Objective: To investigate the characteristics of human epidermal growth factor receptor 2 (HER2) protein expression and gene status in uterine serous carcinoma (USC) patients. Methods: A total of 36 formalin-fixed and paraffin-embedded USC tissue specimens obtained between 2021 and 2022 in Peking Union Medical College Hospital were collected. The expression of HER2 protein and the gene status were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) respectively, and the results were interpreted according to the 2020 International Society of Gynecological Pathologists recommendations. Results: Among the 36 cases, 11, 8, 12 and 5 cases showed HER2 IHC scores of 0, 1+, 2+, and 3+, respectively. All IHC 3+cases were pure USC. Out of 25 samples with different level of HER2 expression (IHC 1+, IHC 2+and 3+), 16 (64.0%) tumors with heterogeneous stain, which mainly affects the diseases with IHC 2+ (10/12) and IHC 3+ (3/5) lesions. Ten pure USC cases (27.8%, 10/36), involving HER2 IHC 0, IHC 1+, IHC 2+and IHC 3+tumors, harbored HER2 gene amplification by FISH (1, 1, 3 and 5 cases, respectively). All amplified cases exhibited a HER2/CEP17 ratio≥2.0. In addition, the incidences of chromosome 17 (CEP17) polysomy and monosomy were 25.0% (9/36) and 19.4% (7/36), respectively. Conclusions: Most of USC tumors exhibit intratumoral heterogeneity in HER2 IHC stain. Both HER2 IHC positive (3+) and FISH positive occur exclusively in pure USC tumors. HER2 gene amplification can be observed in any HER2 IHC levels.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It accounts for ~15% of breast cancer diagnoses, and disproportionally affects young women and those of African and Hispanic ancestry. This review encompasses recent advances in the management of early and advanced-stage TNBC. The identification of distinct molecular subtypes of TNBC has allowed for the optimization of systemic therapy. Distinct drivers of TNBC have been identified, resulting in the regulatory approval of targeted therapies for early and advanced stage disease, including immunotherapy, PARP inhibitors, and antibody-drug conjugates. Literature search was performed using PubMed, and included publications between 01/2010 to 11/2025. Until recently, the only treatment available for TNBC was chemotherapy. Advances in the molecular characterization of TNBC has revealed distinct subtypes, enabling the development and approval of targeted therapies, including PARP inhibitors, immunotherapy, and antibody-drug conjugates. Treatment options for both early and advanced-stage TNBC are improving, although it remains the subtype with the poorest outcomes. Ongoing trials are focused on personalizing treatment through predictive biomarkers, response-adaptive strategies, and novel agents, with the goal of maximizing efficacy while minimizing toxicity.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been observed in HR+HER2-positive (HER2+) MBC, with significant progression-free survival (PFS) benefits. Cyclin-dependent kinases 4/6 (CDK4/6) are downstream of HER2 and pathways driving resistance to HER2-targeted therapies. However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody–drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium. The observation that luminal disease defined by a predictive analysis of microarray 50 (PAM50) was independently associated with a significantly longer PFS versus nonluminal disease was important, with researchers inferring that intrinsic molecular subtypes could be used to identify patients most suitable for ET + CDK4/6i + HER2-targeted treatment. Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions.

Predictive factors and prognostic significance of HER2-low early breast cancer with long-term follow-up.

Extensive surgical resection improves survival in cancer patients. Fluorescence-guided imaging techniques have significantly enhanced the precision of cancer resections. Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), and no other targetable molecules have been identified. In this study, we verified that the L-type amino acid transporter 1 (LAT1, also known as SLC7A5) is overexpressed in triple-negative breast cancer (TNBC) cells and we constructed a novel near-infrared fluorescent dye Cys-PEG5-IR target to SLC7A5. We then report the SLC7A5 receptor specificity of Cys-PEG5-IR as a contrast agent for TNBC imaging in vitro and in vivo. The conjugation elevated cell fluorescence on SLC7A5-overexpressing TNBC cells and produced minimal cell fluorescence when treated with SLC7A5 knockdown. Tumor uptake of Cys-PEG5-IR was significantly higher than the unlabeled IR in the subcutaneous MDA-MB-231 TNBC xenograft. This work highlights the prospect of using methionine (Met) transport pathway as an alternative strategy for targeting cancer cells, especially TNBC cells.

