kaplan-Meier curves with log-rank test and Cox proportional hazards model. ResultsIn this study, we analyzed 71 patients with the HER2-low breast cancer subtype and 64 patients with the HER2-zero subtype. Despite the limited sample size, our findings revealed a significantly better OS for patients with HER2-low cancer compared to their HER2-zero counterparts (26 m vs 20 m, p = 0.0017). This trend was particularly notable in the HR-negative group (26 m vs 13 m, p = 0.0078), whereas no significant difference was observed among the HR-positive patients. Furthermore, Cox regression analysis revealed that the HER2-low status was an independent prognostic factor for better survival in the HR-negative patients (p = 0.046 in multivariate analysis). ConclusionsPatients diagnosed with HER2-low BCBM exhibited a more favorable prognosis than those with HER2-zero BCBM, particularly within the HR-negative subgroup. The low expression of HER2 is supposed to be linked to the prolonged survival of BCBM patients.

Loss of Human Epidermal Receptor 2 Expression in Formalin-Fixed Paraffin-Embedded Breast Cancer Samples and the Rescuing Effect of Enhanced Antigen Retrieval and Signal Amplification.

As an important therapeutic target in breast cancer, HER2 expression assessed by immunohistochemistry plays a critical role in breast cancer treatment. Recent advances in HER2 antibody-drug conjugate therapy have enabled patients with HER2-low expression breast cancer to benefit from the drugs. However, it is not known whether the HER2-low expression in breast cancer FFPE blocks would be lost as storage time increased. In this study, we aimed to assess the loss of HER2 antigenicity in stored FFPE blocks of breast cancer and the rescue effect of modifying the protocol of antigen staining. We selected archived HER2-low breast cancer FFPE blocks with stored time ranging from 1 year to over 15 years and re-detected the expression of HER2. Our study showed that HER2 antigenicity loss increased with storage time and could cause false negativity in HER2-low detection. Moreover, we showed that by either increasing the antigen retrieval time or applying the tyramide signal amplification (TSA) kit, the HER2 signal can be rescued and detected in about half of the cases with HER2-low loss without causing false positivity.

Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy

ObjectiveThe present study aimed to evaluate the clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy (NAC). MethodsPatients with HER2 negative breast cancer receiving NAC from January 2017 to December 2020 were enrolled in this study. The clinicopathological characteristics, response to NAC, evolution of HER2 and prognostic value were retrospectively analyzed. Results410 patients were included. The proportion of HR positive disease in HER2-low cases was higher than in HER2-zero population (75.8 % vs. 65.8 %, P = 0.040). No statistical significant difference in pCR rate was observed between HER2-low and HER2-zero patients (33.8 % vs. 39.3 %, P = 0.290) when pCR was defined as ypTis/0ypN0. Exploratory analysis revealed that the pCR rate of HER2-low cases was significantly lower than HER2-zero patients in the entire population (19.8 % vs. 33.3 %, P = 0.004) and HR positive population (12.6 % vs. 29.9 %, P = 0.001) when pCR was defined as ypT0ypN0. The evolution rate of HER2 expression after NAC was 31.0 % in HER2-zero patients and 24.7 % in HER2-low patients. Compared with patients with HR positive disease, patients with TNBC had higher evolution rate of HER2 expression after NAC (37.7 % vs. 23.6 %). Significant association was observed between HER2 evolution with histology type and Ki-67 index in HER2-zero patients and with lymph node involvement, HR status and Ki-67 index in HER2-low patients. Prognostic impact of HER2 evolution was not observed. ConclusionsHR positive and HR negative HER2-low breast cancer exhibit different clinicopathological features, response to NAC and HER2 evolution after treatment.

The use of transcriptomic data in developing biomarkers in breast cancer

AbstractHER2 and hormone receptors are biomarkers for selecting breast cancer therapy and predicting outcomes. In the era of antibody‐drug conjugates (ADC), a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Data from 57 breast cancers was used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with IHC and FISH results. There was a significant overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression‐free survival (PFS). Similarly, the ESR1 RNA accurately reflected estrogen receptor (ER) status. Patients with high AR mRNA had better PFS (p = 0.05). Patients expressing high ER and AR levels had better PFS than those expressing low ESR1 and AR (p = 0.03). These findings suggest that RNA analysis can be an alternative to IHC and FISH and provides continuous data that can better determine cut‐off points for predicting response to ADC.

