Effect of HER2-low status on brain metastasis-free survival and survival after brain metastasis in patients with breast cancer.

AIMS AND OBJECTIVES: The discovery of novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates has accelerated the identification of the HER2-low subtype. However, the biological significance of low HER2 expression in breast cancer brain metastasis (BCBM) is unclear. METHODS: Patients with HER2-negative BC and brain metastasis were retrospectively screened between February 2012 and November 2023. Brain metastasis-free survival (BMFS) and survival after brain metastasis (SABM) were analyzed according to HER2 expression. RESULTS: A total of 201 female patients, 84 of whom were HER2-low and 117 of whom were HER2-zero, were evaluated. The median BMFS in the entire cohort was 35.6 months (95% CI 29.8-41.4). Although HER2-low patients had numerically longer median BMFS than HER2-zero patients (43.7 m vs. 30.1 m, p = 0.025), multivariate analysis revealed that the difference was not significant (p = 0.167). BMFS between the HER2-low and HER2-zero groups was similar in the hormone receptor (HR)-positive (52.8 m vs. 47.6 m, p = 0.276) and HR-negative (15.3 m vs. 19.7 m, p = 0.930) cohorts. The median SABM in the entire cohort was 6.0 months (95% CI 3.8-8.1). HER2-low and HER2-zero patients had similar median SAMB (5.4 m vs. 6.1 m, p = 0.816). The SABM between the HER2-low and HER2-zero groups was similar in the HR-positive (6.3 m vs. 8.7 m, p = 0.375) and HR-negative (3.3 m vs. 4.2 m, p = 0.783) cohorts. CONCLUSIONS: Low HER2 expression does not affect BMFS or SAMB in brain metastatic breast cancer patients in this real-world population.

Weakly-supervised deep learning models enable HER2-low prediction from H &E stained slides.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a new subtype of tumor, for which novel antibody-drug conjugates have shown beneficial effects. Assessment of HER2 requires several immunohistochemistry tests with an additional in situ hybridization test if a case is classified as HER2 2+. Therefore, novel cost-effective methods to speed up the HER2 assessment are highly desirable. METHODS: We used a self-supervised attention-based weakly supervised method to predict HER2-low directly from 1437 histopathological images from 1351 breast cancer patients. We built six distinct models to explore the ability of classifiers to distinguish between the HER2-negative, HER2-low, and HER2-high classes in different scenarios. The attention-based model was used to comprehend the decision-making process aimed at relevant tissue regions. RESULTS: Our results indicate that the effectiveness of classification models hinges on the consistency and dependability of assay-based tests for HER2, as the outcomes from these tests are utilized as the baseline truth for training our models. Through the use of explainable AI, we reveal histologic patterns associated with the HER2 subtypes. CONCLUSION: Our findings offer a demonstration of how deep learning technologies can be applied to identify HER2 subgroup statuses, potentially enriching the toolkit available for clinical decision-making in oncology.

Subcutaneous versus intravenous administration of Trastuzumab: a minimization cost analysis with real world data from a reference cancer centre in Peru.

Breast cancer (BC) is a global concern, with Peru experiencing a high incidence and mortality. Trastuzumab, a crucial treatment for human epidermal growth factor receptor 2-positive BC, is administered intravenously or subcutaneously (SC). This study evaluates the costs associated with both methods at Peru's Instituto Nacional de Enfermedades Neoplásicas. Real data indicate that SC administration reduces treatment costs by approximately S/15,049.09. Cross-continental comparisons highlight a global trend favouring SC administration for efficiency and cost-effectiveness. The analysis provides insights for informed decision-making in resource-constrained healthcare settings like Peru, emphasising the need to consider local contexts in optimising oncology care.

Proteomic Characterization of a 3D HER2+ Breast Cancer Model Reveals the Role of Mitochondrial Complex I in Acquired Resistance to Trastuzumab.

