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Breast Cancer Research and Treatment Sep 2023In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody...
PURPOSE
In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody trastuzumab and the patient's outcome. In this HER2 + patient cohort, our aim was to study the numbers of FoxP3 + regulatory TILs and CD8 + cytotoxic TILs, their correlations with CD68 + and CD163 + TAMs, and the prognostic and predictive value of the studied factors.
METHODS
We evaluated 139 non-metastatic HER2 + breast cancer patients operated between 2001 and 2008. The FoxP3+TIL count (FoxP3+TILs) was assessed using the hotspot method, and the CD8 + TIL count (CD8+mTILs) utilizing a digital image analysis from invasive margin areas. The ratios between CD8+mTILs and FoxP3+TILs as well as CD8+mTILs and TAMs were calculated.
RESULTS
FoxP3 + TILs and CD8 + mTILs correlated positively with each other (p<0.001). FoxP3+TILs had a positive correlation with CD68+and CD163+TAMs (p≤0.038), while CD8 + mTILs correlated only with CD68+TAMs (p<0.001). In the HER2 + and hormone receptor-positive Luminal B subgroup, high numbers of FoxP3+TILs were associated with shorter disease-free survival (DFS) (54% vs. 79%, p = 0.040). The benefit from adjuvant trastuzumab was extremely significant among patients with a high CD8 + mTILs/CD68 + TAMs ratio, with overall survival (OS) 84% vs. 33% (p = 0.003) and breast cancer-specific survival (BCSS) 88% vs. 48% (p = 0.009) among patients treated with or without trastuzumab, respectively.
CONCLUSION
In the HER2 + Luminal B subgroup, high FoxP3 + TILs were associated with shorter DFS. A high CD8 + mTILs/CD68 + TAMs ratio seems to associate with impressive efficacy of trastuzumab.
Topics: Humans; Female; Prognosis; Breast Neoplasms; Lymphocytes, Tumor-Infiltrating; Tumor-Associated Macrophages; Trastuzumab; CD8-Positive T-Lymphocytes
PubMed: 37428418
DOI: 10.1007/s10549-023-07017-8 -
Current Oncology (Toronto, Ont.) Sep 2022In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients' general conditions in metastatic... (Review)
Review
In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients' general conditions in metastatic gastric cancer (mGC), allowing them to receive further treatments. The choice of treatment is driven by performance status, age, stage of disease, number of metastatic sites and time from the first to third line of treatment. Targets such as microsatellite instability, PD-L1 expression, and HER2 overexpression or amplification may be addressed to personalise treatment and prolong survival. Despite a growing number of third line options that have provided clinicians with greater opportunities to customise treatments, up to date few agents have been demonstrated as effective after two standard lines for mGC; for these reasons, chemotherapy, immunotherapy, and targeted therapy were all widely investigated in both phase II and phase III studies. Overall, TAS-102, apatinib, regorafenib, nilotinib, trastuzumab, and pembrolizumab were demonstrated to be valid options in the third line scenario for mGC patient refractory to at least two lines of therapy. A multimodal approach based on chemotherapy, immunotherapy, targeted agents, a personalised nutritional programme as well as the research of new predictive biomarkers may pave the way to new strategies to identify the best treatment for each patient.
Topics: Antineoplastic Agents; B7-H1 Antigen; Humans; Stomach Neoplasms; Trastuzumab
PubMed: 36135075
DOI: 10.3390/curroncol29090506 -
Current Oncology (Toronto, Ont.) Aug 2023Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast cancer (EBC). A randomized trial was performed to assess the feasibility of a larger study.
METHODS
Lower-risk HER2-positive EBC patients were randomized to either P-H or TC-H treatment arms. The co-primary feasibility outcomes were: ≥75% patient acceptability rate, active trial participation of ≥50% of medical oncologists, ≥75% and ≥90% treatment completion, and receipt rate of planned cycles of chemotherapy, respectively.
SECONDARY OUTCOMES
Febrile neutropenia (FN) rate, treatment-related hospitalizations, health-related quality of life (HR-QoL) questionnaires. Analyses were performed by per protocol and intention-to-treat.
RESULTS
Between May 2019 and March 2021, 49 of 52 patients agreed to study participation (94% acceptability rate). Fifteen (65%) of 23 medical oncologists approached patients. Rates of FN were higher (8.3% vs. 0%) in the TC-H vs. P-H arm. Median (IQR) changes in scores from baseline in FACT-Taxane Trial Outcome Index at 24 weeks were -4 (-10, -1) vs. -6.5 (-15, -2) for TC-H and P-H arms, respectively.
CONCLUSIONS
A randomized trial comparing P-H and TC-H was feasible. Expansion to a larger trial would be feasible to explore patient-reported outcomes of these adjuvant HER2 chemotherapy regimens.
Topics: Humans; Female; Breast Neoplasms; Quality of Life; Standard of Care; Chemotherapy, Adjuvant; Trastuzumab
PubMed: 37623016
DOI: 10.3390/curroncol30080535 -
Journal For Immunotherapy of Cancer Nov 2023It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).
BACKGROUND
It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.
METHODS
In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).
RESULTS
Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms.
CONCLUSIONS
SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.
TRIAL REGISTRATION NUMBER
NCT03144947, and EudraCT number: 2016-000435-41.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; B7-H1 Antigen; Docetaxel; Neoadjuvant Therapy; Neoplasm, Residual; Receptor, ErbB-2; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38016718
DOI: 10.1136/jitc-2023-007667 -
Journal of Oncology Pharmacy Practice :... Dec 2021Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2...
