HER2-positive Cases Research Articles

Investigation of IDO1 and TDO2 expression in breast tumors by immunohistochemistry and real-time polymerase chain reaction methods

Although diagnostic and therapeutic advances have been made in the treatment of breast cancer, the challenge of effectively controlling tumor progression persists. The objective of this study was to determine the relationship between IDO1 and TDO2 expression in breast cancer by immunohistochemistry and real-time polymerase chain reaction, hormone receptor status, Ki67 proliferation index, molecular classification, metastasis, and to investigate whether IDO1 and TDO2 expression can be used in combination with targeted therapy or as a marker to increase treatment efficacy in selected cases. The study included 74 cases of breast cancer and 14 cases of normal breast tissue as controls. All cases were analyzed for IDO1 and TDO2 by both immunohistochemistry and real-time polymerase chain reaction. The immunohistochemical analysis revealed that IDO1 immunoreactivity was significantly higher in tumor tissue compared to normal breast tissue. A statistically significant correlation was observed between IDO1 immunoreactivity and histologic subtypes. Furthermore, IDO1 gene expression was correlated with IDO1 immunoreactivity. TDO2 immune reactivity did not differ between tumor and non-tumor tissues and no correlation was found between histological subtypes. There was no correlation between TDO2 immunoreactivity and gene expression. The significant increase in IDO1 levels in tumor tissue and high positivity in age, HER2 positive and triple negative cases compared to other cases suggest that IDO1 inhibitors may be suitable for the target patient group in treatment selection.

Expression of human epidermal growth factor receptor 2 (HER2) in colorectal cancer and its correlation with clinicopathological characteristic among Jordanian patients

Abstract Introduction/Objective Human epidermal growth factor receptor 2 (HER2/neu) is a well-established therapeutic target in breast and gastric cancers. Currently HER2 expression is being considered in other solid tumors including colorectal cancer (CRC). We aimed to investigate HER2 expression in CRC among Jordanians and its association with clinicopathological variables. Methods/Case Report Formalin-fixed, paraffin-embedded tissue blocks of 69 CRC cases were retrieved with their clinicopathological data. Tissue microarray (TMA) were constructed and immunostained using anti-HER2/neu 4B5 monoclonal antibody (Ventana, Tucson, AZ). HER2 scoring was performed by two experienced pathologists using the HERACLES criteria (HER2 positivity: cases of (3+) in ≥10% of cells and FISH-positive equivocal cases). Fisher’s exact/Chi-square test was used to investigate the association between HER2 s and clinicopathological data such as age, gender, histological differentiation, node and metastasis (NM) stage, and tumor site. Survival analysis was evaluated using Kaplan–Meier curves. Results (if a Case Study enter NA) Any degree (score) of HER2/neu expression was seen in 43.5 % of the cases. In 25 (36.2%), 4 (5.8%) and 1 (1.5%) the HER2 score was 1+, 2+ and 3+ respectively. The rest of the cases, 39 (56.5%) were scored as 0. Two of the four cases with a score (2+) required ISH testing to confirm amplification which was not performed. No significant association was found between HER2/neu expression and clinicopathological parameters or with survival. However, survival analysis showed that combined 2+/ 3+ group tend to have worse overall (OS) and event -free survival than the (0/1+) group. Conclusion The prevalence of HER2 overexpression in CRC is low among Jordanian patients, with only 1.5% of the study sample exhibiting definite HER2 overexpression. This rate is lower than the 3-5% rate reported in general, however the small sample size and lack of FISH confirmation might have contributed to this low rate. There was a trend towards worse OS and EFS in HER2 positive cases

Immunohistochemical Expression of ROS1 in invasive ductal carcinoma of breast in association with hormonal receptor status and Her2Neu expression

Objective: To determine the frequency of immunohistochemical expression of ROS1 in invasive ductal carcinoma of the breast in relation to hormonal receptor status and HER2 expression. Study Design and Setting: Descriptive cross-sectional study. Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi from May 2022 to Dec 2022. Methodology: This study was conducted on a sample size comprising 137 patients diagnosed with invasive breast carcinoma (ductal carcinoma) on histopathological biopsy specimen. Immunohistochemistry was performed using ROS1, estrogen receptor, progesterone receptor and HER2 antibodies on patients’ tissue samples. Results were interpreted by two independent histopathologists. Finally data was analyzed using SPSS version 25. Results: The mean age of sample population was 50.85 ± 12.17 years. 131 patients were women and 6 were men. ROS1 was positive in 54 cases. ROS1 shows weak staining in 41 cases and moderate to strong staining in 13 cases. ER and PR showed no significant statistical correlation with ROS1 expression. HER2 was positive in 37 cases, equivocal in 11 cases and negative in 89 cases. A significant statistical correlation was seen between ROS1 and HER2 as 23 of HER2 positive cases showed ROS1 expression (p=<0.001). Conclusion: Significant number of ROS1 expressing cases in invasive breast carcinoma can be more revealing in the understanding of pathogenesis of breast carcinoma. In addition, it can also lead to use of certain recent tyrosine kinase inhibitors for treatment of this most common carcinoma in females.