HER2 low expression breast cancer subtyping and their correlation with prognosis and immune landscape based on the histone modification related genes

Human epidermal growth factor receptor 2 (HER2) plays an important role in diagnosis and treatment of breast cancer (BRCA). The histone modification has been found to be related to the progression of cancer. This study aimed to probe the low HER2 expression BRCA heterogeneity by histone modification genes. The BRCA data and cell lines were collected from The Cancer Genome Atlas database. Weighted gene co-expression network analysis and non-negative matrix factorization clustering were jointly applied to obtain BRCA clusters. The expression of hub histone modification gene was detected using western blot assay. The gene ontology term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal functional information. The overall survival analysis was performed using survival and survminer packages, and the immune landscape was mainly analyzed using CIBERSORT software. Totally 43 histone modification genes correlated with survival of BRCA patients with HER2 low expression were screened. Based on these 43 histone modification genes, the BRCA samples were classified into cluster1, cluster2 and cluster3. Histone modification gene NFKBIZ exhibited high expression, while RAD51 demonstrated low expression in low HER2 expression BRCA cell. Cluster1 exhibited the best prognosis, while cluster3 had the worse outcomes. Tumor mutational burden (TMB) was remarkably increased in cluster3 group compared to cluster1 and cluster2. Moreover, the relative proportion of 16 immune cell infiltration and 8 immune checkpoint expression were remarkably differential among cluster1, cluster2 and cluster3, and the drug sensitivity exhibited difference among cluster1, cluster2 and cluster3 in BRCA patients with low HER2 expression. This study identified three HER2 low expression BRCA clusters with different characteristics based on histone modification genes. The TMB, immune cell infiltration, immune checkpoints and drug sensitivity were different among the three clusters.

Abstract B037: A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors

Abstract Background: DS-8201a (Trastuzumab (T) deruxtecan(D)) is an antibody-drug conjugate consisting of the HER2-targeting antibody T covalently bound via a lysosomal protease-cleavable linker to the novel topoisomerase 1 (Top1) inhibitor D with activity in tumors with low HER2 IHC scores of 1+ or 2+. The primary purpose of this study is to investigate the pharmacodynamic (PD) mechanisms underlying the activity of DS-8201a in advanced solid tumors, including those with low HER2 expression. Methods: This multicenter pilot study enrolled patients (pts) with advanced solid tumors expressing HER2 as defined by CLIA-certified labs i.e., a HER2 IHC score of 1+ or greater or ERBB2 amplifications (amp) or mutations (mut). DS-8201a was administered at 5.4 mg/kg intravenously once every 3 weeks, in 21-day cycles (C). PD biomarkers of Top1 target engagement by D payload, consequent DNA damage and repair (DDR), and immune microenvironment changes were analyzed in mandatory tumor biopsies collected at baseline, post-dose C1 and pre-dose C3. Blood samples for biomarker analyses were taken at several time points. Safety and overall response were also evaluated. Results: As of June 16, 2023, a total of 48 pts have been enrolled with diverse HER2 status distribution: 11 IHC 1+, 20 IHC 2+, 6 IHC 3+, 7 ERBB2 amp, 3 ERBB2 mut, and 1 with both IHC 1+ and ERBB2 amp. Median number of prior lines of systemic therapy was 3.5 (range 1-13) and 11 pts received prior Top1 inhibitor therapy. Grade (Gr) 3 or higher treatment-related adverse events (trAEs) were reported in 12 pts (25%). The most common Gr3/4 trAEs were myelosuppression. There were 7 pts (15%) with Gr2 and 1 pt (2%) with Gr3 pneumonitis. One pt with Gr2 pneumonitis was retreated after trAE resolution with steroid therapy and continued for another 9 Cs prior to progression. Of the evaluable patients, 1 pt (2%) had complete response (cervical, HER2 2+), 6 pts (13%) had confirmed partial response (PR) (uterine, 2+; ovarian, 2+; bladder, ERBB2 mut; uterine carcinosarcoma, 2+; 2 head and neck cancers, 1+ and 2+), 4 pts (8%) had unconfirmed PR (breast, 1+; extramammary Paget’s disease, 2+; pancreas, ERBB2 amp; uterine, 2+), and 17 pts (35%) had stable disease as their best response. Median progression free survival was 3.4 months (range 0.5-17.2). Top1 target engagement and induction of nuclear biomarkers of DDR (RAD51, pNBS1) were observed in more than half of the paired biopsies tested to date. DDR biomarker response was associated with both HER2 1+ and 2+ status. PD analyses are currently ongoing. Conclusion: DS-8201a demonstrated responses in various tumor types outside of breast cancer with HER2 low/ERBB2 alteration status. Preliminary PD data demonstrated expected Top1 target engagement and DDR induction, the extent of which is possibly independent of the degree of HER 2 staining. Analyses are currently underway to further define the effect of DS-8201a in advanced solid tumors. Citation Format: Sarah J Shin, Geraldine O'Sullivan-Coyne, Elizabeth K Lee, Arjun Mittra, Cora N Sternberg, Mary Jane Ong, Deborah Wilsker, Katherine Ferry-Galow, Jared Foster, Lamin Juwara, Naoko Takebe, Cheryl A Pickett, Ralph Parchment, James Doroshow, Alice Chen. A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B037.

