Emerging molecular Therapeutic targets in breast Cancer: Pathologic identification and clinical implications.

Breast carcinoma represents a biologically heterogeneous group of malignancies with diverse clinical behaviors, highlighting the need for robust molecular markers to support accurate diagnosis, prognosis, and therapeutic decision-making. Histopathologic evaluation and assessment of established biomarkers, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, remain central to clinical management, yet these biomarkers do not fully capture the disease complexity. Advances in genomics have enabled identification of intrinsic breast cancer subtypes, improving risk stratification and personalization of therapy.

IL-6 predicts CDK4/6 inhibitor resistance, identifying STAT3 as a target in HR + /HER2-negative metastatic breast cancer.

Resistance to CDK4/6 inhibitors (CDK4/6i) is a major challenge in treating hormone receptor-positive, HER2-negative metastatic breast cancer. This study aimed to identify a biomarker predictive of resistance that could also serve as a therapeutic target. Circulating IL-6 levels in 166 patients significantly increased at progression, making IL-6 a non-invasive biomarker to predict CDK4/6i resistance.

Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors.

Purpose: Intratumoral injection of Clostridium novyi-NT, lacking alpha toxin, germinates and subsequently replicates in the tumor hypoxic regions, causing cell lysis and inflammation. This phase 1b study investigated the safety and synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors.

Paving the path ForwARd: Advances and challenges in androgen receptor targeting in breast cancer.

The role of androgen receptors (AR) in breast cancer is crucial for preclinical and clinical research. While AR-targeted therapy is a standard treatment for prostate cancer, the application of this therapeutic strategy to breast cancer has not been established. Indeed, AR is expressed in around 60-90% of breast cancers, making it imperative that we learn more about its prognostic and predictive impacts and targeting potential in breast cancer.

Clinical Characteristics and Survival Outcomes of Metastatic Invasive Lobular and Ductal Carcinoma.

Importance: Comparing the clinical and molecular features of metastatic invasive lobular carcinoma (mILC) and metastatic invasive ductal carcinoma (mIDC) is essential to enhance understanding of breast cancer biology and improve personalized treatment approaches.

Objective: To compare mILC and mIDC in terms of survival outcomes and to investigate the association of clinicopathologic characteristics with those outcomes.

Design, Setting, And Participants: This cohort study included adult patients at the University of Texas MD Anderson Cancer Center with their first metastatic diagnosis occurring between January 1997 and December 2020.

ELAINE 3: phase 3 study of lasofoxifene plus abemaciclib to treat ER+/HER2-, -mutated, metastatic breast cancer.

Endocrine therapy (ET) is recommended for patients with estrogen receptor-positive (ER+) metastatic breast cancer (mBC), but most patients will develop treatment resistance, often due to mutations in the ER-α-coding gene, . Therapeutic options are limited for endocrine-resistant mBC, particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Lasofoxifene had anti-tumor activity in two separate phase 2, open-label studies (ELAINE 1 and 2) when given as monotherapy or combined with abemaciclib.

Single-cell RNA sequencing identifies molecular biomarkers predicting late progression to CDK4/6 inhibition in patients with HR+/HER2- metastatic breast cancer.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.

Methods: Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression.

Phase I trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2- breast cancer.

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses.

Human Epidermal Growth Factor Receptor 2 Loss following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer.

Purpose: Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) that is HER2 positive [immunohistochemistry (IHC) score of 3+ or in situ hybridization (ISH) positivity] or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2-overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 status might change following T-DXd therapy.

Experimental Design: We retrospectively reviewed patients with MBC who received T-DXd at the University of Texas MD Anderson Cancer Center.

Durable disease regression with copanlisib treatment in PI3K-mutated metastasizing ameloblastoma: A case report.

Ameloblastoma is a rare tumor arising from odontogenic cells that is benign, yet locally aggressive. Metastasizing ameloblastoma (METAM) is an ultra-rare ameloblastoma variant in which both primary and secondary tumors have histological features of benign ameloblastoma. This is a case report of a patient who presented with a jaw mass and subsequent lung metastases, later diagnosed as METAM.

Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses.

Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to multiple single agents cannot be delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination.

Antitumor Activity and Biomarker Analysis for TROP2 Antibody-Drug Conjugate Datopotamab Deruxtecan in Patient-Derived Breast Cancer Xenograft Models.

Purpose: Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.

Phase 2 study of neoadjuvant enzalutamide and paclitaxel for luminal androgen receptor-enriched TNBC: Trial results and insights into "ARness".

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC.

Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models.

Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan.

TROP2 antibody drug conjugates (ADCs) are under active development. We seek to determine whether we can enhance activity of TROP2 ADCs by increasing TROP2 expression. In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG).

Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers.

Unlabelled: Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression.

Operational Metrics for the ELAINE 2 Study Combining a Traditional Approach With a Just-in-TIME Model.

Purpose: There are numerous barriers to enrollment in oncology biomarker-driven studies.

Methods: The ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with an mutation.

Targeting chemotherapy resistance in mesenchymal triple-negative breast cancer: a phase II trial of neoadjuvant angiogenic and mTOR inhibition with chemotherapy.

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple-negative breast cancer.

Background: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.