ABSTRACTObjectiveThe study is to investigate differential signaling pathways within the tumor microenvironment across molecular subtypes of breast cancer (BC).MethodsSingle‐cell RNA (scRNA‐seq) sequencing data of BC samples were obtained from the Gene Expression Omnibus database. Cell types were identified using the SingleR package, in conjunction with the analysis of marker genes. Subsequently, Monocle was used for pseudotime analysis of epithelial cells, fibroblasts, and macrophages to characterize their differentiation states. CellChat was employed to study the ligand‐receptor interactions among various cell types across different BC molecular subtypes. In addition, we used common bulk RNA sequencing data from The Cancer Genome Atlas to investigate the correlation between key signaling pathway factors identified by scRNA‐seq and clinical outcomes.ResultsInference of copy number variation analysis using T cells revealed significantly elevated copy number variation scores in epithelial cells and fibroblasts. In the communication between epithelial cells and fibroblasts, the ANGPTL pathway is critical in estrogen receptor‐positive breast cancer (ER+BC), while the PTN pathway plays a key role in both ER+BC and human epidermal growth factor receptor 2‐positive breast cancer (HER2+BC), and the GAS pathway is associated with poor prognosis in triple‐negative breast cancer (TNBC). In the interaction between fibroblasts and macrophages, the macrophage subpopulation supporting tumor angiogenesis exhibits significant activity in ER+BC, with the associated SPP1 and GRN pathways strongly influencing tumor progression. The SEMA3 pathway mainly acts through dividing tumor‐associated fibroblast clusters across all BC subtypes. When exploring the role of lymphocytes, the PTN pathway also plays a role in HER2+BC, while in TNBC, CXCL and CD70 pathways are significantly involved in immune response modulation.ConclusionOur comprehensive analysis of cell–cell communication networks among epithelial cells, fibroblasts, macrophages, and lymphocytes across BC subtypes focuses on ligand‐receptor interactions. This study revealed that certain molecules within these networks exhibit significant prognostic value and therapeutic promise.

Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2–positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence– (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.

ObjectivesMammographically spiculated breast cancer is frequently less aggressive than cancers with alternative appearances. This study aims to investigate whether the degree of spiculations relative to the tumor mass on mammography, termed the spic mass ratio (SMR), is associated with breast cancer characteristics and survival.Materials and methodsThis retrospective exploratory single-center study analyzed mammograms from 161 women with spiculated breast cancer in the Malmö Diet and Cancer Study cohort (2004–2014). Radiologists segmented the tumor mass and the spiculation areas. The SMR was calculated by dividing the combined tumor and spiculation area by the tumor area alone. The subjects were stratified into tertiles with low, medium, and high SMR. The study examined associations between SMR and breast density, mode of detection, age, tumor size, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, Ki67, histological grade, axillary lymph node involvement (ALNI), histological type, and breast cancer-specific survival, utilizing the Chi-squared test, ANOVA, Fisher’s exact test, Kaplan–Meier curves, and Cox regression.ResultsThe mean age was 68 years (range 55–91). SMR was statistically significantly associated with both age and breast density. No other significant associations were observed. Among the nine women with the highest SMR values, axillary lymph node negativity, estrogen positivity, and an overall low Ki67 index were noted.ConclusionsThe SMR, representing the degree of spiculations relative to tumor mass, was not significantly associated with breast cancer survival or ALNI. Further research is necessary to explore the prognostic implications of extensive spiculations in spiculated breast cancer.Critical relevance statementThe degree of spiculation relative to the tumor mass is an unexplored mammographic feature that can be measured subjectively, as in this study. Extensive spiculation was associated with higher age and lower breast density. No certain conclusions could be drawn regarding the impact on breast cancer survival.Key PointsThe degree of spiculation relative to the tumor mass on mammography is an unexplored mammographic feature.A high ratio of spiculations in relation to tumor mass was associated with higher age and lower breast density.The nine women with a very high spiculation to tumor mass ratio were all axillary lymph node negative.Graphical

