Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.

HER2 (human epidermal growth factor receptor 2) is highly expressed in a variety of cancers, including breast, lung, gastric, and pancreatic cancers. Its amplification is linked to poor clinical outcomes. At the genetic level, HER2 is encoded by the ERBB2 gene (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), which is frequently mutated or amplified in cancers, thus spurring extensive research into HER2 modulation and inhibition as viable anti-cancer strategies. An impressive body of FDA-approved drugs, including anti-HER2 monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and HER2-tyrosine kinase inhibitors (TKIs), have demonstrated success in enhancing overall survival (OS) and disease progression-free survival (PFS). Yet, drug resistance remains a persistent challenge and raises the risks of metastatic potential and tumor relapse. Research into alternative therapeutic options for HER2+ breast cancer therefore proves critical for adapting to this ever-evolving landscape. This review highlights current HER2-targeted therapies, discusses predictive biomarkers for drug resistance, and introduces promising emergent therapies-especially combination therapies-that are aimed at overcoming drug resistance in the context of HER2+ breast cancer.

Overexpression of cytoplasmic poly(A)-binding protein 1 as a biomarker for the prognosis and selection of postoperative regimen in breast cancer.

PURPOSE: The dysregulation of the cytoplasmic poly(A)-binding protein 1 (PABPC1) is involved in a variety of tumors but little is known about its role in human breast cancer. Therefore, the effect of PABPC1 in the prognosis and regimen selection in breast cancer patients was evaluated. METHODS: A total of 791 cases of invasive breast cancer were included in this study, although only 416 were involved in subsequent analyses after the propensity score matching (PSM) test. PABPC1 expression was detected by immunohistochemistry. The relationship between PABPC1 expression and clinicopathological factors, postoperative regimens, and outcomes was determined. RESULTS: In the total 791 cases, 583 cases were positive for PABPC1, but only 212 (26.8%) showed high PABPC1 expression (PABPC1-HE). The overall survival (OS) and disease-free survival (DFS) of PABPC1-HE patients after PSM were significantly worse than those in patients with PABPC1 low expression (PABPC1-LE), regardless of age, molecular type, tumor size, nodal status, or pStage. Postoperative chemotherapy (CT) increased the OS of PABPC1-HE patients but not that of PABPC1-LE patients. Among patients receiving endocrine therapy, those in the PABPC-LE group had an extended OS, while CT or chemoradiotherapy (CT/CRT) only significantly extended the OS time of PABPC-HE patients. CT/CRT did not significantly extend the survival of PABPC1-LE HER2-positive patients but extended the OS of PABPC1-HE HER2-positive patients. However, the OS of patients treated with CT/CRT + trastuzumab therapy was significantly longer than that of other patients under other therapies in the PABPC1-HE group, suggesting that PABPC1-HE might be sensitive to trastuzumab-based therapy. The multivariate analysis revealed that PABPC1-HE was an independent prognostic factor for both poor OS and DFS in breast cancer except luminal A type. CONCLUSIONS: Our results revealed that PABPC1 might be considered as a biomarker to help in subtyping, as well as in the prognosis and regimen selection of breast cancer patients.

Perspectives on shorter durations of anti-HER2 therapy in early-stage HER2-positive breast cancer: a patient survey.

PURPOSE: Despite previous studies proposing shorter durations of anti-HER2 therapy for selected patients with HER2-positive early breast cancer (EBC), 12-months remains standard of care. A survey was performed to assess patient perspectives and willingness to participate in studies evaluating shorter durations of anti-HER2 therapy. METHODS: Patients with HER2-positive EBC completing or having previously completed anti-HER2 therapy, were recruited by healthcare professionals at The Ottawa Hospital Cancer Centre to participate in an anonymous online survey. The primary objective was to learn about patients' perspectives on shorter durations (less than 12-months) of anti-HER2 therapy. Secondary objectives were to explore patients' interest in clinical trials of shorter durations of anti-HER2 therapy and the degree of increased breast cancer risk they would accept with a shorter treatment duration. RESULTS: Responses were received from 94 eligible patients. Most patients received Trastuzumab alone (78%, 73/94), while 13% (12/94) received trastuzumab and pertuzumab. Side effects were experienced by 52% (46/89), the most common being; fatigue (61%, 28/46), myalgia (37%, 17/46), and diarrhea (24%, 11/46). Most patients (88%, 78/89) did not find treatment bothersome. Regarding perspectives on shorter durations of anti-HER2 therapy, most (79%, 74/94) respondents stated they would agree to less treatment if it were possible to receive fewer treatments with the same cancer benefits. 56% of patients were interested in clinical trials, however, about half stated they would not be accepting of any increase in breast cancer recurrence risk. CONCLUSION: Trials to investigate who can safely and effectively be treated with shorter durations of anti-HER2 therapy are needed. This study provides important insights to patients' perspectives on shorter durations of anti-HER2 treatment, and their concerns regarding potential increased cancer risk with less treatment.

Neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy for human epidermal growth factor receptor 2 positive breast cancer: a real-world retrospective single-institutional study in China.

INTRODUCTION: Real-world studies on neoadjuvant dual anti-HER2 therapy combined with chemotherapy for breast cancer (BC) are scarce in China. This study aimed to evaluate the efficacy and safety of neoadjuvant dual anti-HER2 therapy combined with chemotherapy in a real-world setting. Moreover, differences in estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation cell nuclear antigen (Ki-67) expression pre- and post-neoadjuvant therapy were analyzed. METHODS: Clinical and pathological data of patients with HER2-positive BC who received neoadjuvant dual anti-HER2 therapy combined with chemotherapy at Liaoning Cancer Hospital & Institute, China, between September 2021 and September 2023, were retrospectively reviewed. RESULTS: Among 179 included patients, a pathologic complete response (pCR) was achieved in 109 patients (60.9%). The univariate analysis results indicated that the hormone receptor (HR) status (P = 0.013), HER2 status (P = 0.003), and cycles of targeted treatment (P = 0.035) were significantly correlated with pCR. Subsequent multivariable analysis showed that HR negative and HER2 status 3 + were independent predictive factors of pCR. Anemia was the most common adverse event (62.0%), and the most common grade 3-4 adverse event was neutropenia (6.1%). The differences in HER2 (34.5%) and Ki-67 (92.7%) expression between core needle biopsy and the residual tumor after neoadjuvant therapy were statistically significant, whereas the differences were insignificant in terms of ER or PR status. CONCLUSIONS: The combination of neoadjuvant trastuzumab and pertuzumab with chemotherapy showed good efficiency, and the toxic side effects were tolerable in patients with BC. In cases where pCR was not achieved after neoadjuvant therapy, downregulation of HER2 and Ki-67 expressions was observed.

Chemotherapy for Salivary Gland Malignant Carcinoma : Meta-analysis and Systemic Review.

 The primary form of treatment for salivary gland cancer is surgical resection. Radiation therapy is used as adjuvant therapy in cases of aggressive tumours, currently patients with recurrent or metastatic cancer who are not suitable for surgery or radiation are most often treated with chemotherapy. PRISMA guidelines for systematic reviews were followed to evaluate salivary gland malignancies involving cytotoxic chemotherapy and biologic agents. An electronic literature search of Medline, PubMed, Scopus, etc. was performed and relevant articles were selected based on the inclusion criteria. Cytotoxic chemotherapies and biologic drugs such as anti HER - 2, anti-EGFR and anti-C-Kit are used to treat salivary gland cancer. Although most trials have respond poorly to standard chemotherapy with short durability and significant toxicity. Most of the research has focused on ACC and the use of combination therapy with cisplastin in conjunction with other treatments has been found to improve overall survival rate. Due to the limited patient population it was difficult to assess the efficacy of chemotherapy, which achieved very modest results. There are potential molecular targets such as HER2,NTRK and targeted treatments are becoming more popular. However to further explore potential treatment alternatives SGC patients should be enrolled in clinical trials.

Human epidermal growth factor receptor-2 (HER2) expression in FIGO3 high-grade endometrial endometrioid carcinoma: Clinicopathologic characteristics and future directions.

