ERBB2

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare and aggressive tumor with limited understanding of its clinicopathologic and molecular features. This multi-institutional study characterized 35 cases, showing a female predominance and advanced stage at presentation. Genomic alterations were found in 91% of cases, frequently involving chromatin modifiers such as ATRX, KMT2C, ARID1A, and ARID1B. The heterogeneous molecular profile of these tumors highlights the critical role of molecular analysis in identifying potential therapeutic targets.

An open-label, phase 3 trial evaluated zanidatamab, a HER2-targeted bispecific antibody, with or without tislelizumab (anti-PD-1), combined with chemotherapy, as first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma. Patients were randomized to receive zanidatamab-tislelizumab-chemotherapy, zanidatamab-chemotherapy, or trastuzumab-chemotherapy. Both zanidatamab-tislelizumab-chemotherapy and zanidatamab-chemotherapy arms demonstrated significantly longer progression-free survival (median 12.4 months for both) compared to trastuzumab-chemotherapy (8.1 months). Overall survival was also longer with zanidatamab-tislelizumab-chemotherapy (26.4 months) than with trastuzumab-chemotherapy (19.2 months). Diarrhea was the most common grade 3 or higher adverse event.

This review examines established and emerging biomarkers for stratifying patients with early-stage breast cancer to optimize adjuvant systemic therapy. It highlights that while clinicopathological factors remain fundamental, decision-making is increasingly driven by precise biological markers. ER and HER2 status are crucial, and multigene assays refine recurrence risk and chemotherapy benefit in hormone receptor-positive cancers. Immune and DNA-repair biomarkers inform targeted therapies in HER2-positive and triple-negative subtypes, while mutation profiling of genes like ESR1, PIK3CA, AKT, MTOR, and PTEN guides targeted treatments. Emerging approaches, including liquid biopsy and artificial intelligence, offer dynamic insights but require prospective validation.

This study analyzed the genomic profile of 480 patients with metastatic adenocarcinoma of unknown primary (ACUP) using the FoundationOne CDx platform. The most frequent mutations included TP53, KRAS, and CDKN2A. Results showed that GNAS and PIK3CA mutations were associated with better overall survival. Conversely, ARID1A and NOTCH1 alterations were linked to a worse prognosis. These findings highlight the significance of specific genomic alterations as prognostic markers in ACUP.

This article discusses the increasing complexity of therapeutic decision-making for early-stage, hormone receptor-positive, HER2-negative breast cancer. It highlights the significance of advances in tumor biology, particularly genomic assays, in improving risk stratification and identifying patients most likely to benefit from chemotherapy. The review also explores current challenges and controversies, such as the use of genomic assays in premenopausal women with node-positive disease. Furthermore, it examines the emerging role of circulating tumor DNA as a prognostic and predictive biomarker.

The treatment paradigm for hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) has significantly evolved from sequential therapies to more personalized strategies. CDK4/6 inhibitors combined with endocrine therapy remain the first-line standard of care, consistently improving progression-free survival and, for some agents, overall survival. The emergence of antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan is reshaping the therapeutic landscape, including for HER2-low and HER2-ultralow disease. Metastasis-directed therapy is also considered for oligometastatic or oligoprogressive disease, requiring nuanced decision-making. Overall management now integrates tumor biology, therapeutic advances, and patient-defined goals of care.