Performance of a HER2 testing algorithm tailored for urothelial bladder cancer: A Bi-centre study

AimsThis study aimed to develop an AI algorithm for automated HER2 scoring in urothelial bladder cancer (UBCa) and assess the interobserver agreement using both manual and AI-assisted methods based on breast cancer criteria. Methods and ResultsWe utilized 330 slides from two institutions for initial AI development and selected 200 slides for the ring study, involving six pathologists (3 senior, 3 junior). Our AI algorithm achieved high accuracy in two independent tests, with accuracies of 0.94 and 0.92. In the ring study, the AI-assisted method improved both accuracy (0.66 vs 0.94) and consistency (kappa=0.48; 95 % CI, 0.443–0.526 vs kappa=0.87; 95 % CI, 0.852–0.885) compared to manual scoring, especially in HER2-low cases (F1-scores: 0.63 vs 0.92). Additionally, in 62.3 % of heterogeneous HER2-positive cases, the interpretation accuracy significantly improved (0.49 vs 0.93). Pathologists, particularly junior ones, experienced enhanced accuracy and consistency with AI assistance. ConclusionsThis is the first study to provide a quantification algorithm for HER2 scoring in UBCa to assist pathologists in diagnosis. The ring study demonstrated that HER2 scoring based on breast cancer criteria can be effectively applied to UBCa. Furthermore, AI assistance significantly improves the accuracy and consistency of interpretations among pathologists with varying levels of experience, even in heterogeneous cases.

Personalized treatment approach for HER2-positive metastatic breast cancer.

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

Characterization of HER2-Low Breast Tumors among a Cohort of Colombian Women.

HER2-low tumors have shown promise in response to antibody-drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group's clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes (ERBB2, GRB7 and MIEN1), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer.

Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma

ObjectiveWhile human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma—especially in the p53 aberrant type— conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. MethodsImmunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. ResultsOf the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183–5.971, p = 0.008) as an independent prognostic factor. ConclusionsThis study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

Characteristics of sphingomyelin metabolism in the MCF7 and BT474 radiotherapy‑resistant HER2‑positive breast cancer cell lines.

Breast cancer is the most common cancer globally in terms of incidence. This cancer is classified into subtypes based on histological or immunological characteristics. HER2-positive cases account for 15-25% of breast cancer cases, and one of the first events in breast carcinogenesis is HER2 upregulation. Furthermore, HER2 expression increases the detection rate of metastatic or recurrent breast cancers by 50-80%. The epidermal growth factor receptor family includes HER2, which is a transmembrane receptor protein. In our previous case report, patients who were resistant to anti-HER2 monoclonal antibody therapy, chemotherapy and radiotherapy had higher concentrations of phospholipid metabolites such as phosphatidylcholine and sphingomyelin (SM), which was associated with cancer recurrence progression. To better understand the relationship between radiotherapy resistance and SM expression, breast cancer cell lines with and without HER2 expression (MCF7 and BT474) after exposure to ionizing radiation (IR) were examined. In the cell culture supernatant, similar levels of SM in MCF7 cells were identified after 1-4 Gy exposure. However, SM levels in BT474 cells were upregulated compared with those of in the control group. Intracellular SM levels were upregulated in BT474 cells exposed to 1 and 4 Gy compared with the non-irradiated control group. Furthermore, significantly increased mRNA expression levels of sphingomyelin synthase 2 (SGMS2) in BT474 cells exposed to IR were observed compared with those in nonirradiated cells; however, the SGMS2 levels in MCF7 cells did not differ significantly among the 0, 2 and 4 Gy groups. These findings suggested that a higher dose of IR induced the secretion of SM and its associated gene expression in HER2-positive breast cancer cells.

Breast Cancer Patient's Outcomes after Neoadjuvant Chemotherapy and Surgery at 5 and 10 Years for Stage II-III Disease.

