Negative HER2 Research Articles

HER2-neu Expression and Survival in Colorectal Cancer in the South of Egypt; Immunohistochemistry and Genetic Study.

Colorectal cancer (CRC) is a major public health problem and one of leading cancer related death all over the world. One of the prognostic parameters that play a role in different types of cancer is HER2. However, the role of HER2 in CRC and its relation with clinicopathological features and survival is conflicting. We hypothesize that HER2 has different patterns of expression in CRC which may affect the prognosis of patients. We studied sixty specimens of colorectal carcinoma for HER2 immunohistochemistry and gene amplification and correlate it with clinicopathological features and patients` survival. Our data showed that negative HER2 expression was statistically associated with female gender (P = 0.010) and low & intermediate tumor budding (P = 0.030). There was a statistically significant relation between HER2 IHC and HER2 FISH amplification (P=0.000). Although neither HER2 immunoexpression and FISH amplification showed significant relation with overall survival nor disease free survival, HER2 amplified CRCs tended to have a worse survival compared with negative CRCs (40 months versus 50 months). The presence of male gender, lymphovascular invasion, nodal metastasis and distant metastasis (P = 0.013, 0.006, 0.006 and 0.000 respectively) were significantly statistically associated with poor overall survival. The presence of tumor grade III and high tumor budding (P = 0.035 and 0.007 respectively) were significantly statistically associated with shorter disease free survival. Our results showed that HER2 IHC 3+ staining is highly predictive of HER2 gene amplification in colorectal carcinomas. There is a tendency towards poorer prognosis in amplified HER2 CRC cases.

Identifying mutations in ctDNA to predict antibody-drug conjugate response in breast cancer.

e13074 Background: Metastatic breast cancer (mBC) is a complex disease, and outcomes remain poor because new therapies are needed. A new class of drugs, antibody-drug conjugate (ADC), has shown effectiveness across all breast cancer subtypes. Yet FDA- approval for these therapies is restricted only to HER2 and triple-negative subtypes. Therefore, we urgently need to identify which patients, regardless of subtype, will respond to ADCs. The advent of circulating tumor DNA (ctDNA) offers a unique noninvasive method to capture breast cancer (BC) heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for mBC, particularly in cases of hormone receptor positive (HR+) disease with mutations in PIK3CA and ESR1. The clinical implications to predict response to ADC therapy in BC remains unclear. Here we test the hypothesis that ctDNA can detect mutations that predict response to novel ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with mBC who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. The data was analyzed from a single academic medical center between the initial year of ctDNA collection in 2019 to 2023. We identified detectable mutations from patients and addressed a relationship by using Metascape. Relevant signaling pathways were identified: APOBEC, ErbB signaling, p53 and Ras-MAPK pathway. Patients with triple negative, HER2, and HR BC were examined for ADC response and associated mutations. Survival analyses were estimated using Kaplan-Meier and Gehan Breslow Wilcoxon test for statistical analysis. Results: We identified 43 patients with HR+ mBC who had at least one mutation within the Ras-MAPK pathway and 10 of 43 received ADC therapy. Median survival of patients who received ADC therapy 58 months (n=10) vs not receiving ADC therapy 33 months (n=33) (p < 0.05). Of the ten patients who received ADC treatment, 60% had 1+ HER2 staining on tissue biopsy. 70% of patients received Trastuzumab deruxtecan (T-DXd) and 30% received Sacituzumab govitecan (SG). SG was given to patients with negative HER2 staining on biopsy. Patients with at least one mutation within ABOBEC, ErbB signaling, and p53 pathways did not have statistically significant differences in mOS. Conclusions: In HR+ mBC, detection of mutated genes associated with the Ras-MAPK pathway by ctDNA was associated with a more favorable response when treated with ADCs. These findings are exciting because HR+ BCs are being targeted with ADCs regardless of HER2 or TROP2 expression, highlighting the need for new biomarkers to distinguish which HR+ patients to treat. Our retrospective analysis findings are limited by the number of patients with ctDNA testing and also timing of testing. Further studies are needed to solidify the observed correlation between Ras-MAPK pathway mutations and favorable response to ADC treatment.

Molecular characterization of breast cancer cell lines in correlation with clinical markers

Cell lines are indispensable for biomedical research, offering a consistent platform for investigating cellular processes and disease mechanisms. Despite their value, cell lines possess limitations such as genetic drift and phenotypic alterations over successive passages, potentially compromising their relevance. Monoclonal derivation may not represent in vivo heterogeneity, particularly in cancer. Therefore, characterizing them becomes imperative. We aimed to identify breast cancer subtype-specific cell lines by assessing ER, PR, and HER-2 expression via immunohistochemistry and their concordance with molecular expression. We selected cell lines with consistent phenotypes that mimic primary cells and confirmed concordance in ER, PR, and HER-2 expression at protein and mRNA levels. Evaluation of ER, PR, and HER-2 was conducted using Immunocytochemistry (ICC), Immunofluorescence (IF), and real-time PCR across commonly used breast cancer cell lines. Results revealed differential expression patterns, with MCF-7 and T-47D cells showing positive ER and PR staining but negative HER-2 staining, while SK-BR-3 and HCC1954 cells exhibited positive HER-2 staining and negative ER and PR staining. Conversely, MDA-MB-231 and MDA-MB-468 cells displayed negative staining for all three markers. Real-time PCR analysis highlighted variations in HER-2 expression among the cell lines. Our investigation underscores MCF-7, SK-BR-3, MDA-MB-231, and MDA-MB-468 cell lines as pertinent models for studying major molecular subtypes of breast cancer.