OBJECTIVES: To study the expression of HER2 in high-grade FIGO3 endometrial endometroid carcinoma (EEC) and to correlate our findings with the clinicopathologic characteristics of this tumor. METHODS: HER2 expression by immunohistochemistry (IHC) was performed on 10% formalin-fixed paraffin embedded tissue on cases diagnosed as FIGO3 EEC. HER2 expression was interpreted as negative (0), low (1+ and 2+) or positive (3+) using similar criteria as in the breast. HER2 amplification by Fluorescence in situ hybridization (FISH) was performed on cases interpreted as 2+ and 3+ by IHC. RESULTS: One hundred and forty-three FIGO3 EEC were identified. Of these, 70 (49%) cases were HER2 negative (IHC 0), and 73 (51%) cases expressed/amplified HER2 by IHC and/or FISH. Of the 73 cases expressing or amplifying HER2, 59 cases were IHC 1+, 12 cases were IHC 2+, and 2 cases were IHC 3+. FISH testing was performed in 12 cases. Only one of the two HER2 IHC 3+ cases showed HER2 gene amplification by FISH and the other 11 cases were not amplified. The 5-year overall survival (OS) rate for HER2 IHC 1+ cases was 92.20% (95% CI: 83.97-100.00), and the 5-year OS rate for HER2 IHC 2+/3+ cases was 89.50% (95% CI: 56.41-100.00). CONCLUSION: Our findings indicate that about one half of FIGO3 EEC variably expresses HER2 and with the emerging concept of "HER2 low", anti-HER2 agents may be explored as potential therapeutic options in these patients, for possible survival benefits.

The tumor immune microenvironment remodeling and response to HER2-targeted therapy in HER2-positive advanced gastric cancer.

Combination therapy with anti-HER2 agents and immunotherapy has demonstrated significant clinical benefits in gastric cancer (GC), but the underlying mechanism remains unclear. In this study, we used multiplex immunohistochemistry to assess the changes of the tumor microenvironment in 47 advanced GC patients receiving anti-HER2 therapy. Additionally, we performed single-cell transcriptional sequencing to investigate potential cell-to-cell communication and molecular mechanisms in four HER2-positive GC baseline samples. We observed that post-treated the infiltration of NK cells, CD8+ T cells, and B lymphocytes were significantly higher in patients who benefited from anti-HER2 treatment than baseline. Further spatial distribution analysis demonstrated that the interaction scores between NK cells and CD8+ T cells, B lymphocytes and M2 macrophages, B lymphocytes and Tregs were also significantly higher in benefited patients. Cell-cell communication analysis from scRNA sequencing showed that NK cells utilized CCL3/CCL4-CCR5 to recruit CD8+ T cell infiltration. B lymphocytes employed CD74-APP/COPA/MIF to interact with M2 macrophages, and utilized TNF-FAS/ICOS/TNFRSR1B to interact with Tregs. These cell-cell interactions contribute to inhibit the immune resistance of M2 macrophages and Tregs. Our research provides potential guidance for the use of anti-HER2 therapy in combination with immune therapy.

[HER2 epidermal growth factor receptor, tests used to look for its amplification in breast cancer: Principles and limitations]. / Récepteur du facteur de croissance épidermique HER2, tests utilisés pour rechercher son amplification dans le cancer du sein : principes et limites.

HER2-positive breast cancer accounts for 20 % of all invasive breast cancers. It is associated with increased recurrence, a higher risk of brain metastases and a shorter overall survival than luminal A and B cancers. The presence of ERBB2 gene amplification is predictive of a good response to anti-HER2 therapies. Determining HER2 status is a hot topic, given recent studies on HER2-low subtypes. Although several techniques are available, the latest 2018 update from the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) recommends a first immunohistochemical study followed by a fluorescence in situ hybridisation study indicated only for equivocal cases. This article summarises the different techniques used to determine HER2 status and provides a detailed review of the literature on pre-analytical factors and intrinsic tumour-specific factors that can distort or complicate the interpretation of results.

Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer.

BACKGROUND: The clinical characteristics and efficacy of human epidermal growth factor receptor-2 (HER-2)-directed agents against HER2 mutations and HER2 fusions in breast cancer are obscure due to their low frequency. METHODS: We conducted a retrospective study in patients with advanced breast cancer harboring HER2 mutations and/or HER2 fusions between January 1, 2017 and January 1, 2021. RESULTS: Among a total of 22 patients, 17 HER2 mutations were detected, including L755S, S310F, R100=, V777L, R897W, T862A, 440-17C > G, H878Y, V842I, 73 + 9G > C, T278fs, E1069K, L755P, 226-11C > T, 574 + 12C>T, L114V and P128L. The majority of patients had ductal carcinoma, which mostly coexisted with HER2 amplification/overexpression. The median progression-free survival (PFS) of the 22 patients was 6.9 months (95% CI: 4.7, 9.1) in the first-line setting. The median PFS of patients who received first-line trastuzumab-based regimens was significantly longer than that of patients who received a first-line tyrosine kinase inhibitor (TKI) (10.8 months [95% CI: 2.9, 18.7] vs. 1.9 months [95% CI: 0.8, 3.0], p < 0.005). A total of 14 patients were treated with anti-HER2 antibody-drug conjugate (ADC), among whom the median treatment line of first-time of administration of anti-HER2 ADC was 4.5 (range, 1-10). Anti-HER2 ADC reached an objective response rate (ORR) of 42.9%, a disease control rate (DCR) of 85.7% and a median PFS of 7.3 months (95% CI: 4.4-10.1) from the first-time of administration. CONCLUSION: Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.

Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: A meta-analysis and bioinformatic analysis of TCGA­BRCA data.

BACKGROUND: This study aimed to comprehensively explore the clinical significance of PIK3CA mutation in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with anti-HER2 therapy. METHODS: We systematically searched PubMed, Embase, and the Cochrane databases for eligible studies assessing the association between PIK3CA mutation and outcomes in patients with HER2-positive breast cancer receiving anti-HER2 therapy. The main outcomes included: (1) pathological complete response (pCR) or disease-free survival (DFS) for the neoadjuvant setting; (2) DFS or invasive DFS for the adjuvant setting; (3) objective response rate (ORR), progression-free survival (PFS), time-to-progression (TTP), or overall survival (OS) for the metastatic setting. The mutational landscape of HER2-positive breast cancer according to PIK3CA mutation status was examined based on TCGA breast cancer dataset. RESULTS: Totally, 43 eligible studies, covering 11,099 patients with available data on PIK3CA mutation status, were identified. In the neoadjuvant setting, PIK3CA mutation was significantly associated with a lower pCR rate (OR=0.23, 95% CI 0.19-0.27, p<0.001). This association remained significant irrespective of the type of anti-HER2 therapy (single-agent or dual-agent) and hormone receptor status. There were no significant differences in DFS between PIK3CA mutated and wild-type patients in either the neoadjuvant or adjuvant settings. In the metastatic setting, PIK3CA mutation predicted worse ORR (OR=0.26, 95%CI 0.17-0.40, p<0.001), PFS (HR=1.28, 95%CI 1.03-1.59, p = 0.024) and TTP (HR=2.27, 95%CI 1.54-3.34, p<0.001). However, no significant association was observed between PIK3CA mutation status and OS. Distinct mutational landscapes were observed in HER2-positive breast cancer between individuals with PIK3CA mutations and those with wild-type PIK3CA. CONCLUSIONS: PIK3CA mutation was significantly associated with a lower pCR rate in HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy. In the metastatic setting, PIK3CA mutation was predictive of worse ORR, PFS and TTP. These results suggest the potential for developing PI3K inhibitors as a therapeutic option for these patients.

A Rare Case of Pertuzumab-Induced Toxic Epidermal Necrolysis.

Pertuzumab is a targeted therapy drug that is employed in the management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer and works by blocking the ability of cancer cells to receive growth and proliferation signals. Toxic epidermal necrolysis (TEN) is a severe cutaneous manifestation characterized by widespread erythema, necrosis, and bullous detachment of the skin involving more than 10% of the body surface area (BSA) and may be precipitated by an immunologic response to the administration of certain medications. However, TEN development as a consequence of HER2 inhibitor therapy has not been described in the existing literature. A 44-year-old female with a history of metastatic breast cancer to the liver presented with a diffuse blistering rash following a first-time administration of pertuzumab three days prior. Her rash began as painful and pruritic blisters 12 hours after the last infusion of pertuzumab and progressed to involve her arms, chest, groin, and thighs with a positive Nikolsky sign. She was managed supportively with high-dose steroids and antihistamines, and although her hospital course was complicated by hypotension requiring pressor support, she gradually made a full recovery and was released to a rehabilitation facility.