Introduction: Neoadjuvant chemotherapy in breast cancer offers the possibility to facilitate breast and axillary surgery; it is a test of chemosensibility in vivo with significant prognostic value and may be used to tailor adjuvant treatment according to the response. Material and Methods: A retrospective single-institution cohort of 482 stage II and III breast cancer patients treated with neoadjuvant chemotherapy based on anthracycline and taxans, plus antiHEr2 in Her2-positive cases, was studied. Survival was calculated at 5 and 10 years. Kaplan-Meier curves with a log-rank test were calculated for differences according to age, BRCA status, menopausal status, TNM, pathological and molecular surrogate subtype, 20% TIL cut-off, surgical procedure, response to chemotherapy and the presence of vascular invasion. Results: The pCR rate was 25.3% and was greater in HER2 (51.3%) and TNBC (31.7%) and in BRCA carriers (41.9%). The factors independently related to patient survival were pathology and molecular surrogate subtype, type of surgery, response to NACT and vascular invasion. BRCA status was a protective prognostic factor without reaching statistical significance, with an HR 0.5 (95%CI 0.1-1.4). Mastectomy presented a double risk of distant recurrence compared to breast-conservative surgery (BCS), supporting BCS as a safe option after NACT. After a mean follow-up of 126 (SD 43) months, luminal tumors presented a substantial difference in survival rates calculated at 5 or 10 years (81.2% compared to 74.7%), whereas that for TNBC was 75.3 and 73.5, respectively. The greatest difference was seen according to the response in patients with pCR, who exhibited a 10 years DDFS of 95.5% vs. 72.4% for those patients without pCR, p < 0001. This difference was especially meaningful in TNBC: the 10 years DDFS according to an RCB of 0 to 3 was 100%, 80.6%, 69% and 49.2%, respectively, p < 0001. Patients with a particularly poor prognosis were those with lobular carcinomas, with a 10 years DDFS of 42.9% vs. 79.7% for ductal carcinomas, p = 0.001, and patients with vascular invasion at the surgical specimen, with a 10 years DDFS of 59.2% vs. 83.6% for those patients without vascular invasion, p < 0.001. Remarkably, BRCA carriers presented a longer survival, with an estimated 10 years DDFS of 89.6% vs. 77.2% for non-carriers, p = 0.054. Conclusions: Long-term outcomes after neoadjuvant chemotherapy can help patients and clinicians make well-informed decisions.

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer.

Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

Landscape of HER2-low breast cancer: Insights from a six-year study on incidence and clinicopathological characteristics.

e13148 Background: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+ or 2+ in immunohistochemistry (IHC) and the absence of the ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2 breast cancer to novel anti-HER2 antibody-drug conjugates, rising interest in the HER2-low subtype. To date, data on characteristics of HER2-low breast cancer subtype is limited. Herein, we describe the clinicopathological characteristics of HER2-low breast cancer subtype compared HER2-zero/negative breast cancer. Methods: Real-world data from the Anatomic Pathology Division of Hotel Dieu de France, spanning 2017-2022, was retrospectively collected. Patients with HER2-IHC 3+ and HER2-IHC 2+ with ISH-amplified (HER2-positive) were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Patients were then categorized based on their hormone receptor (HR) status. Clinicopathological characteristics between the groups were compared using a Chi-Square and Mann–Whitney U tests. Results: Out of 1195 patients, we observed 341 (28.5%) HER2-low breast cancers cases. HER2-positive breast cancer cases (n=178; 14.9%) were subsequently excluded. There was no significant difference in age and sex between the HER2-low and the HER2-zero group (p=0.3 and 0.8, respectively). HER2-low breast cancer was associated with positive estrogen receptor (ER) status and positive progesterone receptor (PR) status (p&lt;0.001 and p=0.01, respectively). Ductal adenocarcinomas were more frequently observed in the HER2-low group, whereas lobular and metaplastic adenocarcinomas were especially prevalent in the HER2-zero group (all p&lt;0.001). When stratified by HR status, 87.4% of patients had HR-positive status and 12.6% were HR-negative. Furthermore, the occurrence rate of tumors with a low Ki-67 labeling index was comparable between the two groups (p=0.9). However, among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (p = 0.04; Table). Conclusions: In conclusion, this study showed that HER2-low is a distinct from HER2-zero and is frequently present among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Our findings suggest that, within HR-negative breast cancer, breast cancer with low HER2 expression exhibits a less aggressive profile when compared to HER2-zero tumors. [Table: see text]

Population based assessment of HER-2 and PD-L1 positivity in gastric and gastroesophageal junction adenocarcinomas in a Canadian population.

