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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 -
Critical Reviews in Oncology/hematology Apr 2023The benefit of adjuvant trastuzumab treatment in patients with HER2-positive breast tumors ≤ 10 mm without lymph node involvement (T1abN0) is insufficiently... (Meta-Analysis)
Meta-Analysis Review
The benefit of adjuvant trastuzumab treatment in patients with HER2-positive breast tumors ≤ 10 mm without lymph node involvement (T1abN0) is insufficiently investigated. The aim of this systematic review and meta-analysis was to examine if adjuvant trastuzumab improves the prognosis in these patients. Databases were searched to identify interventional and observational studies evaluating the effect of trastuzumab on breast cancer specific survival (BCSS), disease free survival (DFS), distant recurrence free survival (DRFS), overall survival (OS) or recurrence free survival (RFS). Twelve studies examining the effect of trastuzumab and nine control studies without trastuzumab were identified (n = 6927). Median follow-up was 36-123 months. Significantly improved DFS (Hazard Ratio (HR) 0.14, p < 0.0001) and OS (HR 0.17, p = 0.011) were found for patients receiving trastuzumab and chemotherapy compared to no trastuzumab/chemotherapy based on four and two studies. The prognosis was good even for patients without trastuzumab treatment: 5-year DFS 88.3% and 5-year OS 95.9%.
Topics: Humans; Female; Trastuzumab; Receptor, ErbB-2; Breast Neoplasms; Prognosis; Disease-Free Survival; Adjuvants, Immunologic; Chemotherapy, Adjuvant
PubMed: 36854373
DOI: 10.1016/j.critrevonc.2023.103952 -
International Journal of Molecular... Dec 2023Antibody-drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still...
Antibody-drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options for the treatment of these challenges. Sortilin-1 (SORT1) may be a promising target for ADC as it is upregulated in breast cancer. To evaluate the possibility of SORT1 as an ADC target, a humanized antibody_8D302 with high affinity against SORT1 was generated. Additionally, 8D302 was conjugated with MMAE and DXd to generate two ADCs_8D302-MMAE and 8D302-DXd, respectively. Both 8D302-MMAE and 8D302-DXd showed effective cytotoxicity against SORT1 positive breast tumor cell lines and induced bystander killing. Consequently, 8D302-MMAE showed relatively better anti-tumor activity than 8D302-DXd both in vitro and in vivo, but 8D302-DXd had superior safety profile and pharmacokinetics profile over 8D302-MMAE. Furthermore, SORT1 induced faster internalization and lysosomal trafficking of antibodies and had a higher turnover compared with HER2. Also, 8D302-DXd exhibited superior cell cytotoxicity and tumor suppression over trastuzumab-DXd, a HER2-targeted ADC. We hypothesize that the high turnover of SORT1 enables SORT1-targeted ADC to be a powerful agent for the treatment of SORT1-positive breast tumor.
Topics: Animals; Humans; Female; Immunoconjugates; Trastuzumab; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Cell Line, Tumor; Mammary Neoplasms, Animal; Receptor, ErbB-2
PubMed: 38139459
DOI: 10.3390/ijms242417631 -
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 -
PloS One 2023Monoclonal Antibodies (mAbs) are being used in the treatment of both malignant and non-malignant diseases and whilst highly effective, certain products have very short...
Monoclonal Antibodies (mAbs) are being used in the treatment of both malignant and non-malignant diseases and whilst highly effective, certain products have very short expiry times. Clinical deterioration and supply chain disruption can often lead to wastage and there is a need to reduce this by improving efficiency in logistics practices between manufacturing sites and administration locations. This study aimed to investigate the influence of drone flight on the stability of cancer medicines. Clinically expired, premanufactured monoclonal antibodies (mAbs) were investigated, contained inside instrumented Versapaks, and flown in a Skylift (Mugin) V50 vertical take-off and landing drone through seven phases of flight, (take-off, hover, transition, cruise, transition, hover, and landing). Storage specifications (2-8°C) were met, and any vibrations emanating from the drone and transmitted through the packaging during flight were monitored using accelerometers. Vibration occurred largely above 44 Hz which was consistent with rotor speeds during operation and was significantly greater in amplitude during transition than in forward flight or in hover. Bench experiments validated assurance practices, exploring the edge-of-quality failure by applying extremes of rotational vibration to the mAbs. Aggregation and fragmentation represented a loss of quality in the mAbs and would pose a risk to patient safety. No significant difference was identified in the aggregation and fragmentation of all flown mAbs samples, indicating structural integrity. Flown mAbs in their infusion bags had similar particle sizes compared to controls, (Bevacizumab 11.8±0.17 nm vs. 11.6±0.05 nm, Trastuzumab 11.2±0.05 nm vs. 11.3±0.13 nm, Rituximab 11.4±0.27 nm vs. 11.5±0.05 nm) and aggregate content (Bevacizumab 1.25±0.03% vs 1.32±0.02% p = 0.11, Trastuzumab 0.15±0.06% vs. 0.16±0.06% p = 0.75, Rituximab 0.11±0.02% vs. 0.11±0.01% p = 0.73). The quality of the three mAbs was assured, suggesting that the V50 drone did not induce sufficient levels of vibration to adversely affect their quality.