Inetetamab in combination with rapamycin and chemotherapy for trastuzumab-treated metastatic human epidermal growth factor receptor 2-positive breast cancer with abnormal activation of PI3K/Akt/mTOR pathway.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression is an independent prognostic factor of poor prognosis and a predictor of efficacy of anti-HER2 therapy. A limited number of patients can receive standard second-line therapy (DS-8201 or T-DM1) for metastatic HER2-positive in some parts of the world, including China, due to many factors, such as cost-benefit ratios. CASE: A 51-year-old premenopausal woman was diagnosed with HER2-positive breast cancer. The pathological stage was ypT3N2M0 and stage IIIA. Trastuzumab targeted therapy combined with goserelin depot was started along with letrozole endocrine therapy. After eight courses of treatment, magnetic resonance imaging (MRI) examination revealed new multiple metastases in the liver, and progression disease (PD) was evaluated. Due to abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the patient, treatment was changed to the mammalian target of rapamycin (mTOR) inhibitor combined with the anti-HER-2 agents inetetamab and paclitaxel, while partial response (PR) was evaluated after 6 cycles of treatment. As the patient was hormone receptor (HR) positive, treatment was changed to the inetetamab + rapamycin + exemestane regimen. The lesion continued to shrink and PR was evaluated for 8 cycles. The original regimen was continued, PR was evaluated after 12 courses of treatment. The abdominal MRI performed showed an increase in the volume of intrahepatic multiple metastatic tumor lesion. Efficacy was used to assess for PD and the progression-free survival (PFS) was 317 days. CONCLUSION: A phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in trastuzumab-treated metastatic HER2-positive breast cancer female had a long PFS by treating with the mammalian target of rapamycin inhibitor in combination with the anti-HER-2 agent inetetamab.

A Case of HER2 Mutated Colorectal Cancer Treated Successfully With Fam-Trastuzumab Deruxtecan.

Colorectal cancer is a malignant tumor arising from the inner lining of the colon or rectum and is the third most common cancer and the third leading cause of cancer-related deaths in the United States. Human epidermal growth factor receptor 2 (HER2) gene overexpressed or amplified colorectal cancer has shown treatment responses with HER2-directed therapies. We present a 78-year-old woman with metastatic colorectal cancer with a HER2 L726I mutation identified in tumor sequencing with amplification or overexpression of HER2. She had an excellent response to fam-trastuzumab deruxtecan. Our case is the first and most noteworthy case of a patient with metastatic colorectal cancer and a HER2 L726I mutation who achieved a remarkable clinical response to fam-trastuzumab deruxtecan.

SEOM-GEICAM-SOLTI clinical guidelines in advanced breast cancer (2022).

Advanced breast cancer represents a challenge for patients and for physicians due its dynamic genomic changes yielding to a resistance to treatments. The main goal is to improve quality of live and survival of the patients through the most appropriate subsequent therapies based on the knowledge of the natural history of the disease. In these guidelines, we summarize current evidence and available therapies for the medical management of advanced breast cancer.

Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis.

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.

Paget disease of the breast with underlying invasive ductal cancer in neurofibromatosis type 1: a case report.

Background: Neurofibromatoses (NFs) are a group of rare autosomal dominant genetic disorders characterized by tumors growing in the nervous system. Neurofibromas, which are soft noncancerous tumors, have been found on or under the skin in patients with NF1. Furthermore, patients with NF1 are susceptible to various cancers, including breast cancer. Neurofibromas under the skin of the breast can delay the diagnosis of breast cancer, which severely reduces life expectancy. Paget disease of the breast (PDB) is a rare type of breast cancer that causes eczema-like changes of the nipple. Case Description: Here, we present a rare case of a 50-year-old woman who was diagnosed with NF1 and an invasive ductal breast carcinoma accompanied by PDB. The patient underwent mastectomy, sentinel lymph node biopsy, and adjuvant therapies, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and endocrine therapy. No local recurrence or distance metastasis was found at 3 years of follow-up. Conclusions: NF1 patients aged <50 years have a higher risk of breast cancer and a worse prognosis. Moreover, neurofibroma in the breast can easily mask signs of breast cancers. Therefore, early breast cancer screening is crucial for patients with NF1. Radiotherapy should be avoided because of potential carcinogenicity to the neurofibromas. Mastectomy, and not breast-conserving surgery, is the optimal choice. Patients should undergo regular postoperative follow-up so that contralateral breast cancer can be detected early.

HER2 Targeting in Esophagogastric Cancer: Redefining the Landscape and Breaking Barriers.

HER2 is overexpressed in approximately 20% of esophagogastric cancer (EGC) cases. The addition of the anti-HER2 antibody, trastuzumab, to chemotherapy in 2010 was the first targeted treatment to demonstrate an improvement in survival. The aggressive nature and heterogeneous biology of EGC have posed a particular challenge and resulted in numerous negative trials without a change in standard of care for more than a decade. However, with the incorporation of dual HER2 and PD-1 blockade as well as the advent of a new, potent antibody-drug conjugate, trastuzumab deruxtecan, there have been 2 new FDA approvals for this patient population within the past 2 years. Consequently, the management and landscape of HER2-positive EGC is rapidly changing and increasingly optimistic.