e16038 Background: Current standard of care for advanced gastric and gastroesophageal cancers combines systemic chemotherapy with either human epidermal growth factor receptor 2 (HER-2) or programmed death ligand 1 (PD-L1) targeting therapy. New data is emerging that for patients whose tumours are positive for both HER-2 overexpression and have a PD-L1 combined positive score (CPS) &gt;1%, combining all three treatment modalities results in superior outcomes. There is limited international data, and no Canadian data, exploring the frequency of patients who have tumours that are both HER-2 and PD-L1 positive who will be eligible for this novel treatment approach. Objective: To determine the proportion of patients in Nova Scotia with HER-2 positive gastric and GEJ adenocarcinomas who have a PD-L1 CPS score above established clinical thresholds. Methods: A retrospective review of PD-L1 and HER-2 status for all patients diagnosed with gastric and GEJ adenocarcinomas in Nova Scotia between June 3, 2022 and August 13, 2023 was completed. PD-L1 CPS was evaluated using the 28-8 assay and was considered positive if &gt;1%. HER-2 overexpression was evaluated by immunohistochemistry and in cases with equivocal expression, status was based on fluorescence in situ hybridization. Results: Over the study period, 56 cases of gastric and 42 cases of GEJ adenocarcinoma were identified for a total of 98 cases. The median age of the study population was 73 years (range 38 - 91). 73 patients (74%) were male and 25 patients (26%) were female. HER-2 expression was evaluated in 92 cases, and PD-L1 CPS was evaluated in 95 cases. 19 cases (21%) were HER-2 positive and 86 cases (91%) were PD-L1 positive. 17 HER-2 positive cases were also PD-L1 positive (89%). Conclusions: This study provides population level data in a Canadian context on patients with gastric and GEJ adenocarcinoma with respect to HER-2 overexpression and PD-L1 status. This data will be helpful in planning allocation of clinical and financial resources as a new standard of care for these patients is established.

Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: the Breast Cancer Etiology in Minorities study

BackgroundAssociations between reproductive factors and risk of breast cancer differ by subtype defined by joint estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status. Racial and ethnic differences in the incidence of breast cancer subtypes suggest etiologic heterogeneity, yet data are limited because most studies have included non-Hispanic White women only.MethodsWe analyzed harmonized data for 2,794 breast cancer cases and 4,579 controls, of whom 90% self-identified as African American, Asian American or Hispanic. Questionnaire data were pooled from three population-based studies conducted in California and data on tumor characteristics were obtained from the California Cancer Registry. The study sample included 1,530 luminal A (ER-positive and/or PR-positive, HER2-negative), 442 luminal B (ER-positive and/or PR-positive, HER2-positive), 578 triple-negative (TN; ER-negative, PR-negative, HER2-negative), and 244 HER2-enriched (ER-negative, PR-negative, HER2-positive) cases. We used multivariable unconditional logistic regression models to estimate subtype-specific ORs and 95% confidence intervals associated with parity, breast-feeding, and other reproductive characteristics by menopausal status and race and ethnicity.ResultsSubtype-specific associations with reproductive factors revealed some notable differences by menopausal status and race and ethnicity. Specifically, higher parity without breast-feeding was associated with higher risk of luminal A and TN subtypes among premenopausal African American women. In contrast, among Asian American and Hispanic women, regardless of menopausal status, higher parity with a breast-feeding history was associated with lower risk of luminal A subtype. Among premenopausal women only, luminal A subtype was associated with older age at first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter interval since last FTP, with similar OR estimates across the three racial and ethnic groups.ConclusionsSubtype-specific associations with reproductive factors overall and by menopausal status, and race and ethnicity, showed some differences, underscoring that understanding etiologic heterogeneity in racially and ethnically diverse study samples is essential. Breast-feeding is likely the only reproductive factor that is potentially modifiable. Targeted efforts to promote and facilitate breast-feeding could help mitigate the adverse effects of higher parity among premenopausal African American women.

Implementation of HER2 Testing in Endometrial Cancer, a Summary of Real-World Initial Experience in a Large Tertiary Cancer Center.

HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we report on the initial two-year experience of HER2 testing at a major academic center with a reference gynecologic oncology service and biomarker reference laboratory. All patients who underwent HER2 testing based on physician discretion, reflex HER2 testing, and reference laboratory requests were included. From February 2021 to October 2023, HER2 testing was performed on 192 tumor tissue samples from 180 EC patients. Serous carcinoma constituted 52% of samples, reflecting diagnostic challenges and limited therapeutic options for advanced EC. HER2 positivity was found in 28% of all cases and 30% of p53-aberrant cases. An immunohistochemistry (IHC) score of 3+ was found in 15% of samples, while IHC 2+ was found in 45% (13% IHC 2+/ISH+ and 32% IHC 2+/ISH-). The newly identified 'HER2-low' category comprised 46% of the samples. Heterogeneity was noted in 42% of HER2-positive cases, with complex patterns in 3%. NGS and HER2 IHC-FISH showed a 24% discordance, attributed to intratumoral heterogeneity, tumor cellularity, a small number of amplified cells, and the HER2/CEP17 ratio near the cut-off. This study offers real-world insights into HER2 testing in EC, highlighting the challenges and underscoring the need for standardized guidelines in specimen handling, proficiency testing, and scoring criteria to enhance patient management and therapeutic decision-making.