HER2 amplification in cases with low HER2 expression by immunohistochemistry (IHC): A Single Institutional Experience

Abstract Introduction/Objective HER2 testing in invasive breast carcinoma (IBC) is the standard of care to determine patient eligibility for HER2 directed therapy with trasuzumab. Initial testing of tissue by HER2 immunohistochemistry (IHC) can be positive, negative, or equivocal. In equivocal cases as well as negative cases in our institution HER2 FISH is also performed. According to ASCO/CAP guidelines a subset of equivocal and negative IHC cases are considered HER2 positive if they meet criteria for increased HER2/CEP17 ratio and HER2 copy number by FISH, allowing more patients to be treated with HER2 directed therapies. HER2 grouping per ASCO is as follows; Group 1: HER2 copy number ≥4 signals/cell, Group 2: &amp;lt;4.0 signals/cell, Group 3: ≥6 signals/cell, Group 4: HER2 copy number ≥4 and &amp;lt;6 signals/cell, Group 5: HER2 copy number &amp;lt;4 signals/cell Methods/Case Report All cases of IBC resection with HER2 IHC and FISH results from Jan 2018-Dec 2021 were included in this study. All cases positive for HER2 by IHC alone (3+ staining) were excluded. The ASCO/CAP 2018 guidelines for HER2 testing in breast cancer were used to evaluate HER2 positivity by FISH and the relation to IHC scores Results (if a Case Study enter NA) A total of 2630 IBC cases with both HER2 IHC and FISH testing were included. Of these, 131 (5.0%) were in FISH group 1, 17 (0.7%) in group 2, 11 (0.4%) in group 3, 161 (6.1%) in group 4, and 2310 (87.8%) in group 5. A total of 142 (5.4%) cases that were HER2 equivocal or negative by IHC were HER2 positive by FISH. Specifically, 0.3% of cases with an IHC score of 0, 1.4% with a score of 1+, and 14.6% of cases with a score of 2+ were positive by FISH. Of the 14.6% IHC 2+ cases that were FISH positive 13.3% were in FISH group 1 (115 cases) and 1.3% (11 cases) in FISH group 3. Of FISH positive cases 1.4% had an IHC score of 0, 9.9% had an IHC score of 1 and 88.7% had a score of 2 Conclusion At our institution 14.6% of IBC with equivocal HER2 staining on IHC, 1.4% of cases with negative (1+) staining and 0.3% of cases with negative (0) were HER2 FISH positive. Since HER2 FISH is not reflexively performed on cases HER2 negative by IHC, this additional 1.7% will qualify for HER2 targeted therapy Interpretation of low HER2 expression by IHC by traditional IHC assay may miss a small percentage of cases eligible for HER2 directed therapy. Accurate interpretation of HER2 low by IHC is critical as recent clinical trials have shown that low HER2 expression with IHC scores of 1+ or 2+ without gene amplification by FISH could benefit from Trastuzumab Deruxtecan

Impact of HER2 assay sensitivity on the ability to detect tumors with low to ultra-low HER2 expression: A TMA study on more than 10,000 tumors from more than 100 tumor entities