Use of MRI Radiomics Models in Evaluating the Low HER2 Expression in Breast Cancer.

To investigate the magnetic resonance imaging (MRI) radiomics models in evaluating the human epidermal growth factor receptor 2(HER2) expression in breast cancer. The MRI data of 161 patients with invasive ductal carcinoma (non-special type) of breast cancer were retrospectively collected, and the MRI radiomics models were established based on the MRI imaging features of the fat suppression T2 weighted image (T2WI) sequence, dynamic contrast-enhanced (DCE)-T1WIsequence and joint sequences. The T-test and the least absolute shrinkage and selection operator (LASSO) algorithm were used for feature dimensionality reduction and screening, respectively, and the random forest (RF) algorithm was used to construct the classification model. The model established by the LASSO-RF algorithm was used in the ROC curve analysis. In predicting the low expression state of HER2 in breast cancer, the radiomics models of the fat suppression T2WI sequence, DCE-T1WI sequence, and the combination of the two sequences showed better predictive efficiency. In the receiver operating characteristic (ROC) curve analysis for the verification set of low, negative, and positive HER2 expression, the area under the ROC curve (AUC) value was 0.81, 0.72, and 0.62 for the DCE-T1WI sequence model, 0.79, 0.65 and 0.77 for the T2WI sequence model, and 0.84, 0.73 and 0.66 for the joint sequence model, respectively. The joint sequence model had the highest AUC value. The MRI radiomics models can be used to effectively predict the HER2 expression in breast cancer and provide a non-invasive and early assistant method for clinicians to formulate individualized and accurate treatment plans

Abstract PO4-18-11: Phase 1 study of the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors (JEWEL-101): Design of the triple-negative and hormone receptor-positive breast cancer expansion cohorts

Abstract Background: Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor, initiating the extrinsic coagulation cascade. TF is aberrantly expressed in multiple solid tumors, including breast cancer (BC), and its expression is associated with disease progression and poor prognosis (van den Berg et al. Blood 2012). Microtubule-targeting agents are a cornerstone of treatment for metastatic BC. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to the zovodotin linker-payload. Zovodotin consists of an auristatin-based payload and a protease-cleavable linker and is designed to lower off-target deconjugation and improve tolerability compared with other microtubule inhibitor linker-payloads. In preclinical studies, XB002 did not interfere with coagulation and demonstrated antitumor activity with an encouraging safety profile. XB002 is being evaluated in JEWEL-101, an ongoing trial in patients (pts) with advanced solid tumors, including BC. Preliminary results from the dose-escalation stage of JEWEL-101 showed XB002 was well tolerated at multiple dose levels with no bleeding events or treatment-related peripheral neuropathy (PN) and low-grade ocular toxicity (Ulahannan et al. ENA 2022). Presented here is the study design of the tumor-specific expansion stage, including triple-negative BC (TNBC) and hormone receptor-positive BC (HR+ BC) cohorts. Trial design and statistical methods: JEWEL-101 (NCT04925284) is a multicenter, open-label, phase 1 trial evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of XB002 in advanced solid tumors. Single-agent XB002 at the recommended dose will be assessed in the BC expansion cohorts utilizing Simon’s Two-Stage design. Eligibility criteria: The trial will enroll adult pts with TNBC (ER-/PR-/HER-2-negative or low) and HR+ BC (ER+ and/or PR+ and HER-2-negative or low) into 2 separate cohorts. HER-2 negativity is defined as either HER-2 negative or low by local ISH or IHC assessment. For both cohorts, pts must have received 1–3 lines of prior systemic anticancer therapies for locally advanced or metastatic disease. Pts in the HR+ BC cohort must have received prior endocrine therapy and CDK4/6 inhibitor. All pts must have cytologically or histologically and radiologically confirmed BC that is inoperable, locally advanced, metastatic, or recurrent. Documented radiographic progression during or following their last systemic anticancer therapy is required. All pts must also have measurable disease per RECIST 1.1 by investigator assessment, archival (< 2 years) or fresh tumor tissue, ECOG PS 0 or 1, and adequate organ and marrow function. Pts with grade 1 PN are allowed. Concomitant anticoagulation therapy while receiving XB002 is permitted if clinically indicated. Key exclusions are prior use of TF-targeting or auristatin derivate-based ADC; uncontrolled, significant intercurrent or recent illness, including acute or chronic significant ocular disorders; major surgery within 4 weeks; and corrected QT interval calculated by the Fridericia formula >480 ms per ECG. Specific aims: The primary objective of the expansion stage is to evaluate the preliminary efficacy of XB002 by estimating the objective response rate per RECIST 1.1 as assessed by the investigator. Secondary objectives include safety and tolerability, PK, immunogenicity, progression-free survival, duration of response, and overall survival. Accrual: Up to 28 pts will be enrolled into each BC cohort. Enrollment is planned across sites in the US, Europe, and Asia-Pacific. Contact information: Exelixis Clinical Trials, druginfo@exelixis.com, 1-888-393-5494 Citation Format: Susanna Ulahannan, Melissa Johnson, Mia Weiss, Andrae Vandross, Sofia Vidal-Cardenas, Mustafa Syed, Anthony Tolcher. Phase 1 study of the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors (JEWEL-101): Design of the triple-negative and hormone receptor-positive breast cancer expansion cohorts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-11.