Landscape of HER2-low breast cancer: Insights from a six-year study on prevalence and clinicopathological characteristics

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+/2+ in immunohistochemistry (IHC) and absence of ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2-low breast cancer to novel anti-HER2 antibody-drug-conjugates. Data on characteristics of HER2-low breast cancer subtype is limited. Real-world data from the Anatomic Pathology Department of Hotel-Dieu de France, spanning 2017–2023, was retrospectively collected. HER2-positive patients were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Clinicopathological characteristics between the groups were compared using a Chi-Squared test. Out of 1195 patients, we observed 341 (28.5 %) HER2-low breast cancers cases. HER2-positive breast cancer cases (n = 178; 14.9 %) were excluded. There was no significant difference in age and sex between HER2-low and HER2-zero group (p = 0.33 and 0.79, respectively). HER2-low breast cancer was associated with positive estrogen receptor status and positive progesterone receptor status (p < 0.001 and p = 0.01, respectively). Ductal adenocarcinomas were more commonly observed in HER2-low group (p < 0.001). When stratified by hormone (HR) status, 87.4 % of patients had HR-positive status and 12.6 % were HR-negative. Among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (25%vs.10 %, p = 0.04). This study showed that HER2-low is distinct from HER2-zero and is common among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Within HR-negative breast cancer, those with low HER2 expression exhibit a less aggressive profile compared to HER2-zero tumors.

Abstract PO1-27-03: Studies on factors for pathological complete response after neoadjuvant chemotherapy in relation to HER2 status in primary breast cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) has been increasingly used as the frontline therapy for the management of high-risk localized breast cancer (BC). Achieving pathological complete response (pCR) following NAC is associated with significantly better disease-free (DFS) and overall survival (OS), particularly for triple negative (TN) and HER2+ breast cancer. Among HER2 negative BC, HER2-low BC is a newly defined subset that has a HER2 immunohistochemical (IHC)-1+ or 2+/ISH negative phenotype. HER2 status is divided into 3 categories: HER2 positive, HER2-low, and HER2-zero. In this study, we investigated factors for pCR in relation to HER2 status and survival after NAC. Methods: A total of 197 cases with primary BC from January 2013 to July 2023 were enrolled in this study. There were 83 HER2 positive cases (including 7 HER2 2+/ISH+ cases) and 114 HER2 (78 HER2-low and 36 HER2-0) negative cases. HER2 3+ was dichotomized according to the staining cell rate (cut-off point; 90%) into the following two groups; HER2 3+/&amp;gt;90% (70 cases) and HER2 3+/&amp;lt; 90% (6 cases). The chemotherapy regimen was anthracycline and taxane with the addition of anti-HER2 therapy if the cases were HER2-positive. The clinicopathological factors examined were age, nodal status, tumor size, ER/PgR (cut-off points; 1% and 10%), and the Ki-67 index value (cut-off points: 20% and 40%). pCR was defined as the absence of residual invasive cancer on H&amp;E evaluation of the complete resected breast specimen (ypT0/Tis). We investigated the correlation between pCR and clinicopathological factors. The DFS and OS were calculated using the Kaplan-Meier method and analyzed using the log-rank procedure. Uni- and multivariate analyses of factors for pCR were performed using regression analysis. Results: 1. pCR was observed in 48 cases (57.8%) after NAC in the HER2 positive group and 17 cases (14.9%) in the HER2 negative group. 2. There was no significant relationship between the pCR rate and ER, PgR, Ki-67, menopausal and nodal status in the HER2 positive group. However, pCR was significantly observed more often in smaller tumors. HER2 3+( &amp;gt;90%) had a significantly higher pCR rate than HER2 3+(≤90%) and HER2 2+(ISH+). Multivariate analysis revealed that HER2 3+( &amp;gt;90%) and tumor size (≤5cm) were significant factors for pCR in HER2 positive BC cases. 3. Patients with pCR after NAC had significantly better DFS in HER2 positive BC cases. 4. There was a significant correlation between the pCR rate and ER≤10%, PgR≤10% and tumor size &amp;lt; 5cm in the HER2 negative BC cases. There was no relationship between the pCR rate and the HER2 status; 19.4% in HER2-0 and 12.8% in HER2-low. 5. Multivariate analysis revealed that the PgR status and tumor size were significant factors for pCR in the HER2 negative BC cases. 6. There was no significant difference in DFS between patients with pCR and non-pCR, especially in the luminal type BC cases. Moreover, no significant difference was observed between HER2-low and HER2-0. Conclusion: pCR rate after NAC was 57.8% in the HER2 positive cases and 14.9% in the HER2 negative cases. Moreover, the HER2 3+( &amp;gt;90%) group had a significantly higher pCR rate than the HER2 3+(≤90%) and HER2 2+(ISH+) groups. There was no correlation between the HER2 status (HER2-low and HER2-0) and pCR rate in the HER2 negative BC cases. In addition, the ER/PgR negativity (≤10%) was a significant factor for pCR in the HER2 negative cases. These findings suggest that the IHC data on the HER2 and ER/PgR status may be effective in predicting the pCR rate after NAC in BC cases. Citation Format: Nobuyuki Arima, Reiki Nishimura, Kazuhiro Muramoto, Atsushi Inayoshi, Tomio Tanigawa, Sugiko Watanabe. Studies on factors for pathological complete response after neoadjuvant chemotherapy in relation to HER2 status in primary breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-03.

