EGFR-directed antibodies promote HER2 ADC internalization and efficacy.

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context.

Predictors of response to CDK4/6i retrial after prior CDK4/6i failure in ER+ metastatic breast cancer.

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution.

Predictors of Response to CDK4/6i Retrial After Prior CDK4/6i Failure in ER+ Metastatic Breast Cancer.

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution.

Incidence of HER2-expressing brain metastases in patients with HER2-null breast cancer: a matched case analysis.

The HER2-directed antibody-drug conjugate trastuzumab deruxtecan is active against lower levels of HER2 expression than prior-generation therapies. The rate of HER2 expression in brain metastases among patients with initially HER2-null breast cancer is undefined, and receptor discordance in advanced breast cancer with brain metastases may underestimate CNS response potential in the absence of brain metastasis sampling. In this cohort study including 136 patients with 401 samples scored according to ASCO/CAP guidelines, 15/28 patients (54%) with HER2-null primary breast cancer have detectable HER2 expression in subsequently resected brain metastases, a significant discordant population.

ADCs or: How I Learned to Stop Worrying and Love Chemotherapy.

Antibody-drug conjugates are transforming cancer treatment, and payload characteristics are emerging as crucial determinants of clinical activity. As exemplified by Weng and colleagues, advancements in the linker and payload chemistry may provide the next evolutionary step in enabling this class of drugs to overcome chemoresistance and deliver even more profound responses. See related article by Weng et al.

Beyond HER2: Targeting the ErbB receptor family in breast cancer.

Targeting the HER2 oncogene represents one of the greatest advances in the treatment of breast cancer. HER2 is one member of the ERBB-receptor family, which includes EGFR (HER1), HER3 and HER4. In the presence or absence of underling genomic aberrations such as mutations or amplification events, intricate interactions between these proteins on the cell membrane lead to downstream signaling that encourages cancer growth and proliferation.

Morphologic and Genomic Characteristics of Breast Cancers Occurring in Individuals with Lynch Syndrome.

Purpose: Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.

Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions.

The development of anti-HER2 agents has been one of the most meaningful advancements in the management of metastatic breast cancer, significantly improving survival outcomes. Despite the efficacy of anti-HER2 monoclonal antibodies, concurrent chemotherapy is still needed to maximize response. Antibody-drug conjugates (ADCs) are a class of therapeutics that combines an antigen-specific antibody backbone with a potent cytotoxic payload, resulting in an improved therapeutic index.

A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with -Mutated HER2-Positive Metastatic Breast Cancer.

Purpose: Activating mutations in promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.

Patients And Methods: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with -mutant HER2-positive (HER2) metastatic breast cancer (MBC) using the continual reassessment method.

Unlocking the potential of antibody-drug conjugates for cancer therapy.

Nine different antibody-drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors.

Inferences About Drug Safety in Phase III Trials in Oncology: Examples From Advanced Prostate Cancer.

Background: Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature.

Methods: We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer.

Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor-Positive (HR) Breast Cancer.

Purpose: While amplification has been described in breast cancer, the optimal treatment approach for -amplified (FGFR1) metastatic breast cancer (MBC) remains undefined. We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR)/HER2 MBC and validated the functional role of -amplification in mediating response/resistance to hormone therapy .

Results: In the clinical cohort ( = 110), we identified that patients with FGFR1 tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs.

Targeting Apoptosis: A New Paradigm for the Treatment of Estrogen Receptor-Positive Breast Cancer.

Standard treatment for estrogen receptor-positive metastatic breast cancer involves antiestrogen therapy used alone or in combination with inhibitors of CDK4/6 or mTOR; this approach works mechanistically by eliciting and reinforcing cell-cycle arrest. In this issue, Lok and colleagues diverge from this paradigm by combining the BCL2 inhibitor venetoclax with tamoxifen in a phase Ib clinical trial, building on preclinical work to demonstrate that targeting apoptosis could represent a promising new strategy in the treatment of breast cancer..

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study.

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors.

The Harm in Kratom.

A case of severe hepatic toxicity associated with the use of kratom, a plant derivative increasingly used as a psychostimulant, is discussed.