Abstract PO5-19-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information. Pathological complete response (pCR) following neoSACT, particularly in patients with earlier clinical TNM stage at diagnosis, identifies a population with excellent survival outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to absolute clinical benefit. Aims >HER2-RADiCAL seeks to reduce the treatment burden and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less systemic therapy with minimal/no loss of efficacy. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort/threshold-crossing design study embedded within a real-world data-driven clinical pathway model. Patients with ER-positive or negative HER2+ EBC with cT1N1 or cT2N0-1 stage at diagnosis are eligible after completion of standard of care neoSACT and locally determined pCR (ypT0/Tis ypN0). Patients with pathological features consistent with previous malignant involvement in >4 nodes are not eligible. Adjuvant trastuzumab +/- pertuzumab may have continued prior to study entry provided no more than 9 cycles of trastuzumab are received. After registration all participants receive a total of 9 cycles of trastuzumab including those administered prior to study entry. Participants receive no further pertuzumab and no adjuvant chemotherapy. Adjuvant endocrine therapy and radiotherapy are given as per standard of care. Central pathology review of pCR status will be conducted in a subset of cases. A Study Within a Trial (SWAT) will explore identification of factors influencing patient decision-making for participation in studies of response-adapted treatment. Statistical methods The primary endpoint is relapse-free interval. Recruitment of 720 participants over 3.5 years will provide 90% power to exclude an event rate >6.5% at 3 years (expected event rate ≤4%). Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, overall survival, treatment pathway adherence and cost-effectiveness. An interventional cohort is preferred to a randomised non-inferiority trial based on the known event rate in this population which is sufficiently low such that any deviation from this expected event rate would indicate failure of the reduced therapy strategy. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway derived from anonymised data for all patients treated for HER2+ EBC within the UK NHS. Patient and public involvement Our PPI partners continue to shape this research, holding key roles as trial management group members, overseeing progress of the study, contributing to protocol amendment development, and design and implementation of the SWAT. Current status The first patient was enrolled in December 2021. At 10th July 2023, 25 research sites have opened with 39 participants recruited. Site opening continues with a minimum target of 40. Responding to continued use of anthracycline-based regimens in UK practice, eligibility criteria have recently been extended to permit entry of patients who have received anthracycline-containing neoSACT. For further information contact her2radical-icrctsu@icr.ac.uk. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Laura Moretti, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Cliona Kirwan, Ciara O'Brien, Duncan Wheatley, Jennifer Glendenning, Mairead MacKenzie, Hilary Stobart, Claire Snowdon, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-01.

Abstract PO2-14-05: COMPARISON OF HER2 mRNA PCR LEVELS AND IMMUNOHISTOCHEMISTRY (IHC) IN HORMONE RECEPTOR POSITIVE (HR+)/HER2 NEGATIVE (HER2-) EARLY BREAST CANCER

Abstract BACKGROUND IHC assays were developed to identify HER2-positive breast cancers deemed to be treated with trastuzumab-based therapies. However, these assays lack sensitivity to reliably identify tumors with low levels of HER2 protein on the cell surface. HR+/HER2-low may benefit from Trastuzumab Deruxtecan (TDxd) and therefore accurate quantification of HER2 expression levels becomes a critical issue. As a result, additional technologies are needed to achieve a quantitative and reproducible detection of HER2 in the low range expression compared with the standard IHC testing. METHODS We conducted a retrospective study of all incident stage I-II HR +/HER2- breast cancer patient whose genomic risk was assessed with the Oncotype 21 gene assay from 2009 to 2022 in Hospital Clínico San Carlos (Spain). Local HER2 expression (IHC w/wo cerbB2 FISH) was performed in all patients according to ASCO/CAP guidelines available during the different periods. HER2 mRNA expression levels by RT-PCR were obtained from OncotypeDx patient reports. The primary objective was to determine the distribution of HER2 mRNA levels across the different HER2 expression groups. Other objectives were to compare the clinicopathological characteristics, management and OncotypeDX Recurrence Score (RS) in the different HER2 expression groups. Qualitative variables are presented with their frequency distribution. Quantitative variables are summarized in their mean and standard deviation (SD). Welch’s F-test ANOVA was used to measure association between the two HER2 measuring methods. RESULTS 500 early breast cancer patients with HER2 IHC 0, 1+ and 2+ (FISH negative) and HER2 mRNA expression by RT-PCR tumors were included. Among them, 169 (34%) were IHC 0, 211(42%) were IHC 1+ and 120 (24%) were IHC 2+ (FISH negative). The distribution of clinicopathological characteristics was similar between different IHC HER2 expression groups, and the distribution of chemotherapy treatment was also similar among them (Table 1). All patients had undergone surgery, and most of them had received hormone therapy (487, 97%) and radiotherapy when indicated (375, 77%). The mean OncotypeDx® recurrence score across HER2 IHC 0, 1, 2 showed not significant difference between groups (16,85, 17,36 and 17,89 respectively). The mean OncotypeDx® HER2 gene score expression across the different levels of HER2 (0, 1+, 2+) determined by IHC were 9.07, 9.25 and 9.51, respectively. One-way ANOVA and Games-Howell post-hoc test revealed that differences between all the groups were significant. The ranges of HER2 gene score data for the 3 IHC groups were widely overlapped, with IQR of [8,5-9,5], [8,83-9,7] and [9,07-10] respectively. CONCLUSIONS Our data show statistically significant differences between HER2 mRNA expression levels and IHC groups. This suggests that RT-qPCR could complement the data obtained by IHC. However, the wide range and dispersion of mRNA expression within groups limits its clinical utility. Clinicopathological characteristics and management between different IHC HER2 expression groups. Citation Format: Julia Tejerina-Peces, Marta Amann-Arévalo, Pablo Ballestín, Beatriz González-Diez, Mateo Paz-Cabezas, Alejandro Pascual, Alicia de Luna, Vanesa García-Barberán, Alfonso López de Sá, Jose Angel García-Sáenz, Fernando Moreno. COMPARISON OF HER2 mRNA PCR LEVELS AND IMMUNOHISTOCHEMISTRY (IHC) IN HORMONE RECEPTOR POSITIVE (HR+)/HER2 NEGATIVE (HER2-) EARLY BREAST CANCER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-14-05.