Abstract PO5-24-06: Genomic findings in metastatic breast cancer

Abstract Introduction: Although metastatic breast cancer is the second leading cause of cancer death in women, the genomic findings in metastatic breast cancer are not as well characterized as those of primary breast cancers. Metastatic tumors are genetically heterogenous, enriched for resistance mutations, and often lack targetable alterations. Improved understanding of the molecular mechanisms that drive metastatic disease of all receptor subtypes is required to identify possible molecular targets and to develop new targeted therapies in an effort to reduce the mortality. Methods: A cohort of 50 metastatic breast cancer cases (n=33 ER+/PR+, n=3 ER+/HER2+, n=3 ER-/HER2+ n=11 TNBC) sequenced at our medical center between 2018-2023 was evaluated, and the molecular findings of the major subtypes were analyzed. Genomic data included mutations, copy number alterations, tumor mutation burden and microsatellite instability. Results: The most frequent somatic alteration were PIK3CA mutations, involving 17/33 of ER+/PR+/HER- tumors, 5/11 TNBC tumors and 5/6 HER+ cases. TP53 mutations (frameshift and missense) were more frequently identified in TNBC and HER2+ cases (p&amp;lt; 0.05). Recurrent CCND1, FGFR1 and MYC copy number amplifications were seen almost exclusively in hormone receptor positive/HER2- tumors (p &amp;gt;0.05). ESR1 mutations involved 15% of the ER positive cancers and were frequently associated with co-occurring CCND1 and FGFR1 copy number gains. Significant genomic losses that drive tumorigenesis were also detected. Both CDKN2a and PTEN deletions were found in ER/PR positive disease, as well as triple negative tumors. Genomic deletions associated with worse outcomes such as TP53 and DICER1 were also detected. ERBB2 amplification was 100% concordant with our immunohistochemical and FISH results for the 6 HER2 positive cases. All 50 cases demonstrated a low tumor mutation burden and were microsatellite stable. Conclusion: We detected driver alterations that involve multiple pathways including estrogen receptor signaling, PI3K/AKT/MTOR, the cell cycle, and receptor tyrosine kinases. The genomic alterations are enriched for resistance mechanisms, like ESR1 mutations and FGFR1 gains that mediate resistance to endocrine treatment, as well as PIK3CA, also implicated in both endocrine and HER2-targeting therapy resistance. Of particular interest, were the amplifications detected in the ER+/PR+ tumors, such as CCND1 on chromosome 11q, FGFR1 on 8p and MYC on 8q, which were detected in almost half (45%) of our hormone receptor positive cohort. Some of the identified driver amplifications also define a subset of the Integrated Molecular Subtypes (Curtis et al., Nature; 486(7403): 346–352), i.e., Clusters 2, 6 and 9 that are typically hormone receptor positive but associated with either a very poor prognosis (Cluster 2) or an intermediate prognosis (Clusters 6 and 9), unlike the copy neutral ER positive tumors or those with the classic 1p and 16q alterations. Therefore, copy number profiling of advanced-stage breast cancers may be a useful tool for determining prognosis, identifying possible targetable driver pathways and selecting appropriate patients for molecularly guided clinical trials. Citation Format: Kimberly Cole, Melissa Tjota, Jeremy Segal, Peng Wang, Susanne Crespo-Ramos. Genomic findings in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-06.