Topics: Humans; Bevacizumab; Rituximab; Unmanned Aerial Devices; Antibodies, Monoclonal; Trastuzumab; Neoplasms
PubMed: 36607896
DOI: 10.1371/journal.pone.0278873 -
Breast Cancer Research and Treatment Jan 2021Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization.
RESULTS
A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65-80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients.
CONCLUSION
Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lapatinib; Neoadjuvant Therapy; Receptor, ErbB-2; Trastuzumab
PubMed: 32951084
DOI: 10.1007/s10549-020-05915-9 -
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 -
Cancer Medicine Dec 2016This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with... (Meta-Analysis)
Meta-Analysis Review
Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis of randomized controlled trials.
This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR = 0.82, 95% CI: 0.73-0.93; Z = 3.00; P = 0.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR = 1.33, 95% CI: 1.18-1.50; Z = 4.70; P < 0.00001), diarrhea (RR = 14.59, 95% CI: 7.69-27.67; Z = 8.20; P < 0.00001), and dermatologic toxicity (RR = 3.10, 95% CI: 1.61-5.96; Z = 3.39; P = 0.007), but none was found for neutropenia (RR = 1.38, 95% CI: 0.82-2.31; Z = 1.22; P = 0.22) or CHF (RR = 0.14, 95% CI: 0.02-1.17; Z = 1.02; P = 0.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2-positive breast cancer patients with no additional cardiac events. Trastuzumab, which is still the first-line therapy in breast cancer, increases the pCR rate more than lapatinib.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lapatinib; Odds Ratio; Quinazolines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 27882700
DOI: 10.1002/cam4.963 -
International Journal of Clinical... Dec 2023Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but...
BACKGROUND
Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice.
METHODS
Between May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated.
RESULTS
The majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25-143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment.
CONCLUSIONS
This is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome.
Topics: Humans; Lung Diseases, Interstitial; Trastuzumab; Pneumonia; Neoplasms; Receptor, ErbB-2
PubMed: 37787866
DOI: 10.1007/s10147-023-02414-x -
Cellular Signalling Sep 2022Receptor Tyrosine Kinases of the Epidermal Growth Factor Receptor Family play a pivotal role as drivers of carcinogenesis and uncontrolled cell growth for a variety of... (Review)
Review
Receptor Tyrosine Kinases of the Epidermal Growth Factor Receptor Family play a pivotal role as drivers of carcinogenesis and uncontrolled cell growth for a variety of malignancies, not least for breast cancer. Besides the estrogen receptor, the HER2 receptor was and still is a representative marker for advanced taxonomic sub-differentiation of breast cancer and emerged as one of the first therapeutic targets for antibody based therapies. Since the approval of trastuzumab for the therapy of HER2-positive breast cancer in 1998 anti-HER2 treatment strategies are being modified, refined, and successfully combined with complementary treatments, nevertheless there is still potential for improvement. The HER2 relatives, namely HER1 (i.e., EGFR), HER3 and HER4 share a high degree of molecular homology and together form a functional unit for signal transmission. Under regular conditions, receptor coexpression patterns and receptor interaction represent key parameters for signaling robustness, which ensures cellular growth control and enables tissue differentiation. In addition, treatment efficiency of e.g., an anti-HER2 targeting is substantially determined by the expression pattern of HER receptors on target cells. Within the receptor family, the HER4 plays a particular role and is engaged in exceptional signaling activities. A favorable prognostic impact has been attributed to HER4 expression in breast cancer under specific molecular conditions. HER4-specific cellular effects are initially determined by a ligand-dependent or -independent receptor activation. Essential processes as cell growth and proliferation, cell differentiation, and apoptotic cell death can be initiated by this receptor. This review gives an overview of the role of HER4 in normal and malignant breast epithelial cells and tissues. Specific mechanism of HER4 activation and subsequent intracellular signaling will be described by taking a focus on effects provoked by receptor shedding. HER4 activities and specific effects will be correlated to breast cancer subtypes and the impact of HER4 on course and outcome of disease will be considered. Moreover, current and potential therapeutic approaches will be discussed.
Topics: Receptor, ErbB-2; Receptor, ErbB-4; Receptors, Estrogen; Signal Transduction; Trastuzumab
PubMed: 35820544
DOI: 10.1016/j.cellsig.2022.110401