Background: Urothelial carcinoma of the bladder is a significant global cause of morbidity and mortality. These tumors are classified into low-grade and high-grade lesions based on architectural patterns, cytological features, and nuclear atypia. Muscle invasion remains a critical determinant in treatment planning and prognosis. Aims and Objectives: The aim of this study is to evaluate the immunohistochemical expression of human epidermal growth factor receptor 2 (HER2)/neu in urothelial carcinoma of the bladder and to correlate this expression with various clinico-pathological parameters. The objectives include analyzing the age-wise, gender-wise, and site-wise distribution of urothelial carcinoma; correlating histopathological grade with tumor stage; assessing the relationship between urine cytology and tumor grade; and evaluating HER2/neu expression in relation to age, gender, tumor size, grade, stage, and invasiveness to aid in patient management. Materials and Methods: This study was conducted in the Department of Pathology, Stanley Medical College and Hospital, Chennai, over 1 year (September 2024–September 2025). Immunohistochemical evaluation of HER2/neu was performed on biopsy-proven urothelial carcinoma cases. Prospective and retrospective data were analyzed, and HER2/neu expression was correlated with clinical and pathological variables, including age, gender, tumor size, grade, stage, and invasiveness. Results: Urothelial carcinoma showed a peak incidence above 50 years. Males constituted 69% of cases. The lateral wall was the most common tumor site. Urine cytology demonstrated higher sensitivity for high-grade tumors. High-grade carcinomas were predominantly stage II-III, whereas low-grade lesions were more often stage I-II. Conclusion: HER2/neu expression showed significant correlation with tumor grade but not with invasiveness, stage, age, gender, or size. Overexpression may indicate a poorer prognosis and potential eligibility for targeted therapy.

Background: Breast cancer has emerged as the most common malignancy among Indian women, increasingly affecting younger populations. Determination of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) status plays a pivotal role in molecular classification and therapeutic decision-making. Aims and Objectives: This study aimed to assess the expression of ER, PR, and HER2/neu receptors, evaluate tumor proliferative index using Ki-67, and classify molecular subtypes in patients with invasive breast carcinoma. Materials and Methods: A prospective cross-sectional study was conducted in the Department of General Surgery, Maharani Laxmi Bai Medical College, Jhansi, from October 2023 to March 2025. Fifty newly diagnosed patients of invasive breast carcinoma were included after histopathological confirmation. Immunohistochemistry was performed to evaluate ER, PR, HER2/neu, and Ki-67 status. Tumors were categorized into molecular subtypes (Luminal-A, Luminal-B, HER2-enriched, and triple-negative). Data were analyzed using the Statistical Package for the Social Sciences version-25.0, with categorical variables expressed as frequencies and percentages. Results: The majority of patients (54%) were aged 41–60 years, with breast lump as the commonest presentation. Molecular subtyping revealed 40% basal-like, 36% HER2-enriched, 20% Luminal A, and 4% Luminal B tumors. ER and PR expression were observed in 24% of cases, showing a significant inverse relationship with Ki-67 index (P=0.002), indicating higher proliferation in hormone receptor-negative tumors. HER2/neu positivity was noted in 56% but showed no significant correlation with clinicopathological features. Conclusion: This study highlights the predominance of aggressive subtypes – basal-like and HER2-enriched – in this Indian cohort. The low hormone receptor expression and high Ki-67 index support the need for routine molecular profiling to inform targeted treatment strategies, especially in resource-limited settings.

Chemotherapy improves outcomes in patients with high-risk early or locally advanced breast cancer, but older adults often experience higher toxicity that leads to treatment delays, dose reductions, and reduced relative dose intensity (RDI). This study examined predictors of low RDI and its impact on overall survival (OS) in women aged over 65 years treated with neoadjuvant or adjuvant chemotherapy at San Juan de Dios Hospital (Costa Rica) between November 2018 and April 2023. A total of 264 patients (mean age: 70.1 years) were included. Nearly one-third had a Charlson Comorbidity Index (CMI) greater than 6. Tumor subtypes were hormone receptor (HR)+/ human epidermal growth factor receptor (HER2)-(48.9%), HR+/HER2+ (15.9%), HR-/HER2+ (33%), and triple-negative (17.8%). Most patients (68.6%) received anthracycline-based regimens. Overall, 17.4% had an RDI below 80%. After a median follow-up of 54.6 months, 56 deaths were recorded. Low RDI was significantly associated with worse OS [hazard ratio: 1.79, 95% confidence interval (CI): 1.02-3.13; P = 0.04]. Independent predictors of low RDI were anthracycline-based therapy [odds ratio (OR): 4.76, 95% CI: 2.17-9.09], CMI greater than 6 (OR: 2.13, 95% CI: 1.02-4.54), and age more than 70 years (OR: 2.38, 95% CI: 1.14-5.01). These findings suggest that advanced age, comorbidities, and anthracycline regimens increase the risk of reduced RDI, which negatively impacts survival. Supportive measures are critical to maintain chemotherapy intensity in older women.