Abstract PO4-02-09: Clinical outcomes of neoadjuvant chemotherapy in HER2-low early breast cancer

Abstract BACKGROUND: According to immunohistochemistry (IHC) expression of HER2 receptor, breast cancer (BC) can be classified as either IHC score 0, 1+, 2+ or 3+. Until recently, two distinct BC subtypes were recognized depending on the HER2 IHC expression and in situ hybridization (ISH) score: HER2 positive (IHC 3+ or IHC 2+ ISH-amplified) and HER2 negative (IHC 0, 1+ or 2+ ISH negative). More recently a new BC entity termed HER2-low was acknowledged, defined as either HER2 IHC 1+ or 2+ ISH-negative. Given that no treatment benefit was observed in HER2-low group of patients in the pivotal trastuzumab studies, many years had to pass before the discovery of antibody-drug conjugates such as trastuzumab deruxtecan, that led to a significant improvement in the clinical outcome of HER2-low BC, compared to standard therapy options. It is still debated whether HER2-low BC represents a distinct biological subtype. The aim of this study was to determine whether there is an impact of HER2-low status on the effect of neoadjuvant chemotherapy (NACT) and its primary indicator - the rate of the pathologic complete response (pCR). METHODS: A retrospective study of 363 BC cases who received NACT between January 2020 and December 2022 at University Hospital Centre Zagreb, Croatia, was conducted with prior Ethics Committee approval. Histopathological characteristics of tumours available from the hospital information system (BIS), including hormone receptor status (ER, PR), HER2 status and Ki-67 at the time of diagnosis and after neoadjuvant treatment, as well as pCR rates, were analysed. pCR rates were calculated for HER2-low and HER2 0 cases. Chi square test was used to analyse association between pCR rate and HER2 status. RESULTS: After exclusion of HER2 positive BC cases, as well as cases with missing data, a total of 215 patients were included in the analysis. Of those, 101 (47%) were HER2-low, and 114 (53%) were HER2 negative. The majority of patients (N=151, 70.2%) had luminal BC, while 64 (29.8%) patients had triple negative BC (TNBC). In the luminal group, 86 cases (57%) were HER2-low, and 65 (43%) were HER2 0. In the TNBC group, 15 cases (23.4%) were HER2-low and 49 (76.6%) were HER2 0. The rate of pCR among luminal subtypes was 6.2% for HER2-low tumours, and 15.4% for HER2 0 tumours (p=.051559), approaching statistical significance. In the TNBC group, the pCR rate for HER2-low group was 60%, compared to 40% in the HER2 0 group, trending towards, but not reaching statistical significance (p=.191564). CONCLUSION: A trend toward higher pCR rates after neoadjuvant chemotherapy was observed in the luminal HER2 0 group compared to HER2-low luminal BC, almost reaching statistical significance. Interestingly, in TNBC there was a trend towards higher pCR rates among the HER2-low group, although a small number of patients precludes any definitive conclusions. Further trials that include novel targeted therapies are needed, as that might lead to significant changes in therapeutic approach, as well as clinical outcome of HER2-low BC patients. Citation Format: Dora Gudelj, Katarina Čular, Lea Toula, Marija Križić, Marina Popović, Natalija Dedić Plavetić, Ana Kelečić, Gordana Ivanac, Majana Soče, Iva Kukal Gjergjaj, Tajana Silovski. Clinical outcomes of neoadjuvant chemotherapy in HER2-low early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-09.

Abstract PO4-15-08: Comprehensive genomic profiling of HER2-low advanced breast cancers

