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Expert Opinion on Biological Therapy Jun 2024The prognosis of advanced esophageal squamous cell carcinoma (ESCC) is poor. Although cytotoxic drugs have been widely used in advanced ESCC, several antibody agents... (Review)
Review
INTRODUCTION
The prognosis of advanced esophageal squamous cell carcinoma (ESCC) is poor. Although cytotoxic drugs have been widely used in advanced ESCC, several antibody agents have recently been reported to be effective.
AREAS COVERED
Nivolumab and pembrolizumab are anti-PD-1 antibodies that improve immunosuppression by binding to programmed death-1 (PD-1), leading to an antitumor effect. Randomized phase III trials have found these immune checkpoint inhibitors (ICIs) to be effective as second-line treatment. ATTRACTION-3, which compared nivolumab monotherapy with taxane monotherapy in patients with previously treated advanced ESCC, reported prolonged overall survival in the nivolumab group. KEYNOTE-181 found that overall survival was longer in patients with PD-L1-positive ESCC who received second-line treatment with pembrolizumab than in those who received chemotherapy. Sym004 and amivantamab are antibodies that target the epidermal growth factor receptor and have demonstrated efficacy in the treatment of other tumors in recent phase I studies. Furthermore, clinical trials on antibody-drug conjugates such as enfortumab vedotin and DS-7300 for solid tumors are currently ongoing.
EXPERT OPINION
The standard first-line treatments for patients with advanced ESCC contain ICIs. Therefore, drugs with different mechanisms of action that can overcome resistance to ICIs are needed as second-line or later-line treatments to improve clinical outcomes in these patients.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Antibodies, Monoclonal, Humanized
PubMed: 38860728
DOI: 10.1080/14712598.2024.2366493 -
Modern Pathology : An Official Journal... Jun 2024The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC],...
Development and Validation of a HER2-Low Focused Immunohistochemical Scoring System With High-Interobserver Concordance: The Australian HER2-Low Breast Cancer Concordance Study.
The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists' independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which <20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists' accuracy and concordance.
PubMed: 38852812
DOI: 10.1016/j.modpat.2024.100535 -
Cancer Letters Jun 2024HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast...
HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.
PubMed: 38852701
DOI: 10.1016/j.canlet.2024.217023 -
International Journal of Surgery Case... Jul 2024Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after...
INTRODUCTION AND IMPORTANCE
Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after discontinuation of ionizing radiation. The symptoms of RRD can range from mild redness to extensive dermatitis. Antineoplastic drugs such as doxorubicin, docetaxel, paclitaxel, and gemcitabine are most commonly associated with radiation recall reactions. These reactions can also occur with antibiotics and anti-tubercular drugs.
CASE PRESENTATION
A 38-years-old woman with hormone receptor-negative, HER2-positive inflammatory breast cancer (right), clinical stage cT4dN1Mx, received neoadjuvant chemotherapy with AC > TH protocol at 3 weeks intervals (Anthracycline-Doxorubicin plus Cyclophosphamide X 4 cycles, then docetaxel plus Trastuzumab X 4 cycles) followed by modified radical mastectomy followed by adjuvant locoregional radiotherapy. She received the 5th cycle and 6th cycle trastuzumab monotherapy just before the start of surgery and radiotherapy, respectively. After 1 month of completion of radiotherapy, during her seventh cycle of Trastuzumab monotherapy, she developed mild edema with erythematous change over the previously irradiated area with fever. A skin biopsy was taken to exclude any recurrence; however, no evidence of malignancy was found.
CLINICAL DISCUSSION
We diagnosed it as a case of RRD. We managed her conservatively. Later, she was rechallenged with the same dose in subsequent cycles with systemic steroid coverage, which she tolerated very well, except for the reappearance of mild erythema following each cycle of maintenance dose of Trastuzumab.
CONCLUSION
Radiation recall dermatitis is an extremely rare phenomenon; hence, an acquaintance of clinicians with this rare entity is essential for timely diagnosis and appropriate management.