INTRODUCTION
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1).
CASE REPORT
We report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies. The Naranjo Scale indicated a probable drug-induced adverse reaction. The patient fully recovered after thoracentesis and discontinuation of T-DM1. The patient has reported no side effect after the sixth course of trastuzumab.
DISCUSSION
To our knowledge, this is the first case in the literature of bilateral pleural and pericardial effusions in a patient treated with T-DM1. The successful initiation of treatment with trastuzumab following withdrawal of T-DM1 suggests that emtansine played a role in the development of bilateral pleural and pericardial effusions. We hypothesize that the patient's condition was a result of a local inflammatory reaction to emtansine by direct toxicity.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Female; Humans; Maytansine; Pericardial Effusion; Receptor, ErbB-2; Trastuzumab
PubMed: 34000917
DOI: 10.1177/10781552211015772 -
Cancer Discovery Feb 2023The latest phase III data from DESTINY-Breast02 and DESTINY-Breast03 indicate that trastuzumab deruxtecan, or T-DXd, outperforms capecitabine-based chemotherapy and...
The latest phase III data from DESTINY-Breast02 and DESTINY-Breast03 indicate that trastuzumab deruxtecan, or T-DXd, outperforms capecitabine-based chemotherapy and T-DM1 in patients with metastatic HER2-positive breast cancer. According to results from an investigator-initiated trial, TRIO-US B-12 TALENT, T-DXd may also have neoadjuvant potential in HER2-low disease.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Camptothecin; Capecitabine; Immunoconjugates
PubMed: 36484540
DOI: 10.1158/2159-8290.CD-ND2022-0020 -
Frontiers in Immunology 2023Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2...
Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.
Topics: Humans; Trastuzumab; Receptor, ErbB-2; Single-Domain Antibodies; Ligands; Neoplasms; Epitopes
PubMed: 37954614
DOI: 10.3389/fimmu.2023.1292839 -
Eastern Mediterranean Health Journal =... Oct 2022There have been system inefficiencies in the profiling and management of female breast cancer in Alexandria, Egypt.
BACKGROUND
There have been system inefficiencies in the profiling and management of female breast cancer in Alexandria, Egypt.
AIMS
To identify barriers to full implementation of international guidelines for the management of female breast cancer patients.
METHODS
Female breast cancer data were extracted from records of 3 public oncology services in Alexandria, Egypt, from 2007 to 2016 and analysed.
RESULTS
A total of 5236 of the available 7125 records were usable. Median age of the patients was 54 years, and the median duration of pre-diagnosis complaint was 3.1 months. Some 522 (31.5%) of the patients had a family history of cancer. For tumour stage, 2527 (55.2%) were early, 1717 (37.6%) were locally advanced, and 331 (7.2%) were at stage IV. Estrogen receptor, progesterone receptor, and HER2 were positive in 3869 (85%), 3545 (78%), and 461 (15.3%) patients, respectively. Chemotherapy started after a median 1.03 months. Adjuvant chemotherapy was given to 3667 (91.7 %) patients and neoadjuvant chemotherapy to 333 (8.3%); 3686 (92.1%) received anthracycline-based combination chemotherapy, and 3613 (86%) received hormonal treatment. One hundred and eighty of 317 eligible patients received Trastuzumab. Local and/or distant recurrence was seen in 1109 (21.2%) patients. In nonmetastatic cases, median overall and disease-free survival were 149.1 and 77.1 months, respectively. In metastatic cases, median progression-free survival was 19.6 months.
CONCLUSION
We observed defects in the record system, there was delay in diagnosis and treatment, and nonadherence to targeted therapy in many patients. Strengthening of national and hospital-based registries is needed in Alexandria, Egypt, with a robust patient navigation system and targeted information, education and communication strategies. Continuous outcomes monitoring and adaptation to implementation needs should be sustained.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Egypt; Antineoplastic Combined Chemotherapy Protocols; Trastuzumab; Treatment Outcome
PubMed: 36382727
DOI: 10.26719/emhj.22.076 -
Journal For Immunotherapy of Cancer Mar 2023The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα...
BACKGROUND
The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion.
METHODS
We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes.
RESULTS
In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors.
CONCLUSIONS
These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
Topics: Mice; Animals; Trastuzumab; Down-Regulation; Mucin-4; Tumor Necrosis Factor-alpha; Receptor, ErbB-2; Cell Line, Tumor; Immunosuppression Therapy; Neoplasms
PubMed: 36889811
DOI: 10.1136/jitc-2022-005325 -
Gan To Kagaku Ryoho. Cancer &... Jul 2023HER2-positive gastric cancer accounts for 30-40% of gastric cancer patients. Since the ToGA trial, trastuzumab has become the mainstay of first-line therapy for... (Review)
Review
HER2-positive gastric cancer accounts for 30-40% of gastric cancer patients. Since the ToGA trial, trastuzumab has become the mainstay of first-line therapy for HER2-positive gastric cancer over the past decade. Antibody-drug conjugate (ADC)has created a new treatment option recently. The combination and sequence of these anti-HER2 agents with the immune checkpoint inhibitors is reported to be promising. In this article, we review the major clinical trials and discuss the prospects and challenges of treatment strategy for HER2-positive gastric cancer.
Topics: Humans; Stomach Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 37496216
DOI: No ID Found