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Open research questions in Advanced Breast Cancer Therapies

36 unresolved questions extracted from the limitations and future-work sections of 246 Advanced Breast Cancer Therapies papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • However, a molecular understanding of how enhanced signaling through the PI3K/AKT/mTOR pathway effectuates a CDK4/6 independent mechanism for entry into S from G1 is lacking.

    Targeting casein kinase 1α-mediated FADD phosphorylation restores sensitivity in select CDK4/6 inhibitor-resistant breast cancer models · 2026 · DOI

  • While the Clinical Treatment Score at 5 Years (CTS5) and the Breast Cancer Index (BCI) are established tools for assessing late recurrence risk, their comparative utility in real-world practice is underexplored.

    Real-World Experience Using the Clinical Treatment Score at 5 Years (CTS5) and Breast Cancer Index (BCI) to Guide Extended Adjuvant Endocrine Therapy · 2026 · DOI

  • Given the lack of consensus in the literature, premenopausal women diagnosed with HER2-positive breast cancer face a gap in the available evidence to guide them regarding potential gonadotoxicity.

    Impact of trastuzumab on Anti-Müllerian (AMH) levels in patients undergoing (neo) adjuvant treatment for breast cancer: a systematic review · 2026 · DOI

  • The murine E0771 mammary carcinoma cell line is widely used in preclinical studies, yet its molecular identity remains controversial, with reports variably classifying it as luminal B or triple-negative.

    Integrated molecular and functional profiling identifies E0771 as a basal-like triple-negative breast cancer model · 2026 · DOI

  • ARTICLE IN PRESS ARTICLE IN PRESS The clinical implications of BMI in patients with hormone receptor–positive, HER2-negative metastatic breast cancer remain incompletely defined, particularly in the context of CDK4/6 inhibitor therapy.

    Association between obesity and outcomes of first-line CDK4/6 inhibitor therapy in metastatic breast cancer: a multicenter real-world study · 2026 · DOI

  • Future research will examine synthetic lethal interactions, immunological activities following CDK inhibition, and combination with other treatment options including new forms of immunotherapy and epigenetic modulators.

    Targeting Cyclin-Dependent Kinases (CDKs) for Cancer Therapy: An In-Depth Review of Molecular Candidates, Their Synthesis, Evaluation, and Future Directions · 2026 · DOI

  • concluded that TAM is associated with mild subclinical hypothyroidism, primarily reflected by elevated TSH and total T4, with inconsistent effects on free thyroid hormones (10), the interpretation of our FT4 finding is substantially limited by the collinearity between treatment type and menopausal status in our cohort.

    Endocrine therapy and thyroid function in early luminal breast cancer: a controlled longitudinal retrospective analysis · 2026 · DOI

  • The fact that the study group under examination was quite heterogeneous is a limitation of this study, but it also shows how RWD can differ from RCTs and illustrates the benefit of this analysis.

    Real-World Data on the Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced/Metastatic Breast Cancer · 2026 · DOI

  • However, because unequivocal RECIST- defined progression during prior therapy could not be established and molecular profiling was unavailable, this observation should be regarded as hypothesis-generating.

    Sequential CDK4/6 inhibition in bone-only metastatic HR+/HER2- breast cancer: a case of prolonged disease control with abemaciclib after clinical progression on palbociclib-based therapy · 2026 · DOI

  • The study establishes that BMX inhibition stabilizes E2F1 and restores chemosensitivity in SCLC, but does not investigate whether this mechanism applies to other Src-family kinases (Src, Fyn, Lyn) that may compensate for BMX loss or whether dual/triple kinase inhibition is necessary to prevent resistance emergence in long-term treatment scenarios.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • BMX inhibition effects are demonstrated in combination with CDDP (cisplatin) + VP16 (etoposide) in xenograft models, but synergistic interactions with CDK4/6 inhibitor palbociclib or ERK1/2 inhibitor ulixertinib are not systematically evaluated using dose-matrix experiments or combination index analysis despite these agents being purchased and available.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • The PDO (patient-derived organoid) models C23084, LUC240506, LUC23148, and LUC240765 are mentioned as available but only C23084 and LUC22009 PDCs appear in the cytotoxicity and xenograft experiments. Comprehensive testing of IHMT-15137 efficacy across all four PDO lines, with comparison of 3D versus 2D culture responses, is needed to assess relevance to patient tumor architecture.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • The study uses H69AR and H446DDPR chemoresistant cell lines generated through chronic cisplatin and etoposide exposure, but does not examine whether BMX inhibition similarly overcomes resistance to other SCLC chemotherapy agents such as paclitaxel, vincristine, carboplatin, or 5-FU that are listed in the chemical reagents but not tested in cytotoxicity assays.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • The ERK1/2-Cyclin D1/CDK4/6-E2F1 axis is characterized through phosphorylation at Ser332 and Ser337 on E2F1, but the specific mechanisms by which BMX inhibition stabilizes E2F1 protein and prevents its degradation via the ubiquitin-proteasome pathway remain incompletely defined. Direct interaction studies between BMX and E2F1, or between ERK1/2 and E2F1 ubiquitination machinery, are not provided.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • The study demonstrates BMX inhibition overcomes chemoresistance in SCLC cell lines and xenograft models, but clinical validation in SCLC patient cohorts with documented chemoresistance history is absent. The two patient-derived cell lines (C23084 and LUC22009) lack comprehensive comparative analysis of BMX expression levels and phosphorylation status across treatment-naive versus chemoresistant patient samples to establish predictive biomarkers.

    BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis · 2026 · DOI

  • Importance: Given conflicting results regarding the prognosis of erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-low breast cancer, a large-scale, nationally applicable comparison of ERBB2-low vs ERBB2-negative breast cancer is needed.

    Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database · 2023 · DOI

  • Furthermore, there is still a lack of standardization regarding the appropriate patient population for GnRHa use beyond 5 years, long-term management strategies, and drug switching approaches.

    [Expert consensus on the long-term management of gonadotropin-releasing hormone agonists in premenopausal patients with hormone receptor-positive breast cancer (2026 edition)]. · 2026 · DOI

  • The impact of SLNB omission on identifying candidates for CDK4/6 inhibitor therapy remains unclear.

    Role of Sentinel Node Surgery in Identifying Candidates for Adjuvant CDK4/6 Inhibitors: Implications of Choosing Wisely and ASCO Omission Criteria · 2026 · DOI

  • The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

    PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer · 2024 · DOI

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36 open questions have been extracted from the limitations and future-work passages of 246 Advanced Breast Cancer Therapies 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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