PubMed: 38852571
DOI: 10.1016/j.ijscr.2024.109864 -
BMC Cancer Jun 2024Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC.
METHODS
Relevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration's tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis.
RESULTS
Meta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49-0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72-0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable.
CONCLUSION
Statistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment.
Topics: Humans; Breast Neoplasms; Receptor, ErbB-2; Female; Immunoconjugates; Randomized Controlled Trials as Topic; Progression-Free Survival; Treatment Outcome; Trastuzumab; Antineoplastic Agents, Immunological
PubMed: 38851684
DOI: 10.1186/s12885-024-12478-1 -
European Journal of Pharmacology Jun 2024Receptor tyrosine kinases (RTKs) are cell surface receptors with kinase activity that play a crucial role in diverse cellular processes. Among the RTK family members,... (Review)
Review
Receptor tyrosine kinases (RTKs) are cell surface receptors with kinase activity that play a crucial role in diverse cellular processes. Among the RTK family members, Human epidermal growth factor receptor 2 (HER2) and HER3 are particularly relevant to breast cancer. The review delves into the complexities of receptor tyrosine kinase interactions, resistance mechanisms, and the potential of anti-HER3 drugs, offering valuable insights into the clinical implications and future directions in this field of study. It assesses the potential of anti-HER3 drugs, such as pertuzumab, in overcoming resistance observed in HER2-positive breast cancer therapies. The review also explores the resistance mechanisms associated with various drugs, including trastuzumab, lapatinib, and PI3K inhibitors, providing insights into the intricate molecular processes underlying resistance development. The review concludes by emphasizing the necessity for further clinical trials to assess the efficacy of HER3 inhibitors and the potential of developing safe and effective anti-HER3 treatments to improve treatment outcomes for patients with HER2-positive breast cancer.
PubMed: 38851563
DOI: 10.1016/j.ejphar.2024.176725 -
Bioorganic Chemistry Aug 2024The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through...
The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.
Topics: Humans; Immunoconjugates; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Trastuzumab; Molecular Structure; Cell Proliferation; Drug Screening Assays, Antitumor; Maleimides; Dose-Response Relationship, Drug; Antineoplastic Agents; Structure-Activity Relationship; Maytansine; Cell Line, Tumor; Antineoplastic Agents, Immunological
PubMed: 38850783
DOI: 10.1016/j.bioorg.2024.107504 -
Gland Surgery May 2024In the past few years, the combination of trastuzumab and paclitaxel has become an important option for human epidermal growth factor receptor-2 (HER2)-positive breast...
The efficacy and safety of trastuzumab and albumin-bound paclitaxel with or without pyrotinib as neoadjuvant therapy for HER2-positive breast cancer: a prospective observational cohort study.
BACKGROUND
In the past few years, the combination of trastuzumab and paclitaxel has become an important option for human epidermal growth factor receptor-2 (HER2)-positive breast cancer. Small molecule tyrosine kinase inhibitors (TKIs) can bring clinical benefit to HER2-positive breast cancer patients. However, the efficacy and safety of these two regimens have not been compared. This study explored the efficacy and safety of pyrotinib combined with trastuzumab and albumin-bound paclitaxel (nab-paclitaxel).
METHODS
Patients with newly diagnosed HER2-positive early or locally advanced breast cancer treated at The Tumor Hospital of Mudanjiang City from November 2020 to June 2022 were included. The control group received pertuzumab in combination with nab-paclitaxel, whereas the pyrotinib group received pyrotinib in combination with pertuzumab and nab-paclitaxel as treatment, in a 3-week cycle for 4 cycles. The primary endpoints of this study were total pathological complete response (tpCR) rate, breast pathological complete response (bpCR) rate, and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and the occurrence of adverse events (AEs).
