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Open research questions in HER2/EGFR in Cancer Research

30 unresolved questions extracted from the limitations and future-work sections of 225 HER2/EGFR in Cancer Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • After the HER2 positive first-line regimen was established with trastuzumab combined chemotherapy, there was a long-term lack of standard regimens in the second and posteriary lines.

    Application of HER2-Targeted Antibody-Drug Conjugates in the Treatment of Gastric Cancer: A Systematic Review of Pivotal Clinical Evidence · 2026 · DOI

  • PurposeExceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking.

    Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer · 2026 · DOI

  • While the HER2-directed antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) has shown efficacy in HER2-mutant non-small cell lung cancer, its activity in HER2-mutant ILC remains unknown.

    Dual HER2/HER3 Targeting with Antibody-Drug Conjugates Reveals a Novel Therapeutic Strategy for HER2-Mutant Lobular Breast Cancer · 2026 · DOI

  • BackgroundTrastuzumab deruxtecan (T-DXd) is active in HER2-expressing solid tumours, but trials excluded HER2 immunohistochemistry (IHC) 1+ disease, and data in pretreated ovarian cancer are lacking.

    Real-world activity of trastuzumab deruxtecan in heavily pretreated HER2-expressing ovarian cancer: focusing on HER2-low responses and CCNE1 amplification · 2026 · DOI

  • Immunohistochemistry remains an indispensable tool in diagnostic pathology and laboratory medicine, offering a unique combination of molecular specificity and preserved tissue morphology. Its numerous uses infectious, in inflammatory, and neoplastic illnesses highlight its in contemporary medicine.

    Applications of Immunohistochemistry in Disease Diagnosis: Principles, Challenges, and Recent Advances · 2026 · DOI

  • We investigated non-genomic mechanisms enabling drug-tolerant persister cells to survive EGFR inhibition, likely co-opting compensatory HER3 activation, whose underlying mechanisms remain unclear.

    Neuroendocrine-like/EMT dedifferentiation mediates resistance to EGFR inhibitors via the NRG1/HER3 axis · 2026 · DOI

  • Although our results support a role for CD24 in reg- ulating autophagy and apoptosis through the AKT/mTOR pathway, the upstream molecular mechanisms linking CD24 to this signaling axis remain unclear. These issues warrant further investigation in future studies using well-established trastuzumab-resistant models.

    Study on the synergistic efficacy and mechanism of CD24 silencing combined with trastuzumab in HER2-positive breast cancer · 2026 · DOI

  • Trastuzumab deruxtecan (T-DXd) is transforming HER2 targeted therapy with future directions focused on expanding clinical impact and improving patient outcomes. Ongoing trials are exploring its use in earlier treatment lines for HER2 positive breast cancer and in HER2-low or other HER2-expressing tumors potentially broadening its indications beyond traditional cohorts.21 Combination strategies with immune checkpoint inhibitors, other HER2 targeted agents and DNA damage repair inhibitors aim to enhance efficacy and overcome resistance mechanisms. Research into molecular drivers of resistance including HER2 downregulation and drug efflux pathways may guide more durable treatment approaches. Safety optimization remains crucial particularly regarding interstitial lung disease with efforts focusing on predictive biomarkers, risk mitigation and individualized dosing.

    Clinical Efficacy, Safety and Future Horizons of Trastuzumab Deruxtecan (T-Dxd) in Her2 – Driven Tumors · 2026 · DOI

  • While these divergent immune patterns suggest that T-DXd may remodel the tumor immune microenvironment toward an inflamed phenotype, definitive causal inference is limited by the small sample size and the lack of matched pre-treatment transcriptomic data for comparison.

    Tumor genome and microenvironment alteration by trastuzumab deruxtecan as neoadjuvant therapy for HER2-mutant NSCLC · 2026 · DOI

  • The study is underpowered to detect moderate differences. HRs for pCR (1.7–1.8) suggest a potential effect that may not reach statistical significance due to sample size limitations. a small number of events within subgroups, resulting in model instability. This likely reflects limited statistical power rather than absence of biological significance.

    Neoadjuvant FinHer regimen in patients with HER2-positive breast cancer: a retrospective audit · 2026 · DOI

  • Cavaco et al. (2022) reviewed antibody-antibiotic conjugates for bacterial infections, but quantitative data on the relationship between linker cleavage kinetics and intracellular antibiotic concentration thresholds required for pathogen killing in different tissue compartments (lungs for Mycobacterium, skin for Leishmania) is lacking.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • The paper references multiple antibody-drug conjugate payloads and linker strategies (indolinobenzodiazepine, spiropyrimidinetriones) effective against diverse targets, but systematic head-to-head comparisons of payload-linker combinations specifically optimized for infectious disease-associated antigens versus cancer antigens are absent.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • Baryakova et al. (2024) developed DBCO-mediated labeling of Staphylococcus aureus surfaces for click chemistry cargo deposition, but the efficiency and in vivo tolerance of this approach for systemic delivery of antibody-drug conjugates in bacterial infection models requires quantitative assessment.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • The lysosomal-cleavable peptide linker technology for antibody-drug conjugates (Balamkundu and Liu, 2023a,b) shows promise, but comparative efficacy studies between different peptide linker sequences in intracellular compartments of infected macrophages containing Leishmania or Mycobacterium pathogens have not been conducted.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • Castro et al. (2024) emphasize incorporating patient preferences into target product profile development for cutaneous leishmaniasis, but the specific requirements for antibody-drug conjugate design parameters (payload potency, linker stability, immunogenicity) tailored to neglected tropical disease patient populations remain undefined.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • The paper discusses linker and conjugation site synergy (Aoyama et al., 2024) impacting biological activity in antibody-drug conjugates, but specific optimization for neglected tropical disease pathogens such as Leishmania gp63 (Ali et al., 2025) or Mycobacterium tuberculosis targets has not been systematically evaluated across different linker chemistries and drug payloads.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • The referenced work by Cai et al. (2020) characterized tissue distribution and catabolism of anti-Staphylococcus aureus THIOMAB antibody-antibiotic conjugates only in rats; translation to non-human primate models or human pharmacokinetic studies to predict clinical efficacy and safety profiles for infectious disease applications remains unaddressed.

    Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges · 2026 · DOI

  • In colorectal carcinomas, HER2 positivity was limited to the conventional adenocarcinoma subtype.

    Human Epidermal Growth Factor Receptor 2 Expression in Gastric and Colorectal Adenocarcinomas: Positivity Rates in a Single-Center Retrospective Study · 2026 · DOI

  • However, their potential in melanoma remains unclear, as no HER2-targeting ADC is currently approved.

    Abstract A011: Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release · 2026 · DOI

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30 open questions have been extracted from the limitations and future-work passages of 225 HER2/EGFR in Cancer Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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