Abstract PO2-17-08: A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA

Abstract Background: Hormonal receptor positive Her2 negative also described as luminal breast cancer (LBC) is the most frequent tumor corresponding to about 60-65% of cases. There is great heterogeneity in these tumors and a great difference between treatments due to lack of access, mainly in developing countries. Clinical trials are important to understand the benefit of the treatments but only 5% of the breast cancer patients are enrolled in these trials and is because of that that Real World Data (RWD) is It's becoming more and more frequent. Objectives: To evaluate LBC and describe treatments and overall survival (OS) of patients treated in public hospital in São Paulo Brazil. Methods: This was a retrospective, single cohort study, that included female patients over 18 years of age, with a diagnosis of LBC. Clinical and pathological data was collected (date of diagnose, first treatment, type of treatment, stage, type of surgery, DFS and OS). This study was approved by our local ethics committee. Results: We’ve enrolled 5,510 patients in Perola Byington ’database from 2010 to 2021. After excluding patients without minimal complete records, a total of 4,885 patients were analyzed. Most patients were diagnosed in stage I (26,9%) and II (38,2%). There was 23,4% in stage III, 3,1% in stage IV and 5,7% in stage 0. In 2,6% the of the patient’s information was not complete. Mean age at diagnosis was 57.6 years. We identified 4,761 (86.4% of 5510) patients who underwent 4,848 surgical procedures. Of the total, 47.2% were mastectomies, 50.9% partial mastectomies and 1.9% were skin sparing mastectomy. Immediate reconstruction was done in 470 patients (69.8% underwent reconstruction with an expander, 22.3% with flap rotation and 7.9% reconstruction with implants). The mean and median time between diagnosis and the beginning of treatment was analyzed, in the sample it was observed that patients who were diagnosed in stages I, II and IV had the same mean of 2.6 months, but stage IV had the lowest median 1 ,9 months. 474 patients were treated in the first line setting during the follow up, 43 % received hormone therapy (HT) and 57% received chemotherapy (CT) as first line. The duration of the treatment in first line was 17,7 months for HT and 7,7 months for CT (p < 0,01). OS for patients diagnosed in stages I and II did not reach the median in the available period, for patients in stages III and IV, a median of 80.4 months and 41.2 months of overall survival was identified, respectively. Conclusions: These are the first results of this large cohort of luminal patients treated in the public reference center. Most patients are diagnosed in stage I or II and more than half undergo conservative surgery. Immediate reconstruction is not routinely performed. In the public setting CDK4/6 inhibitors are not available and that led to more chemotherapy use in first line (57%) and worse survival when compared to clinical trials. Discussions on the incorporation of drugs consolidated in the literature are important to improve the treatment of advanced cancer. Citation Format: Andre Mattar, Marcelo Antonini, Marina Diogenes, Andressa Amorim, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-08.

Abstract PO1-16-06: LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes

Abstract Background PARP inhibitors (PARPi) improves progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to physician choice of chemotherapy (CT). The AIM of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods We analyzed data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA 1 or BRCA 2 or in the Homologous Recombination Repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. From September 2019 and April 2023, we collected baseline characteristics, previous systemic treatments, type and pattern of use, treatment beyond PARPi progression, and patient predisposition. Objective responses, best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analyzed with R software and RStudio version 14.0. Results After a median follow-up of 18.07 months (CI95% 10.53 - 30.07), 51 patients were treated with PARPi. Mean age at start treatment was 47,08 years. 62.7% had ER+ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talalaparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT (PbCT) in the (neo)adjuvant/metastatic setting. 57.5% had visceral metastasis and the median number of metastatic sites were 2 (range 1-4). Median number of lines at the time to start PARPi was 2 (range 0-8), 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively. The rwORR was 47.0%, and the median rwPFS1 was 7.77 months (CI95% 5.67-14.7). There was a tendence of better rwPFS1 in patients without previous CT versus previous CT in the advance setting, 14.30 months (CI95% 6.47-NR) versus 6.37 months (CI95% 5.03-8.73), respectively (p 0.084). The median rwOS was 26.97 months (CI95% 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (CI95% 27.0-NR) versus 13.0 (IC95%10.1-NR), respectively (p 0.022). 23.5% of patients progressed on PARPi during the first 6 months of treatment, 32.4% with visceral compromise, 27.8% with visceral crisis, and 26.5% with ≥2 metastatic sites. CT was the treatment of choice in most patients (55.3%). The medium rwPFS2 (next treatment after PARPi failure) was 4.00 months (CI95% 3.43 – 7.13). Treatment was discontinued for adverse events in 4.0 % of patients. Conclusion This is the first Latin-American evidence that replicate the data already published in randomized clinical trials and other scanty real-world evidence studies in this field, positive results in rwORR and rwPFS, encouraging data in rwOS. Notably, high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, similar rwOS results among subgroups (TNBC versus ER+ve/HER2-ve, talazoparib versus Olaparib, etc). <graphic> Citation Format: Fernando E. Petracci, Cynthia Villarreal-Garza, Facundo Argañaraz, Gonzalo Gómez Abuin, José Peñaloza, Marcos A. Flores, Luciano Piazzoni, Cecilia Riggi, Lucía Fabiano, Lucía González, Belén Cieplinski, Sergio Rivero, Ernesto Korbenfeld, Pablo Mandó. LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-06.