Radiation recall dermatitis (RRD) is an inflammatory skin reaction confined to areas previously exposed to radiation, triggered by subsequent systemic therapy. This case report describes a female patient with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. She received 6 cycles of neoadjuvant chemotherapy, followed by mastectomy with immediate tissue expander implantation and axillary lymph node dissection. Adjuvant radiotherapy and intensive endocrine therapy (endocrine therapy and abemaciclib) were administered postoperatively. After radiotherapy, the patient developed small, coin-sized skin flap necrosis. Two months after completing radiotherapy, she initiated abemaciclib treatment, which was followed by rapid progression of flap necrosis and increased exposure of the tissue expander. This flap necrosis was suggestive of RRD. This report details the clinical course, management strategies, and a review of relevant literature, aiming to provide valuable insights for clinicians in handling similar cases and enhance awareness of potential risks associated with this treatment combination.

CD24 overexpression confers resistance to Pyrotinib through inhibiting autophagy in patients with HER2-positive breast cancer.

Immunotherapy has revolutionized treatment for advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC). However, identifying convenient biomarkers for predicting therapeutic efficacy remains challenging. This study investigated the association between clinicopathological characteristics and baseline peripheral blood lymphocyte subsets with efficacy of first-line chemotherapy combined with immune checkpoint inhibitors (ICIs) in proficient mismatch repair (pMMR) human epidermal growth factor receptor 2 (HER2)-negative advanced G/GEJC. This retrospective study enrolled 97 patients with pMMR HER2-negative advanced G/GEJC receiving first-line chemotherapy combined with ICIs. Clinicopathological characteristics and peripheral blood lymphocyte subsets were collected. Overall survival (OS) and progression-free survival (PFS) were used to evaluate efficacy. The univariate and multivariate analyses were conducted using Cox regression analysis. Median PFS and OS were 5.9 and 15.2 months, respectively. Tumor location, Lauren classification, tumor differentiation, peritoneal metastases, neutrophil to lymphocyte ratio (NLR), and regulatory T cells (Tregs) as significantly associated with PFS. Well-differentiated tumor and higher Tregs independently predicted longer PFS. For OS, only higher NLR was an independent risk factor. Optimal cut-offs for NLR (3.5) and Tregs (10.1) stratified patients with significantly different PFS. A nomogram combining Tregs, NLR, peritoneal metastases, and tumor differentiation achieved superior predictive performance compared to PD-L1 CPS alone, with PFS AUC of 0.68-0.77 and OS AUC of 0.69-0.75. Clinicopathological characteristics and baseline peripheral lymphocyte subsets were significantly associated with efficacy of first-line chemotherapy combined with ICIs in pMMR HER2-negative advanced G/GEJC, highlighting the potential utility of integrating these accessible parameters for efficacy prediction.

Versatile fluorescent homobifunctional crosslinkers: expedient synthesis and application to di-affibody constructs for specific HER2+ cancer cell recognition.

Occult malignancy (OM) identified in contralateral prophylactic mastectomy (CPM) presents a challenge for axillary management. This meta-analysis identified retrospective studies using PubMed, Embase, and Cochrane Reviews with the keywords OM and CPM. In this study, OM was defined as invasive disease only. To determine the proportion of OM and node positivity rates, MedCalc software was used. The 27 studies in this meta-analysis included 5728 patients who underwent CPM, with OM identified in 87 patients. The pooled incidence of OM was 1.55%. Of the 73 patients with axillary staging details available, 41 patients with OM (56%) underwent surgical axillary staging. Of these 41 patients, 8 had a positive sentinel lymph node (SLN) (20%), and 4 of the 8 patients had subsequent axillary lymph node dissection (ALND) with no additional positive lymph nodes identified. For 64 of the 87 patients with OM, T category was available. Of these 64 patients, 62 (97%) had pT1 and 2 (3%) had pT2 carcinoma. Histologic subtype was available for 52 OMs. Of these, 39 (75%) were ductal, 8 (15%) were lobular, and 5 (10%) were other. Biomarkers were available for 33 OMs, of which 21 (64%) were luminal A, 3 (9%) were luminal B, 3 (9%) were luminal human epidermal growth factor receptor 2 (HER2), and 6 (18%) were triple-negative. Occult malignancy in CPM is uncommon (1.55%), and when it occurs, it is predominantly pT1, luminal A, or invasive ductal carcinoma. Occult malignancy with SLN metastasis occurs in only 0.1% of CPMs, and when present, SLN metastasis is low volume (≤2 nodes). This supports the current guideline recommendations against routine SLN surgery at the time of CPM.