HER2-targeted therapies, such as Trastuzumab (Tz), have significantly improved the clinical outcomes for patients with HER2+ breast cancer (BC). However, treatment resistance remains a major obstacle. To elucidate functional and metabolic changes associated with acquired resistance, we characterized protein profiles of BC Tz-responder spheroids (RSs) and non-responder spheroids (nRSs) by a proteomic approach. Three-dimensional cultures were generated from the HER2+ human mammary adenocarcinoma cell line BT-474 and a derived resistant cell line. Before and after a 15-day Tz treatment, samples of each condition were collected and analyzed by liquid chromatography-mass spectrometry. The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients. In conclusion, the non-responder phenotype identified here provides a signature of proteins and related pathways that could lead to therapeutic biomarker investigation.

Association between Helicobacter pylori infection, mismatch repair, HER2 and tumor-infiltrating lymphocytes in gastric cancer.

BACKGROUND: The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information. AIM: To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC. METHODS: Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 immune cells, and dMMR and HER2-status were determined by immunohistochemistry (IHC). H. pylori infection was evaluated by routine histology and quantitative PCR (qPCR) in a subset of samples. RESULTS: dMMR was found in 34.4%, HER2+ in 5% and H. pylori-positive in 55.7% of samples. High IT-TIL was associated with grade-3 (P = 0.038), while ST-TIL with grade-1 (P < 0.001), intestinal-histology (P < 0.001) and no-recurrence (P = 0.003). dMMR was associated with high TIL levels in the ST (P = 0.019) and IB (P = 0.01) compartments, and ST-CD3 (P = 0.049) and ST-CD8 (P = 0.05) densities. HER2- was associated with high IT-CD8 (P = 0.009). H. pylori-negative was associated with high IT-TIL levels (P = 0.009) when assessed by routine-histology, and with high TIL levels in the 3 compartments (P = 0.002-0.047) and CD8 density in the IT and ST compartments (P = 0.001) when assessed by qPCR. A longer overall survival was associated with low IT-CD163 (P = 0.003) and CD8/CD3 (P = 0.001 in IT and P = 0.002 in ST) and high IT-CD3 (P = 0.021), ST-CD3 (P = 0.003) and CD3/CD163 (P = 0.002). CONCLUSION: TIL levels were related to dMMR and H. pylori-negativity. Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Germline rare variants in HER2-positive breast cancer predisposition: a systematic review and meta-analysis.

Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571). Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene. Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571.

Real-World Study of Adjuvant Biosimilar Trastuzumab-dkst for HER2-Positive Breast Cancer Treatment in a Brazilian Population.

INTRODUCTION: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. METHODS: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. RESULTS: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. CONCLUSION: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. GOV REGISTRATION: NCT03892655.

Survival outcomes of Zo-NAnTAx: a five-year analysis of zoledronic acid added to a neoadjuvant regimen for HER2-positive breast cancer.

Background: Zoledronic acid (ZA) improved outcomes in breast cancer. In pre-clinical studies, ZA increased tumour regression in combination chemotherapy and anti-human epidermal growth factor receptor 2 (HER2) target therapy. The Zo-NAnTax study, a clinical trial combining ZA with neoadjuvant therapy for HER2-positive tumours met the primary endpoint, showing a higher pathological complete response (pCR) rate than predicted in patients receiving surgery. Here, we report the exploratory relapse-free survival (RFS) and overall survival (OS) analysis after five years of follow-up. Methods: Adult women with HER2-positive breast cancer amendable to curative surgery who consented to the study received four cycles of ZA at 4 mg + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of ZA at 4 mg + docetaxel 100 mg/m2 + trastuzumab 6 mg/kg (8 mg/kg as a loading dose), all in a 21 days-cycle, totalizing 8 cycles before surgery. To achieve the primary endpoint of pCR rate between 22% and 35%, 56 patients were needed. The secondary endpoints included safety, gene expression according to treatment response, prediction of pCR rate by an interim breast magnetic resonance imaging (bMRI). Results: Beyond the overall pCR rate of 42%, alongside a good safety profile, we showed similar pCR rates in both hormonal receptor (HR) positive (40%) and HR-negative (44%). RFS and OS at five years were evaluated in 58 subjects, and the overall rate was 79.3% and 86.2%, respectively. Numerically higher values of both RFS and OS were observed in patients achieving pCR vs. non-achieving, respectively 83.3% vs. non-pCR 76.5% (P=0.57) and 95.8% vs. non-pCR 79.4% (P=0.08). Although not statistically significant, OS was numerically equivalent according to HR status, respectively 85.7% vs. 87.5% for HR-positive and HR-negative (P=0.91), which contrasted with RFS, HR-positive 81% vs. HR-negative 75% (P=0.58). None of the assessed clinicopathological biomarkers significantly correlated with survival. Conclusions: ZA plus neoadjuvant therapy in HER2-positive breast cancer shows provoking survival outcomes. Clinical and pre-clinical investigation with dual anti-HER2 blockage is warranted.