Abstract Introduction/Objective Detection of low level HER2 expression is important for therapy with new HER2 inhibitors in breast cancer. HER2 assays with high sensitivity are therefore needed. These may identify low level HER2 expression in various types other than breast cancer. Methods/Case Report A tissue microarray containing &amp;gt;10,000 tissue samples from more than 100 different tumor types and subtypes was analyzed for immunohistochemical expression of HER2 using different immunohistochemistry protocols and anti-HER2 antibodies, including the HercepTest and laboratory developed tests designed for high sensitivity. HER2 IHC evaluation included the recording of HER2 low (1+), ultralow (any staining, less than 1+), and 0 (negative). Results (if a Case Study enter NA) Irrespective of the assay sensitivity all assays showed the expected/tolerable association with HER2 FISH data in 308 breast cancers. In non-breast cancers, the use of different assays yielded variable rates of low or ultra-low HER2 expression in different tumor entities. For example, low (1+) and ultra-low (+) expression was observed in 7-24% (1+) and 11-28% (+) of serous ovarian cancers, 6.2-24% (1+) and 3.4-19% (+) of endometrioid endometrial cancers, 5.5-14% (1+) and 7.7-13% (+) of intestinal gastric cancers, 1.8-9.2% (1+) and 4.5- 11% (+) of ductal adenocarcinomas of the pancreas, 19-33% (1+) and 5.5-11% (+) of muscle invasive urinary bladder cancers, 2.9-16% (1+) and 4.3-12% (+) of adenocarcinomas of the colon. Conclusion Low level HER2 expression occurs commonly in many cancer types. The rate of identifiable tumors with HER2 low or HER2 ultra-low expression varies depending on assay parameters that can easily be modified. Irrespective of assay sensitivity, our data identify various tumor entities with significant fractions of “HER2-low” cases that might benefit from therapy with new antibody drug conjugates.

PATH-59. SYSTEMATIC CHARACTERIZATION OF ANTIBODY-DRUG CONJUGATE TARGETS IN CENTRAL NERVOUS SYSTEM TUMORS

Abstract BACKGROUND Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid cancers, including those expressing ERBB2/HER2, TACSTD2/TROP2, NECTIN4, folate receptor 1 (FOLR1), and tissue factor (CD142/TF). Recently, a next-generation ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level ADC target expression may be sufficient for treatment responsiveness, and CNS tumors may be responsive to next-generation ADC. However, ADC target expression is poorly characterized in most CNS tumors. METHODS To systematically characterize ADC target expression in CNS tumors, we analyzed publicly available RNA-sequencing and proteomic data from the Children’s Brain Tumor Network (n=188 tumors) and GEO RNA-expression datasets (n=356 tumors) to evaluate expression of 14 potential ADC targets that are FDA-approved or under clinical investigation in solid cancers. We also used immunohistochemistry to score the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma (GBM), oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (n=575 total tumors). RESULTS Multi-modal pan-CNS analysis showed consistent subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas (n=44) strongly expressed HER2 (36/44; 81% of cases by IHC), while meningiomas weakly-moderately expressed HER2 in most tumors (201/234; 86%). ACP (n=15) and PCP (n=3) strongly expressed B7-H3 (100% of cases), with TROP2 and HER2 expression in whorled ACP epithelium (100% of cases). AT/RT strongly expressed CLDN6 (8/9; 89%). GBM showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be fruitful.

The Impact of HER2-Low Expression on Oncologic Outcomes in Hormone Receptor-Positive Breast Cancer.

Breast cancer is a prevalent malignancy with increasing incidence, particularly in Asian countries. Classification based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status is pivotal in determining treatment. Recent advances have challenged the traditional dichotomy in HER2 classification, prompting investigation into the HER2-low subtype's characteristics and outcomes. This retrospective study analyzed 10,186 non-metastatic hormone receptor (HR)-positive, HER2-negative breast cancer cases treated from 2008 to 2020. Data encompassed clinical, pathological, and treatment information. Oncologic outcomes included disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS). In total, 56.5% were HER2-low cases. Differences in patient characteristics were noted, with more BRCA1/2 mutations and higher mastectomy rates in the HER2-low group (p = 0.002, p < 0.001, respectively). Fewer received adjuvant chemotherapy or radiation therapy, and fewer histologic and nuclear grade 1 tumors were identified (all p < 0.001). With a median follow-up of 64 months (range: 13-174), HER2-low cases exhibited better DFS, OS, and BCSS than HER2-0 cases (p = 0.012, p = 0.013, and p = 0.013, respectively). Notably, the prognosis differed between premenopausal and postmenopausal subgroups, with BCSS benefitting premenopausal patients (p = 0.047) and DFS and OS benefitting postmenopausal patients in the HER2-low group (p = 0.004, p = 0.009, respectively). Multivariate analysis confirmed HER2 status as an independent predictor of these outcomes (p = 0.010, p = 0.008, and p = 0.014, respectively). This extensive single-center study elucidates the favorable prognosis associated with HER2-low status in HR-positive breast cancer. However, this effect differs among premenopausal and postmenopausal patients, necessitating further research into the underlying tumor biology.

Generation of a Novel SORT1×HER2 Bispecific Antibody-Drug Conjugate Targeting HER2-Low-Expression Tumor.

