Lymphocyte-activating gene-3 expression is associated with tumor-infiltrating lymphocyte levels in HER2-positive breast cancers

Abstract Introduction HER2 over-expression denotes poor prognosis in breast cancers.Bone morphogenetic protein(BMP) signalling is known to interact with EGF signalling, co-regulating breast cancer progression.BMP antagonist Gremlin-1 may influence breast cancer disease progression, but this remains unexplored in HER2 positive breast cancers. Method GREM1 and HER2 expression, and clinical outcomes were examined in clinical cohorts.GREM1 overexpression or pEF control plasmid were transduced into BT474 HER2+breast cancer cells. In vitro function tests using BT474 pEF and BT474GREM1cells include 2D/3D growth, migration, and expression of epithelial to mesenchymal transition(EMT)markers. Signalling cascades were examined in BT474 treated with RhGremlin-1. In vivo, BALB/c nude mice underwent either mammary injection or intra-cardiac injection of BT474pEF or BT474GREM1 cells and disease burden assessed. Result GREM1 expression correlates with HER2 in breast tumours(p=0.03) and is higher in metastatic HER2 positive cancers (p = 0.04). HER2 positive patients with high GREM1 have poor survival(p = 0.0002). BT474GREM1cells have up-regulated markers of EMT compared to control. BT474 RhGremlin-1 treated cells have active AKT pathway signalling, independent of BMP signalling. In vitro, BT474GREM1cells significantly proliferate and migrate compared to control(p<0.05 and p < 0.001).This is confirmed in vivo, BT474GREM1 mice grew significantly larger mammary tumours(p<0.05) and had more PETCT metastatic hotspots. Conclusion Gremlin-1 is correlated with poor outcomes in HER2 patients and promotes breast cancer cellular growth, migration and metastasis.Gremlin-1 is a novel area of research with potential as a prognostic biomarker and therapeutic target for personalised, effective, breast cancer outcomes. Take-home message BMP antagonists are gaining interest for their potential in breast cancer prognosis and therapeutics.This novel area of research shows BMP antagonist Gremlin-1 is of importance in HER2 positive breast cancers. DRAGONS DEN

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Fat Composition Measured by Proton Spectroscopy: A Breast Cancer Tumor Marker?

Diagnostics ◽

10.3390/diagnostics11030564 ◽

2021 ◽

Vol 11 (3) ◽

pp. 564

Author(s):

Almir Bitencourt ◽

Varadan Sevilimedu ◽

Elizabeth A. Morris ◽

Katja Pinker ◽

Sunitha B. Thakur

Keyword(s):

Breast Cancer ◽

Saturation Index ◽

Multivariable Analysis ◽

Area Under The Curve ◽

Resonance Spectroscopy ◽

Breast Cancers ◽

Her2 Positive ◽

Tumor Tissues ◽

Cancer Tumor ◽

Fat Composition

Altered metabolism including lipids is an emerging hallmark of breast cancer. The purpose of this study was to investigate if breast cancers exhibit different magnetic resonance spectroscopy (MRS)-based lipid composition than normal fibroglandular tissue (FGT). MRS spectra, using the stimulated echo acquisition mode sequence, were collected with a 3T scanner from patients with suspicious lesions and contralateral normal tissue. Fat peaks at 1.3 + 1.6 ppm (L13 + L16), 2.1 + 2.3 ppm (L21 + L23), 2.8 ppm (L28), 4.1 + 4.3 ppm (L41 + L43), and 5.2 + 5.3 ppm (L52 + L53) were quantified using LCModel software. The saturation index (SI), number of double bods (NBD), mono and polyunsaturated fatty acids (MUFA and PUFA), and mean chain length (MCL) were also computed. Results showed that mean concentrations of all lipid metabolites and PUFA were significantly lower in tumors compared with that of normal FGT (p ≤ 0.002 and 0.04, respectively). The measure best separating normal and tumor tissues after adjusting with multivariable analysis was L21 + L23, which yielded an area under the curve of 0.87 (95% CI: 0.75–0.98). Similar results were obtained between HER2 positive versus HER2 negative tumors. Hence, MRS-based lipid measurements may serve as independent variables in a multivariate approach to increase the specificity of breast cancer characterization.

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Prognostic role of tumor size in T1 HER2-positive breast cancers treated with adjuvant trastuzumab

Annals of Oncology ◽

10.1093/annonc/mdu058 ◽

2014 ◽

Vol 25 (5) ◽

pp. 1073-1074 ◽

Cited By ~ 4

Author(s):

M. Campiglio ◽

M. Sandri ◽

M. Sasso ◽

F. Bianchi ◽

A. Balsari ◽

...

Keyword(s):

Tumor Size ◽

Breast Cancers ◽

Prognostic Role ◽

Her2 Positive ◽

Adjuvant Trastuzumab

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Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies

Breast Cancer Research and Treatment ◽

10.1007/s10549-016-3848-2 ◽

2016 ◽

Vol 158 (1) ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Akira I. Hida ◽

Yasuaki Sagara ◽

Daisuke Yotsumoto ◽

Shuichi Kanemitsu ◽

Junko Kawano ◽

...