Significance of concurrent evaluation of HER2 gene amplification and p53 and Ki67 expression in gastric cancer tissues.

OBJECTIVE: The primary objective of this study is to explore the significance of concurrent evaluation of HER2 gene amplification and p53 and Ki67 expression in gastric cancer tissues. METHODS: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methodologies were used to detect HER2 gene amplification, as well as the expression levels of HER2, p53, and Ki67 proteins, across a group of 78 gastric cancer cases. RESULTS: The expression rate of the HER2 protein was determined to be 43.6% (34/78), with 17.9% (14/78) categorized as HER2 protein 3 + , 14.1% (11/78) as HER2 protein 2 + , and 11.5% (9/78) as HER2 protein 1 + . Using FISH technology, the HER2 gene amplification rate was identified as 19.2% (15/78), including 3 cases of HER2 gene cluster amplification, 5 cases of large granular amplification, 4 cases of punctate amplification, and 3 cases of high polysomy. The positive rate of p53 in gastric cancer cells was 52.6% (41/78), with 62.8% (49/78) of patients exhibiting a ki67 proliferation index ≤ 30, and 37.2% (29/78) accounting for a ki67 proliferation index > 30. The expression rates of the HER2 gene, p53, and ki67 in gastric cancer tissues were significantly associated with both gastric cancer staging and lymph node metastasis (P < 0.05). CONCLUSION: The HER2 gene amplification rate and gene copy number exhibit a positive correlation with the expression rates of p53 and ki67. Combining these assessments can provide crucial insights into the assessment of metastatic potential, disease progression, and prognosis of gastric tumor cells. This holds paramount importance in steering the formulation of individualized treatment strategies.

HER2/neu 655 polymorphism, trastuzumab-induced cardiotoxicity, and survival in HER2-positive breast cancer patients.

PURPOSE: HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20% of patients treated with the drug. This study aims to investigate the association between the HER2 655 A > G polymorphism, Trastuzumab-induced cardiotoxicity, and patient survival. METHODS: The study involved 88 patients treated with Trastuzumab. Cardiotoxicity, defined as a reduction in left ventricular ejection fraction (LVEF) from baseline or the emergence of clinical signs of congestive heart failure, was identified during treatment follow-up. Genotyping of HER2 655 A > G employed TaqMan SNP technology. RESULTS: Genotype frequencies of HER2/neu 655 (53 AA, 32 AG, and 3 GG) were consistent with Hardy-Weinberg equilibrium. No significant differences were observed in mean baseline LVEF between patients who developed cardiotoxicity and those who did not. Within these groups, neither AA nor AG genotypes showed an association with changes in mean baseline or reduced LVEF levels. Logistic regression analysis, adjusted for hormonal status and anthracycline treatment, revealed that AG genotype carriers face a significantly higher risk of cardiotoxicity compared to AA carriers (OR = 4.42; p = 0.037). No association was found between the HER2/neu 655 A > G polymorphism and disease-free or overall survival, regardless of whether the data was adjusted for stage or not. CONCLUSION: HER2 655 A > G polymorphism is significantly linked to an increased risk of Trastuzumab-induced cardiotoxicity but does not correlate with variations in disease-free survival or overall survival rates.