Abstract PO4-26-02: Evaluation of Tumor Infiltrating Lymphocytes as a predictive biomarker of recurrence in patients with Ductal Carcinoma In Situ of the breast

Abstract Introduction: Ductal carcinoma in situ (DCIS) represents around 20% of early breast cancer diagnoses globally. Some studies evaluated risk factors associated with DCIS recurrence. Among these, age, surgical margins, comedonecrosis (CN), high nuclear grade, negative hormone receptors and HER2 expression stand out. Recent approaches have been evaluating the role of the immune microenvironment and its association with recurrence and progression of DCIS. Objective: To evaluate the association between Tumor Infiltrating Lymphocytes (TILs) in DCIS samples and disease recurrence. To characterize the immunological microenvironment of DCIS, analyzing the presence of TILs, “touching TILs” and desmoplastic reaction and their association with recurrence. Epidemiological, clinical, histological and immunohistochemical (IHC) characteristics were also evaluated. Methods: This is a retrospective cohort study with patients diagnosed with DCIS and treated at Sao Paulo State Cancer Institute and Hospital das Clinicas of University of Sao Paulo. We included women over 18 years old with a diagnosis of DCIS who underwent treatment from Jan/2007 to Dec/2020. Male patients, patients with a diagnosis of invasive or microinvasive disease in the anatomopathological examination of the surgical specimen or patients with history of any neoplasm were excluded. The main outcome was survival analysis according to the quantification of TILs, adjusted for potential confounders. For that, we collected data on age, presence of palpable mass, imaging findings, histological and IHC characteristics, such as expression of estrogen receptor (ER), progesterone receptor (PR) and hyperexpression of HER2, type of surgical approach, type of radiation therapy, use of endocrine therapy, length of follow-up, recurrence, and its type. Two pathologists evaluated TILS in the sample with the highest tumor representation and numerically quantified it as percentage. They also evaluated the presence of “touching tils” (lymphocytes in contact with the basement membrane) and desmoplastic reaction in the tumor stroma. Kaplan-Meier curves, log-rank tests and Cox regression models were used to evaluate survival. Chi-square tests were used to evaluate the association between categorical variables. Results: 283 patients met the eligibility criteria. Mean age of patients was 55 years. 15% had a palpable nodule at physical examination. Clustered amorphous microcalcifications were the most prevalent mammographic presentation, found in 41% of the patients. The most frequent histological and IHC features were cribriform presentation (73%) and ER positivity (86%), respectively. Desmoplastic reaction was absent in 10.5%, discreet in 51.9%, moderate in 24% and intense in 13.6% of the patients. Breast conserving surgery was performed in 189 patients, and 100 of them received adjuvant radiation therapy. Mean follow-up was 77.2 months, with a recurrence rate of 9.2%. We observed that tumors with focal necrosis (HR 6.4 [1.39-34.71] p 0.018) or CN (HR 4.53 [1.34 – 15.28] p 0.015) had higher risks of recurrence. Patients with a percentage value of TILs greater than or equal to 17% also had a higher risks of recurrence (HR 2.97 (1.17-7.51) p 0.02). These patients were mostly under 65 years of age (OR 0.45 [0.21 - 0.97] p 0.049). In a multivariate model, CN and TILs>17% remained significantly associated with recurrence (p=0.034 and p=0.035 respectively). There was a trend for invasive recurrence in 76.9% of the patients that relapsed when TILS were greater than or equal to 17% (p 0.062). “Touching TILs” were present in 12.9% of the patients but were not associated with recurrence (p=0.575). Conclusion: In our cohort, high value of TILs (>= 17%) and presence of CN were independently associated with DCIS recurrence. Our findings suggest that TILS are a prognostic immunological biomarker in DCIS and warrant further investigation in prospective trials to determine the most adequate cut-point. Citation Format: Camila Pasetto, Fernando Aguiar, Marcella Peixoto, Maira Doria, Bruna Mota, Jonathan Maesaka, Jose Roberto Filassi, Edmund Baracat, Rodrigo Gonçalves. Evaluation of Tumor Infiltrating Lymphocytes as a predictive biomarker of recurrence in patients with Ductal Carcinoma In Situ of the breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-26-02.

Abstract PO4-25-11: Inconclusive Her2 by immunohistochemistry compared to in situ hybridization in breast cancer: a cross-sectional study

Abstract Introduction: Breast cancer stands as the most common malignancy diagnosed among women worldwide, with the Her2-positive subtype accounting for approximately 15% of the cases. The introduction of HER-targeted therapies has changed the natural history of this subtype, however, evaluating the Her2 status using immunohistochemistry (IHC), can yield inconclusive results in a significant percentage of cases, which requires the use of in situ hybridization techniques. The study of such cases has not been thoroughly explored, particularly in the brazilian population, and increasing interest in this subgroup of patients arises as the "Her2 low" category gathers evidence of clinical applicability. The present study aimed to assess the final Her2 status of samples with indeterminate IHC results and compare these findings with current literature. Methods: We conducted a cross-sectional study at the breast unit service of a private health network in the state of Minas Gerais, Brazil (Rede Mater Dei de Saúde). Breast tissue samples obtained over the past 5 years were analyzed, and specimens with inconclusive IHC results for Her2 were included in the study. Subsequently, the final Her2 status was determined through fluorescence in situ hybridization (FISH) test, or reanalysis in cases in which a new sample (surgical specimen) was obtained. Results: Among the initially identified 73 samples with indeterminate IHC results for Her2, a total of 15 patients were excluded due to lack of follow-up within the breast unit service. The final cohort consisted of 58 women aged between 28 and 71 years. Notably, approximately 91% of the patients exhibited positive hormone receptor tumors, whereas 9% displayed negative hormone expression. After reviewing the medical records, approximately 36% of the patients were classified as having a positive final Her2 status, while 62% had a negative final status. One patient had an inconclusive FISH result. Conclusion: The present study revealed that approximately 10% of the breast tissue samples included in the study yielded inconclusive results for Her2 by immunohistochemistry. Following FISH testing, the majority of these patients were reclassified into the negative final Her2 status category. The classification of most patients to what is known as the emerging "Her2 low" category, aligns with international publications, and highlights the clinical relevance of exploring this subset of breast cancer that gains relevance as advances provide prospects for targeted therapies. Table 1. Summarized results for the final Her2 status Absolute and percentage values for the final HER2 status in the study cohort Citation Format: Felipe Marcondes de Oliveira Coelho, Renata Capanema Saliba Franco, Enaldo Melo de Lima, Marco Antonio Dias, Anna Dias Salvador, Waldeir José de Almeida Junior, Julia Wanderley Rennó, José Tadeu Campos de Avelar. Inconclusive Her2 by immunohistochemistry compared to in situ hybridization in breast cancer: a cross-sectional study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-11.