Keyword(s):

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Breast Cancers ◽

Her2 Positive ◽

Infiltrating Lymphocytes ◽

Systemic Therapies

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Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.9549 ◽

2010 ◽

Vol 28 (18) ◽

pp. 2966-2973 ◽

Cited By ~ 102

Author(s):

Marco Colleoni ◽

Bernard F. Cole ◽

Giuseppe Viale ◽

Meredith M. Regan ◽

Karen N. Price ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Triple Negative ◽

Alkylating Agents ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Her2 Positive ◽

Node Negative ◽

Tumor Subtypes ◽

Node Negative Breast Cancer

Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

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Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1038 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1038-1038

Author(s):

Sara A. Hurvitz ◽

Haeseong Park ◽

Sophia Frentzas ◽

Catherine M. Shannon ◽

Katharine Cuff ◽

...

Keyword(s):

Solid Tumors ◽

Phase 1 ◽

Salivary Gland Cancer ◽

Breast Cancers ◽

Her2 Positive ◽

Two Phase ◽

Site Specific ◽

Heavily Pretreated ◽

Pretreated Patients ◽

A Site

1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]

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Genomic Insights into Triple-Negative and HER2-Positive Breast Cancers Using Isogenic Model Systems

PLoS ONE ◽

10.1371/journal.pone.0074993 ◽

2013 ◽

Vol 8 (9) ◽

pp. e74993 ◽

Cited By ~ 5

Author(s):

Prakriti Mudvari ◽

Kazufumi Ohshiro ◽

Vasudha Nair ◽

Anelia Horvath ◽

Rakesh Kumar

Keyword(s):

Triple Negative ◽

Model Systems ◽

Breast Cancers ◽

Her2 Positive

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CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918818346 ◽

2018 ◽

Vol 10 ◽

pp. 175883591881834 ◽

Cited By ~ 11

Author(s):

Adriana Matutino ◽

Carla Amaro ◽

Sunil Verma

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Progression Free Survival ◽

Breast Cancers ◽

Cyclin Dependent Kinase ◽

Her2 Positive ◽

Hormone Receptor Positive ◽

Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

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Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s9453 ◽

2014 ◽

Vol 8 ◽

pp. BCBCR.S9453 ◽

Cited By ~ 6

Author(s):

Adam M. Brufsky

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Molecular Mechanisms ◽

Mammalian Target Of Rapamycin ◽

Growth Factor Receptor ◽

Initial Response ◽

Her2 Overexpression ◽

Breast Cancers ◽

Intrinsic Resistance ◽

Her2 Positive

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.

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Influence of Anthropometric Characteristics in Patients With Her2-Positive Breast Cancer on Initial Plasma Concentrations of Trastuzumab

Annals of Pharmacotherapy ◽

10.1177/1060028017715727 ◽

2017 ◽

Vol 51 (11) ◽

pp. 976-980 ◽

Cited By ~ 4

Author(s):

Jonathan González García ◽

Fernando Gutiérrez Nicolás ◽

Gloria Julia Nazco Casariego ◽

José Norberto Batista López ◽

Isaac Ceballos Lenza ◽

...

Keyword(s):

Breast Cancer ◽

Standard Dose ◽

Plasma Concentrations ◽

Breast Cancers ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Initial Plasma ◽

Anthropometric Characteristics ◽

Secondary Objective ◽

Positive Breast Cancer

Background: Plasma concentrations of trastuzumab <20 µg/mL in patients with gastric cancer are associated with reduced progression-free and overall survival. In breast cancer treatment, this relationship has not yet been studied, but a suboptimal pharmacodynamic exposure to trastuzumab could be a reason for therapeutic failure of treatment of HER2-positive breast cancer. Objective: The objective of the present study was to determine the proportion of nonmetastatic HER2-positive breast cancers that do not reach a minimum plasma concentration ( Cmin) of 20 µg/mL after first drug administration, established as therapeutically effective in clinical trials. The secondary objective was to identify the physiological and anthropometric characteristics that determine interindividual pharmacokinetic variability. Methods: Serum concentrations of trastuzumab were assessed by ELISA on day 1 of the second cycle before administration of the second dose ( Cmin). Results: Of 19 patients included, 9 (47.4%) had a mean Cmin of 19.0 µg/mL (±12.1) after the first administration. Body mass index (BMI) and weight was the main variable that determined the achievement of therapeutic levels after the first administration. Thus, the proportion of patients reaching the target concentration was 89% when BMI was ≤30 kg/m2 but only 11% when BMI was >30 kg/m2 ( P < 0.01). Conclusions: The standard dose of 600 mg subcutaneous trastuzumab did not ensure adequate pharmacodynamic exposure from the first administration in 52% of patients, with weight and BMI being related to the plasma levels obtained.

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