Efficacy of First-Line Treatment With Pertuzumab and Trastuzumab in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Routine Clinical Practice.

Background: The first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) involves a combination of trastuzumab, pertuzumab, and a taxane (TPH). This study assessed the efficacy of trastuzumab and pertuzumab (PH) in routine practice, following the treatment protocols of Uruguay's National Resources Fund (FNR), akin to clinical trials. Methods: Patients with advanced MBC treated with PH between 2008 and 2022 per FNR protocols were evaluated. The Kaplan-Meyer method and log-rank test were utilized for analyzing overall survival (OS). Demographic and clinical variables, including age, menopausal status, and hormone receptors (HR), were analyzed. Results: The study included 318 PH-treated patients. The median age was 56 years, with 63.2% being postmenopausal and 60.4% HR and HER-2 positive. With a median follow-up of 17.2 months, the median OS was 29 months. OS varied based on HR status and the presence of metastases at different sites, significantly lower in patients with brain, cutaneous/subcutaneous, and pulmonary metastases. Additionally, OS was higher in patients treated at private institutions compared to public ones. Conclusions: This study demonstrates the disparity in oncological treatment efficacy between clinical trials and clinical reality in Uruguay, emphasizing the importance of authentic environment research for more representative and effective medicine in Latin America.

Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

Management of early-stage HER2-positive breast cancer and attitudes towards HER2DX test in Spain: insights from a nationwide survey.

PURPOSE: This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. METHODS: An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. RESULTS: The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. CONCLUSION: In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

Can neoadjuvant systemic therapy provide additional benefits for T1 HER2+ breast cancer patients: a subgroup analysis based on different high-risk signatures.

INTRODUCTION: Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD: A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS: Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P  <  0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION: Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.

Real-world experience with pertuzumab and trastuzumab combined with chemotherapy in neoadjuvant treatment for patients with early-stage HER2-positive breast cancer: the NEOPERSUR study.

PURPOSE: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. METHODS: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). RESULTS: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients. CONCLUSION: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.

Effect of HER2/CEP17 ratio on survival in metastatic HER2-positive gastric cancer, multicenter study.

AIM: HER2-positive metastatic gastric cancer is still a highly fatal disease despite advances. We aimed to investigate the relationship between HER2/CEP17 ratio and survival in patients with HER2-positive metastatic gastric cancer. METHODS: A total of 99 patients from 8 different centers in Turkey were included in the study. Patients with HER2-positive metastatic gastric cancer and whose HER2/CEP17 ratio was examined were included in the study. Patients were divided into two groups according to HER2/CEP17 values, and survival analysis was performed. RESULTS: The median age was 64 (24-83) years. There were 74 (74.8%) male and 25 (25.2%) female patients. OS in the high HER2/CEP17 ratio group was 21.97 months (95% CI: 16.36-27.58), and in the low ratio group was 16.17 months (95% CI: 10.95-21.38) (p = 0.015). OS was 17.7 months (95% CI: 7.02-28.37) in the high HER2 gene copy number group and 10.13 months (5.55-14.71) in the group with low copy number (p = 0.03). PFS was 10.94 months (95% CI: 7.55-14.33) in the group with high HER2 gene copy number and 7.56 months (4.62-10.49) in the low copy number group (p = 0.06). CONCLUSION: Patients with both high HER2 gene amplification and high HER2/CEP17 ratio had better OS. The PFS of the group with high HER2 gene amplification was also better. To our knowledge, this is the first study in the literature showing that the HER2/CEP17 ratio affects survival in patients with metastatic gastric cancer.

EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells.

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.

Efficacy and delivery strategies of the dual Rac/Cdc42 inhibitor MBQ-167 in HER2 overexpressing breast cancer.

Trastuzumab and trastuzumab-based treatments are the standard of care for breast cancer patients who overexpress the human epidermal growth factor receptor 2 (HER2). However, patients often develop resistance to trastuzumab via signaling from alternative growth factor receptors that converge to activate guanine nucleotide exchange factors (GEFs) that in turn activate the Rho GTPases Rac and Cdc42. Since Rac and Cdc42 have been implicated in high tumor grade and therapy resistance, inhibiting the activity of Rac and Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Therefore, our group developed MBQ-167, a dual Rac/Cdc42 inhibitor with IC50s of 103 nM and 78 nM for Rac and Cdc42, respectively, which is highly effective in reducing cell and tumor growth and metastasis in breast cancer cell and mouse models. Herein, we created a trastuzumab resistant variant of the SKBR3 HER2 positive breast cancer cell line and show that Rac activation is a central mechanism in trastuzumab resistance. Next, we tested the potential of targeting MBQ-167 to HER2 overexpressing trastuzumab-resistant cell lines in vitro, and show that MBQ-167, but not trastuzumab, reduces cell viability and induces apoptosis. When MBQ-167 was targeted to mammary fatpad tumors established from HER2 overexpressing cells via immunoliposomes functionalized with trastuzumab, MBQ-167 and MBQ-167-loaded liposomes show equal efficacy in reducing the viability of trastuzumab-resistant cells, inhibiting tumor growth in mouse xenografts, and reducing metastasis to lungs and liver. This study demonstrates the efficacy of MBQ-167 as an alternative therapeutic in HER2 overexpressing cancers, delivered either in free form or in liposomes.

Safety profile of trastuzumab deruxtecan in advanced breast cancer: Expert opinion on adverse event management.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) and has shown promising results in the treatment of advanced/metastatic breast cancer. The objective of this report is to provide guidance on the prophylaxis, monitoring, and management of adverse events (AEs) in patients with breast cancer treated with T-DXd, and to emphasize that proper management of AEs is needed to optimize the effectiveness of T-DXd treatment and reduce the number of discontinuations. The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical recommendations for managing AEs, such as nausea/vomiting, interstitial lung disease, and hematologic toxicity. Although there are still many knowledge gaps about the cause and incidence of AEs in real-world patients, this document may serve as a valuable resource for clinicians who are involved in the care of breast cancer patients receiving T-DXd treatment.

Distribution of PD-L1, TROP2 and HER2- "lowness" in early triple-negative breast cancer: an opportunity for treatment de-escalation.

BACKGROUND: HER2, TROP2 and PD-L1 are novel targets in triple-negative breast cancer (TNBC). The combined expression status of these targets, and whether they can define prognostic subgroups, is currently undefined. METHODS: Immunohistochemistry was used to determine HER2, TROP2 and PD-L1 levels in 459 TNBC cases, that received in the adjuvant/neoadjuvant setting active surveillance, CMF, anthracycline-, anthracycline plus taxane-, or carboplatin-containing regimes. RESULTS: HER2-low patients with PD-L1 > 1 CPS (double-positive, herein "DP") had a mean PFS of 4768 days (95% CI: 4267-5268) versus 3522 days (95% CI: 3184-3861) for non-DP patients (P = 0.002). Regarding the received adjuvant treatment, DP patients (versus non-DP) receiving anthracyclines plus taxanes exhibited a mean PFS time of 4726 (95% CI: 4022-5430) versus 3302 (95% CI: 2818-3785) days (P = 0.039). Finally, 100% of DP patients that received a carboplatin-based regimen were long-term disease-free. CONCLUSIONS: Early HER2-low, PD-L1-positive TNBC patients have a very good prognosis, particularly if treated with anthracycline/taxane- or carboplatin-containing regimes.