RESULTS
A total of 72 patients were enrolled in the study and completed the study treatment. Baseline characteristics were well balanced between these two arms. In the control group, the tPCR rate was 23.68%, and the bpCR rate was 47.36%. In the pyrotinib group, the tPCR rate was 47.06%, and the bpCR rate was 64.71%. The tPCR rate in the pyrotinib group was significantly higher than that in the control group (P=0.049). The ORR in the pyrotinib group (67.65%) was significantly higher than that in the control group (42.11%, P=0.04 ). The median PFS (mPFS) for the control group was 9.24 months, with a mean PFS of 10.01±0.44 months [95% confidence interval (CI): 9.14-10.88 months]. In the pyrotinib group, mPFS was 9.74 months, with a mean PFS of 11.25±0.29 months (95% CI: 10.67-11.82 months). The PFS in the pyrotinib group was significantly longer than that in the control group (P=0.045). Safety results showed that the overall incidence of AEs in the control group was 68.42%, with a 3-grade adverse reaction rate of 21.05%. In the pyrotinib group, the overall incidence of AEs was 79.41%, with a 3-grade adverse reaction rate of 29.41%. The difference between the two groups was not statistically significant (P>0.05).
CONCLUSIONS
Pyrotinib group in neoadjuvant treatment for HER2 positive breast cancer has obvious short-term efficacy advantages over control group. This treatment regimen can prolong PFS for 1 year, and the safety during medication is controllable. This study still has some limitations, with the relatively small sample size and relatively short follow-up period, and a further large-scale, multicenter, randomized controlled trial is necessary to verify the clinical value of this dual-target treatment regimen.
PubMed: 38845840
DOI: 10.21037/gs-24-81 -
MAbs 2024Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed...
Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. , these data suggest that the KIH mutations and assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG, nor do the Fab mutations used for efficient assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.
Topics: Antibodies, Bispecific; Humans; Immunoglobulin G; Risk Assessment; Trastuzumab; Animals; Bevacizumab; Mutation
PubMed: 38845069
DOI: 10.1080/19420862.2024.2362789 -
Cardio-oncology (London, England) Jun 2024To understand how body composition in those with elevated body mass index impacts left ventricular function decline during cancer treatment, we determined the...
BACKGROUND
To understand how body composition in those with elevated body mass index impacts left ventricular function decline during cancer treatment, we determined the association between baseline body mass index (BMI), intra-abdominal adipose tissue (IAT) and subcutaneous adipose tissue (SAT) with baseline to 3-month left ventricular ejection fraction (LVEF) change among women receiving potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or sarcoma.
METHODS
Women underwent potentially cardiotoxic chemotherapy, such as doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab, for treatment of breast cancer, lymphoma, or sarcoma. We obtained magnetic resonance images (MRIs) of body composition and cardiac function prior to treatment, and then a repeat MRI for cardiac function assessment at three months into treatment. Analyses and assessment of abdominal adipose tissue volumes and LVEF outcomes were conducted by independent reviewers blinded to all patient identifiers. A general linear model was created to examine associations between adipose tissue depots, BMI, and 3-month LVEF change.
RESULTS
Women (n = 210) aged 56 ± 11 years with breast cancer, lymphoma, and sarcoma were enrolled (n = 195, 14, 1 respectively). Baseline BMI, IAT, and SAT fat were independently associated with 3-month LVEF declines (p = 0.001 to 0.025 for all). After adjusting for baseline cardiovascular disease risk factors, BMI, IAT, and SAT, BMI remained the only variable associated with 3-month LVEF decline (p = 0.047).
CONCLUSIONS
These results suggest that factors other than abdominal adipose tissue or traditional cardiovascular risk factors may contribute to 3-month declines in LVEF among women with elevated BMI receiving potentially cardiotoxic chemotherapy. Further investigation should be conducted on psychosocial stress, physical activity, sleep, or diet.
TRIAL REGISTRATION
DETECTIV_NCT01719562, WF99112, & WF97415-NCT02791581.
PubMed: 38845066
DOI: 10.1186/s40959-024-00233-1