Abstract PO5-06-14: Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma

Abstract Background: Triple-negative (TN) invasive lobular carcinoma (ILC) of the breast is a rare entity, comprising roughly 2% of primary ILC. Clinicopathologic studies have shown that TN ILC is associated with more pleomorphism, higher nuclear grade, older patient age, and worse disease-related outcomes compared to estrogen receptor-positive (ER+) ILC. Intrinsic subtyping indicates that TN ILC less frequently expresses basal markers than TN invasive ductal carcinoma (IDC). This prompted investigation of the genomic landscape and clinical management of TN ILC to provide insight into potential therapeutic approaches. Methods: Twenty patients with TN ILC were included in this study. Three patients were treated at a single academic center and underwent comprehensive genomic profiling (CGP) of breast or metastatic tissue; clinicopathologic details were obtained from their electronic health records. Seventeen patients with TN ILC who underwent CGP of breast or metastatic biopsies were included from the Foundation Medicine, Inc. database. PD-L1 testing for all patients was determined by immunohistochemistry (IHC) using the VENTANA SP142 or Dako 22C3 commercial assays. HER2 expression was determined by IHC. Negative HER2 expression was defined as an IHC score of 0, or IHC 1+ or 2+ with non-amplified fluorescence in situ hybridization (FISH). Results: In the Foundation Medicine database of patients with TN ILC, the most frequent genomic alterations were in CDH1 (15/17 patients [88.2%]), TP53 (10/17 patients [58.8%]), and PIK3CA (10/17 patients [58.8%]). Short variant mutations in ERBB2 were found in 3/17 patients (17.6%). Fourteen patients were HER2-low (HER2 IHC 1+ or 2+ with non-amplified FISH). No cases were MSI high or expressed PD-L1 (8 of 17 cases underwent PD-L1 assessment by SP142). Median tumor mutational burden (TMB) was 5 muts/Mb. Among the three patients with TN ILC treated at a single center, the most common somatic mutations were in CDH1 and TP53, and no cases were MSI high or expressed PD-L1 (by SP142 or 22C3). All three patients had pleomorphic ILC, histologic grade 2 or 3, and HER2 IHC 0. One patient with mpT1cN1a(sn) ER+/HER2- ILC of the right breast in 2011 received adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide), breast/axillary radiation, and ten years of adjuvant endocrine therapy. She was diagnosed with TN ILC of the left supraclavicular nodes in 2022; she did not exhibit a response to docetaxel and carboplatin with pembrolizumab, and she subsequently received palliative radiation followed by capecitabine. Another patient with locally advanced TN ILC progressed on the KEYNOTE-522 regimen, immediately developed metastases, and is currently receiving palliative sacituzumab govitecan. The third patient with cT3N1 TN ILC progressed on neoadjuvant therapy (through the I-SPY 2 trial) with oral paclitaxel, encequidar, and dostarlimab, followed by dostarlimab with dose-dense doxorubicin and cyclophosphamide. Her surgical pathology demonstrated ypT3N3a disease with 10 × 7 cm of tumor, and she developed skin metastases on the chest wall within weeks post-operatively. She received comprehensive chest wall and nodal radiation and is currently receiving palliative capecitabine with neratinib given a high variant allele frequency driver somatic ERBB2 mutation. Conclusions: The most common somatic mutations among TN ILC patients included in this study were in CDH1, TP53, and PIK3CA. Currently the management of TN ILC is extrapolated from that of TN IDC, however our patients did not respond to chemoimmunotherapy. The presence of HER2-low status or somatic ERBB2 mutations may provide opportunities for treatment with an anti-HER2 antibody-drug conjugate or tyrosine kinase inhibitor. Studies with larger sample sizes of TN ILC are needed for molecular profiling and assessment of outcomes with specific therapeutic approaches. Citation Format: Hemali Batra-Sharma, Smruthy Sivakumar, Prashanth Ashok Kumar, Ethan Sokol, Rebecca Shatsky, Jeffrey Ross. Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-14.