Abstract Background: With the recent approval of the HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-Dxd) for the treatment of HER2-low advanced breast cancers (aBC), [defined as HER2 immunohistochemistry (IHC) 1+, or 2+ with negative in-situ hybridization (ISH)], there is interest to understand whether this population represents a distinct molecular entity and if there are additional biomarkers that can improve patient selection for these therapies. Here, we examined 2086 aBC cases profiled with comprehensive genomic profiling (CGP) stratified by HER2 status (negative, low, and positive) and hormone receptor (HR) status (positive and negative). Methods: Hybrid-capture CGP targeting 324 genes was performed on advanced BC samples (FoundationOne®CDx). HER2 IHC status was abstracted from pathology reports while HER2 amplification status was abstracted from CGP. Results: We examined 2086 samples of aBC patients distributed as HER2-negative (n=657; IHC 0), HER2-low (n=1012, IHC 1+, 2+ ISH non-amplified), and HER2-positive (n=417; HER2 IHC 3+). HER2-low patients were significantly older than HER2-negative patients (median 60 v 57 years, p=0.0006). HER2-low cases were more common in HR-positive than in HR-negative disease (67% vs 46%, respectively). Overall, characteristics were generally similar for genetic ancestry and TMB-H frequency across all HER2-statuses. MSI-H was rare across all HER2-statuses groups. HER2-low cases were more likely to have alterations in GATA3 (12.6% v 6.5%), ESR1 (12.4% v 7.8%), FGFR2 (4.0% v 1.8%), AR (1.1% v 0.2%), and CDH1 (15.3% v 11.6%) and less likely to harbor alterations in TP53 (44.0% v 62.4%), RB1 (6.8% v 12%), NF1 (5.5% v 9.3%), and BRCA1 (3.0% v 5.2%) when compared to HER2-negative. Some genes showed a consistent pattern of decreased frequency as HER2-IHC expression decreased from HER2-positive to HER2-low and to HER2-negative (e.g. AR alterations seen in 2.6%, 1.1% and 0.2%, respectively) while others had a increasing frequency pattern (e.g. RB1 alterations observed in 2.4%, 6.8% and 12.0%; BRCA1 seen in 1.7%, 3% and 5.2%, respectively). However, some genomic characteristics were unique to the HER2-low population (e.g. TP53 seen in 69.5% of HER2-positive and 62.4% of HER2-negative, but at a lower frequency of 44% in HER2-low cases) [Table 1]. Within the HR-positive subgroup, a lower frequency of NF1 (4.4% v 10.4%), TP53 (30.6% v 41.1%), and RB1 (4.4% v 8.0%) and a higher frequency of AR (1.0% v 0.0%) and GATA3 (16.2% v 10.9%) were observed in HER2-low vs HER2-negative cases, while within the HR-negative subgroup there was a higher frequency of GATA3 (1.2% v 0.7%) and AR (1.2% v 0.4%) and trending lower frequency of TP53 (85.7% v 90.8%) and RB1 (14.3% v 17.4%) in the HER2-low vs. HER2-negative cases. Mutations in homologous recombination repair genes (BRCA1, BRCA2, PALB2) were less frequent in HER2-low cases vs. HER2-negative cases overall (8.4% v 10.7%) and in the HR-positive (3.6% v 5.6%) and HR-negative subgroups (10.6% v 17.4%). Consistent with this, the rate of scar-based HRD signature (HRDsig) was lower in the HER2-low vs. HER2-negative subgroup (15.9% v 20.4%, p=0.02). Conclusions: These data suggest the HER2-low aBC has distinct genomic alterations before and after stratification by HR-status when compared to HER2-negative and HER2-positive aBC cases. Higher prevalence of some potentially actionable alterations in HER2-low cases, including FGFR2, AR, and ESR1, may aid in patient selection and drug development considering new combination approaches. Table 1 Summary of comprehensive genomic profiling alterations observed in HER2-low aBC compared to HER2-positive and HER2-negative cases Citation Format: Adriana Kahn, Ethan Sokol, Jeffrey Ross, Maureen Pelletier, Neal Fischbach, Lajos Pusztai, Maryam Lustberg. Comprehensive genomic profiling of HER2-low advanced breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-08.

State of the art and upcoming trends in HER2-directed therapies in gastrointestinal malignancies.

This review critically evaluates the evolution and current status of human epidermal growth factor receptor 2 (HER2)-directed therapies in upper gastrointestinal (GI) malignancies, a timely and relevant inquiry given the dynamic shifts in therapeutic strategies over the past decade. Initial enthusiasm following the Trastuzumab for Gastric Cancer (ToGA) study's demonstration of trastuzumab's efficacy, however, encountered hurdles due to subsequent trials showing limited progress, underscoring the necessity for a reevaluation of therapeutic approaches and the exploration of novel agents. The review highlights significant breakthroughs in the form of immune checkpoint inhibitors and innovative therapeutic technologies, which have redefined treatment paradigms and shown promising efficacy in HER2-positive cases. Emerging treatments such as trastuzumab deruxtecan (T-DXd), zanidatamab and evorpacept further illustrate the ongoing efforts to leverage unique mechanisms of action for improved HER2-positive antitumor activity. The advancements in HER2-directed therapies underscore a pivotal era in the management of upper GI malignancies. These developments not only reflect the profound impact of integrating novel therapeutic combinations but also highlight the critical role of ongoing research in overcoming resistance mechanisms and tailoring treatment to individual disease profiles.