Human epidermal growth factor receptor 2 (HER2) is considered an ideal antibody-drug conjugate (ADC) target because the gene is overexpressed in many tumors compared to normal tissues. Multiple anti-HER2 ADCs conjugated with different toxic payloads bring benefits to patients with high HER2 expression. However, HER2-targeted ADC technology needs further optimization to improve its effect for the treatment of patients with low HER2 expression. We hypothesized that bispecific antibody-drug conjugate (bsADC) targeting HER2 and Sortilin-1 (SORT1) would overcome this limitation. SORT1 is a suitable target for pairing with HER2 to generate a bispecific antibody (BsAb) since the gene is co-expressed with HER2 in tumors and possesses rapid internalization. We developed a BsAb (bsSORT1×HER2) that exhibited strong binding and internalization activity on HER2-low-expression tumor cells and facilitated higher HER2 degradation. The bsSORT1×HER2 was further conjugated with DXd to generate a bsADC (bsSORT1×HER2-DXd) that showed strong cytotoxicity on HER2-low-expression tumor cells and antitumor efficacy in an MDA-MB-231 xenograft mice model. These results demonstrated that employment of a SORT1×HER2-targeted bsADC may be promising to improve the antitumor efficacy of HER2-targeted ADC for the treatment of tumors with low HER2 expression.

MO58-2 Differences in treatment response to CDK4/6 inhibitors and endocrine therapy between HER2-negative and HER2-low expression groups

MO58-2 Differences in treatment response to CDK4/6 inhibitors and endocrine therapy between HER2-negative and HER2-low expression groups

Trastuzumab deruxtecan in the treatment of patients with advanced breast cancer with HER2-low expression: Recent studies review

The review gives the definition of HER2-low status, shows its clinical and biological role in patients with advanced breast cancer. A unique mechanism of action of trastuzumab deruxtecan and potential for its use in advanced breast cancer with HER2-low expression are described. The key results of the open multicenter phase III DESTINY-Breast04 (DB-04) trial including safety data are presented. Results on the effectiveness of the drug in patients with markers of hormone resistance first presented in 2023 and the place of trastuzumab deruxtecan in the updated ESMO 2023 algorithm of hormone-positive breast cancer treatment are considered.

Prognostic Significance of HER2 Expression in Patients with Bacillus Calmette-Guérin–exposed Non–muscle-invasive Bladder Cancer

BackgroundGuidelines recommend intravesical instillation of bacillus Calmette-Guérin (BCG) as the first-choice treatment for intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC). However, there is no therapeutic biomarker for predicting BCG efficacy, especially in high-risk cases with high failure rates. HER2 expression is considered a prognostic factor for bladder cancer. ObjectiveTo elucidate the predictive value and significance of HER2 expression in patients with BCG-exposed NMIBC. Design, setting, and participantsA total of 454 patients with NMIBC were included. All patients started BCG intravesical instillation (1.2 × 108 CFU, strain D2PB302) 2–6 wk after transurethral resection of bladder tumor and received 19 treatments over a period of 1 yr. HER2 immunohistochemistry (IHC) results available for 314 patients. Outcome measurements and statistical analysisThe outcomes investigated were recurrence-free survival (RFS) and progression-free survival (PFS). Outcome relationships were explored using multivariable Cox regression and log-rank analysis. Results and limitationsIn the IHC population, 35.7% of patients had HER2 overexpression (IHC score 2/3+). This group had a poor 5-yr RFS rate of 16.5%, in comparison to 68.0% in the group with low HER2 expression (p < 0.001). Patients with high-risk NMIBC and HER2 overexpression had the highest risk of BCG treatment failure, with 5-yr RFS and PFS rates of 19.0% and 58.2%, respectively. Conversely, HER2-negative (IHC score 0) patients with high-risk NMIBC experienced a long-term BCG benefit, with 5-yr RFS and PFS rates of 80.8% and 92.1%, respectively. Limitations include the retrospective study design and the limited details regarding BCG use. ConclusionsHER2 was an independent predictor of poor BCG efficacy in NMIBC. Patients with high-risk NMIBC and HER2 overexpression had the highest risk of disease recurrence and progression after exposure to BCG. Anti-HER2 targeted therapies could be considered for these patients. Patient summaryMeasurement of blood levels of the protein HER2 can be used to predict outcomes after BCG (bacillus Calmette-Guérin) bladder therapy for patients with intermediate- or high-risk non–muscle-invasive bladder cancer. Measurement results for HER2 may help in guiding personalized treatment for these patients.