Abstract PS09-03: Neoadjuvant zanidatamab for stage I node negative HER2 positive breast cancer

Abstract Background: The addition of trastuzumab+/-pertuzumab to chemotherapy has changed the natural history of earlyHER2+ breast cancer. However, trials with targeted therapy alone are needed to avoid acute and chronic toxicities of chemotherapy. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular and dimerization domains (ECD2, ECD4) of HER2. The biparatopic nature of zanidatamab results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab has demonstrated antitumor activity in heavily pre-treated HER2 overexpressing metastatic breast cancer with an acceptable safety profile. We hypothesized that zanidatamab would be a safe and effective regimen for women with node negative stage I HER2+ BC. Methods: Patients with 1-3 cm, clinically node negative HER2+ BC were enrolled in a single-institution investigator-initiated clinical trial. Patients had HER2+ breast cancer: HER2 3+ by IHC or IHC 2+ and ISH +. Patients received six to ten doses of zanidatamab, 20 mg/kg IV every 2 weeks prior to surgery. Patients with ER+ tumors also received neoadjuvant endocrine therapy. Post-menopausal patients received letrozole 2.5 mg daily, and pre-menopausal patients received tamoxifen 20 mg daily or GNRH and letrozole 2.5 mg. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab. Results: Twenty patients with HER2+ breast cancer were enrolled. Median age was 62 years old (range 30-73). Fifteen patients had HER2 3+, and 5 HER2 2+/ISH+ tumors with a median size of 1.95 cm (range 1-3 cm) and 10 patients had tumors >2 cm. Seven patients were pre-menopausal. Six received tamoxifen and 8 letrozole. Eleven patients completed 6 cycles and 9 patients will receive 10 cycles of zanidatamab. Eleven patients already had surgery the remainder patients will have surgery by Oct 30, 2023. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). Treatment was tolerated well. There were no grade 3 or 4 toxicities. One patient had minor infusion related reaction and grade 2 acne, and 2 grade 2 diarrhea. Conclusions: Neoadjuvant zanidatamab demonstrates significant preliminary efficacy, (pCR/RCB-1 64%) with a good safety profile in patients with stage I node negative HER2+ BC. An update of efficacy and safety of all patients will be presented at the time of meeting Citation Format: Vicente Valero, Jason Mouabbi, Heather Alonzo, Paula Pohlmann, Adaeze Lheme, Amy Hassan, Rashmi Murthy, Xuelin Huang, Wei Qiao, Miral Patel, Gaiane Rauch, Cristina Checka, W. Fraser Symmans, Kelly Hunt, Debu Tripathy, Funda Meric-Bernstam. Neoadjuvant zanidatamab for stage I node negative HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-03.

Abstract PO3-04-09: Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis

Abstract Abstract: Purpose: To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC) after neoadjuvant chemotherapy (NAC). Methods: A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2− BC who received NAC from 2011 to 2022. All patients received current “standard of care” following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. Results: The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Conclusions: Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status. Keywords: breast cancer; neoadjuvant chemotherapy; survival; prognosis; PR; HER2-low Citation Format: Jin Zhang, Yan Liu, Shichao Zhang. Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-09.

Abstract PO5-05-01: ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT

Abstract BACKGROUND First line treatment of HR-positive, HER2 negative advanced breast cancer is based on endocrine therapy plus CDK 4/6 inhibitors (CDK 4/6i). Recently, there has been published in ASCO 2023 results from SONIA trial, which explores the use of CDK 4/6i in second-line treatment after monotherapy with endocrine therapy. This trial have shown using a CDK4/6i in the first-line setting did not significantly prolong the time from random assignment to progression on second-line therapy (PFS2) or overall survival (OS) when compared with deferred use until the second-line setting. METHODS We conducted a descriptive, observational and retrospective analyses of patients treated in our centre with CDK4/6i, comparing demographic, clinical and survival results. We also analysed different outcomes between first versus second line CDK4/6i. RESULTS A cohort of 153 patients were included, treated between January 2018 and June 2023, with a median age of 50 years. At diagnosis, 49% were stage I-II and 31% stage IV. 59% had visceral metastases at the start of CDK4/6i treatment. Palbociclib was the most commonly CDK4/6i used (55%), followed by Ribociclib (32%) and Abemaciclib (12.5%). The most widely endocrine therapy used was letrozole (60%), followed by fulvestrant (38%). 58% received CDK4/6i in first-line setting while 9% received them in second-line. The overall median progression-free survival (mPFS) was 18 months. In a subgroup analysis, the mPFS was 19 months with Palbociclib, 26 months with Ribociclib, and 31 months with Abemaciclib. Baseline characteristics were similar between subgroups of CDK4/6i. Better survival data were obtained with letrozole than with fulvestrant (not reached versus 29 months OS respectively). After CDK4/6i disease progression the most common subsequent treatment was chemotherapy (capecitabine, 23%). The median OS with palbociclib and abemaciclib was 37 months, while not reached with ribociclib. We analysed PFS2 using CDK4/6i in the first-line setting compared with deferred use until the second-line. The use of CDK4/6i in second-line showed a PFS2 of 45 months, while first-line PFS2 was 26 months. CONCLUSIONS Our study results are consistent with previous studies assesing the efficacy of cyclin inhibitors in first and second-line setting. Palbociclib seems to have a lower PFS rate. Patients treated with letrozole had a stadistically significant benefit in survival outcomes. Our data continue the trend observed in the SONIA trial in terms of PFS2. Using endocrine therapy as first-line monotherapy may be a valid treatment option. However, larger sample sizes are required to draw definitive conclusions. The identification of potential predictors of treatment response may help in the selection of the most effective treatment for patients with HR-positive HER2 negative advanced breast cancer. Citation Format: Alicia Cano-Jimenez, Rocio Urbano-Cubero, Ruben Garcia-Muñoz, Ana Maria Jaen-Morago, Maria Lomas-Garrido, Pedro Sánchez-Rovira. ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-01.