Unveiling the power of quinazoline derivatives: a new frontier in targeted cancer therapy.

While the benefit of neoadjuvant chemotherapy (NAC) has been established in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers, its effectiveness in achieving pathological complete response (pCR) and optimal patient selection in estrogen receptor (ER)-positive, HER2-negative breast cancers remain less clearly defined. This study aimed to identify immunohistochemistry (IHC)-based predictors of pCR and to develop a scoring model for ER-strong positive/HER2-negative breast cancer. Data from a prospective cohort were retrospectively analyzed. We included 522 patients with ER-strong positive/HER2-negative tumors who received NAC and surgery between 2008 and 2021. IHC markers including progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), cytokeratin 5/6 (CK5/6), and p53 were evaluated to identify predictors of pCR. Independent predictors of pCR from multivariate logistic regression were used to develop a weighted 4-point model. Model performance was assessed using receiver operating characteristic analysis. The prognostic impact of pCR was evaluated using Kaplan-Meier and Cox regression analyses. Independent predictors of pCR included PR-negative status, positivity for basal-like markers (EGFR or CK5/6), and Ki-67 ≥ 50%. The scoring model demonstrated good discrimination for pCR (area under the curve = 0.754). pCR rates increased stepwise, with scores of 4.9% (low), 10.7% (intermediate), and 36.2% (high). In the high-score group, pCR was significantly associated with improved disease-free survival (hazard ratio [HR], 0.09; p = 0.023) and distant metastasis-free survival (HR, 0.11; p = 0.035), whereas no significant survival differences according to pCR status were observed in the low and intermediate score groups. This IHC-based model predicts pCR and helps identify subgroups in which pCR is associated with meaningful survival benefit following NAC in ER-positive/HER2-negative breast cancers. High-scoring patients may benefit from NAC, while patients with low- or intermediate-scores may be better managed with surgery and endocrine therapy. This model may support personalized treatment decisions regarding NAC.

BackgroundDual anti–human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor–positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies.MethodsIn this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor–positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival.ResultsA total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P=0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group.ConclusionsThe addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.)

Background/Objectives: Low-grade serous ovarian carcinoma (LGSOC) is known as an uncommon subtype of cancer with poor response to standard chemotherapy, so novel targets are required. The current study aims to highlight the Human Epidermal Growth Factor Receptor-2 (HER2/neu) immunohistochemical (IHC) expression in LGSOCs. Methods: The study was conducted using 33 cases of LGSOCs from the calendar years 2017–2024. IHC staining was performed using antibody anti-HER2/neu (clone 4B5). HER2/neu scoring was performed based on the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) criteria for breast carcinoma. Results: The mean age of the 33 patients was 46.5 years. International Federation of Gynecology and Obstetrics (FIGO) stage data for patients revealed a predominance of advanced disease: 82.7% (24/29) were in advanced stages. Early stages comprised 17.3% (5/29) of cases. The study did not find HER2/neu overexpression in all cases. In 3.0% of samples (1/33), HER2/neu IHC staining was scored as 1+, and in 6.1% (2/33) of all LGSOCs, ultralow phenotype was observed. Of 23 cases in the HER2-negative group, 6 patients were alive with progressive disease, 1 patient died in 5 months, and 16 were alive with no evidence of disease. Of two patients with the HER2-ultralow phenotype, one was alive with no evidence of disease at 16 months follow-up. Conclusions: The results support the idea that HER2/neu overexpression is exceptionally rare in LGSOC; nevertheless, future trials are essential to fully characterize the spectrum of HER2/neu alterations in LGSOC and to determine definitively whether the rare cases with mutations or ultralow expression could represent a small subgroup that might benefit from specific targeted agents.