Current therapeutic targets and promising strategies for triple-negative breast cancer

TNBC refers to breast cancer patients with negative estrogen receptor ER, PR and HER-2. It accounts for about 1520% of all breast cancer cases and has a higher rate of disease recurrence and a worse prognosis than other breast cancer subtypes. Chemotherapy is the most effective treatment now available for TNBC, but it has major adverse consequences on human health. Therefore, the development of new TNBC treatment strategies has become an urgent clinical need. This article first starts with the different subtypes of TNBC, analyzes and summarizes the pathogenesis of TNBC and recent research progress. Secondly, the potential targets of TNBC and the development of targeted treatments based on these targets are analyzed. Finally, it is concluded that it is easier to achieve curative effect by using appropriate specific treatments for different subtypes of TNBC. By summarizing existing treatment regimens and their applicable TNBC subtypes, this article aims to provide new insights for follow-up treatment.

PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study

SummaryBackgroundImmune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC).MethodsThis was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients’ requirements) in combination with albumin paclitaxel (125 mg/m2, intravenously, days 1 and 8, or 250 mg/m2, intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1–21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs).ResultsFrom July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9–9.3), and the median OS was 10.1 months (95% CI, 7.5–14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3–4 immune-related liver damage.ConclusionSecond-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC.Trial registrationClinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724

The expanded indications of HER2-targeted therapies by monitoring of circulating tumor cells.

385 Background: Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate. Methods: Twenty-seven patients with metastatic gastric cancer were treated according to histological HER2 status. On-chip sorting system was used for the isolation of circulating tumor cells (CTCs) before treatments. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the gene panel with 409 cancer related genes. The fluorescence signal intensity > 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Results: Thirteen patients (48%) with HER2 positive in tumor tissues (Group A) were treated with cytotoxic agents and trastuzumab (anti HER2 antibody) while 14 patients (52%) were negative and treated with cytotoxic agents. In these 14 patients, 8 patients (30%) showed HER2 positive (Group B) and 6 patients (22%) displayed HER2 negative (Group C) on CTCs. Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B showed worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012), suggesting Group B could be a candidate for expand indication of Trastuzumab. Genomic analysis showed some mutated genes involved in the PI3K signaling pathway which associated with drug resistance. Conclusions: Monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.

Increased SLC7A3 Expression inhibits Tumor Cell Proliferation and Predicts a Favorable Prognosis in Breast Cancer.

Arginine plays significant and contrasting roles in breast cancer growth and survival. However, the factors governing arginine balance remain poorly characterized. We aimed to identify the molecule that governs arginine metabolism in breast cancer and to elucidate its significance. We analyzed the correlation between the expression of solute carrier family 7 member 3 (SLC7A3), the major arginine transporter, and breast cancer survival in various databases, including GEPIA, UALCAN, Metascape, String, Oncomine, KM-plotter, CBioPortal and Prognosis. Additionally, we validated our findings through bioinformatic analyses and experimental investigations, including colony formation, wound healing, transwell, and mammosphere formation assays. Our analysis revealed a significant reduction in SLC7A3 expression in all breast cancer subtypes compared to adjacent breast tissues. Kaplan-Meier survival analyses demonstrated that high SLC7A3 expression was positively associated with decreased nodal metastasis (HR=0.70, 95% CI [0.55, 0.89]), ER positivity (HR=0.79, 95% CI [0.65, 0.95]), and HER2 negativity (HR=0.69, 95% CI [0.58, 0.82]), and increased recurrence-free survival. Moreover, low SLC7A3 expression predicted poor prognosis in breast cancer patients for overall survival. Additionally, the knockdown of SLC7A3 in MCF-7 and MDA-MB-231 cells resulted in increased cell proliferation and invasion in vitro. Our findings indicate a downregulation of SLC7A3 expression in breast cancer tissues compared to adjacent breast tissues. High SLC7A3 expression could serve as a prognostic indicator for favorable outcomes in breast cancer patients due to its inhibitory effects on breast cancer cell proliferation and invasion.

CircPVT1 Inhibits the Proliferation and Aids in Prediction of the Prognosis of Bladder Cancer.

Circular RNA PVT1 (circPVT1) is aberrantly expressed in several cancers, but its functional role and clinical relevance in bladder urothelial carcinoma (BLCA) remain unknown. This study aimed to identify the expression level of circPVT1 in BLCA and investigated its functional relevance with BLCA progression both in vitro and in vivo. GEPIA, UALCAN, and OncoLnc were referred to presented data. Quantitative real-time PCR (qPCR) was used for the measurement of transnational expression of genes in BLCA specimens and cell lines. Immunohistochemistry (IHC) and fluorescence in situ hybridization analysis (FISH) assays were performedto detect HER2 amplification, Pearson's correlation analysis to analyze the correlation between circPVT1 expression and clinical characteristics, Cox regression and K-M survival analyses to analyze prognostic factors. A nomogram was constructed for predicting prognosis. The proliferation of cells was measured by CCK-8 and colony formation assay, and the proliferation in vivo was evaluated using nude mouse models. qPCR was used to detect the expression of proliferation-related genes. circPVT1 was but mRNA PVT1 was not significantly overexpressed in BLCA. A high circPVT1 expression was associated with a better survival and negative HER2, but not with age, gender, and T stage. circPVT1 was an independent prognostic factor for the overall survival of BLCA patients. Knocking down circPVT1 promoted BLCA proliferation in vitro and in vivo. Knocking down circPVT1 upregulated ERBB2, MKI67, and PCNA expression and downregulated TP53 expression, but exerted no influence on CCND1 and CCNB1 expression. circPVT1 is a tumor suppressor and novel prognostic biomarker for BLCA.