Background and Objectives: Phyllodes tumors are rare breast neoplasms with limited therapeutic options and poorly understood molecular characteristics. This study aimed to analyze genomic alterations and treatment outcomes in advanced phyllodes tumors using Japan’s national clinical genomic testing registry (C-CAT database) to identify potential therapeutic targets and predictive markers. Materials and Methods: We conducted a retrospective analysis of 60 phyllodes tumor cases from 80,329 patients registered in the C-CAT database between June 2019 and August 2024. Comprehensive genomic profiling was performed using multiple platforms including FoundationOne CDx, NCC OncoPanel, and other approved tests. Treatment responses were evaluated according to RECIST criteria, and pathogenic variants were assessed using established databases including ClinVar and OncoKB. Results: The cohort’s median age was 54 years (range: 13–79), with TERT promoter variants (70%), MED12 (52%), and TP53 (50%) mutations being the most frequent alterations. Forty patients received first-line chemotherapy, predominantly anthracycline-based regimens (n = 29). Although not reaching statistical significance, cases with CDKN2A and TERT alterations showed trends toward treatment resistance (OR > 3.0). One patient with a high tumor mutational burden (37/Mb) responded to pembrolizumab. Potential germline variants were identified in two cases (3.3%), involving MSH6 and TP53 alterations. Notably, no cases with CDKN2B alterations demonstrated treatment response (p = 0.09). Conclusions: Our findings suggest distinct molecular patterns in phyllodes tumors compared to other soft tissue sarcomas, with potential implications for treatment selection. The identification of specific genetic alterations associated with treatment resistance may guide therapeutic decision-making, while the presence of actionable mutations in select cases indicates potential opportunities for targeted therapy approaches.

Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, p = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included KRAS Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in TP53 (90.7%), APC (87.0%), and non-V600E BRAF mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants.

Background and Objectives: Phyllodes tumors are rare breast neoplasms with limited therapeutic options and poorly understood molecular characteristics. This study aimed to analyze genomic alterations and treatment outcomes in advanced phyllodes tumors using Japan's national clinical genomic testing registry (C-CAT database) to identify potential therapeutic targets and predictive markers. Materials and Methods: We conducted a retrospective analysis of 60 phyllodes tumor cases from 80,329 patients registered in the C-CAT database between June 2019 and August 2024. Comprehensive genomic profiling was performed using multiple platforms including FoundationOne CDx, NCC OncoPanel, and other approved tests. Treatment responses were evaluated according to RECIST criteria, and pathogenic variants were assessed using established databases including ClinVar and OncoKB. Results: The cohort's median age was 54 years (range: 13-79), with TERT promoter variants (70%), MED12 (52%), and TP53 (50%) mutations being the most frequent alterations. Forty patients received first-line chemotherapy, predominantly an-thracycline-based regimens (n=29). Although not reaching statistical significance, cases with CDKN2A and TERT alterations showed trends toward treatment resistance (OR>3.0). One patient with high tumor mutational burden (37/Mb) responded to pembrolizumab. Potential germline variants were identified in two cases (3.3%), involving MSH6 and TP53 alterations. Notably, no cases with CDKN2B alterations demonstrated treatment response (p=0.09). Conclusions: Our findings suggest distinct molecular patterns in phyllodes tumors compared to other soft tissue sarcomas, with potential implications for treatment selection. The identification of specific genetic alterations associated with treatment resistance may guide therapeutic decision-making, while the presence of actionable mutations in select cases indicates potential opportunities for targeted therapy approaches.

Epidermal growth factor receptor 2 (ERBB2/HER2) is a critical biomarker in gastric cancer management, but the clinical implications of specific ERBB2 mutations remain poorly characterized. Methods/Results: We investigated the ERBB2 R678Q mutation, utilizing the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which involved the analysis of 3116 gastric/gastroesophageal junction adenocarcinomas. ERBB2 mutations were identified in 130 cases, with R678Q present in 40 patients. These patients exhibited significantly lower response rates to oxaliplatin-based regimens compared to ERBB2 wild-type cases (19.0% vs. 38.0%, p = 0.03), while other ERBB2 mutations demonstrated no such resistance. No significant differences in the response were observed to the ramucirumab or nivolumab regimens. Conclusions: Our findings suggest that the ERBB2 R678Q mutation may predict a poor response to oxaliplatin-based therapy. This study provides real-world evidence supporting the potential clinical relevance of this specific ERBB2 mutation in treatment decision making for gastric cancer.

Phyllodes tumors are rare fibroepithelial neoplasms of the breast, and their malignant forms present significant diagnostic and therapeutic challenges. This review summarizes current knowledge across the benign-to-malignant spectrum, focusing on diagnostic approaches, histopathological classification, molecular alterations, and treatment strategies. While recent molecular studies have revealed recurrent genetic mutations, their clinical implications remain under investigation. Surgical excision remains the cornerstone of treatment, and systemic therapies are generally adapted from soft tissue sarcoma protocols. Future efforts should focus on improving diagnostic accuracy, identifying molecular targets for therapy, and fostering international collaboration to advance clinical research in this rare tumor type.

Background/Objectives: Metaplastic breast carcinoma (MpBC) is a rare and aggressive malignancy characterized by significant histological heterogeneity and limited response to standard chemotherapy. Due to its morphological diversity, MpBC often presents diagnostic challenges and can overlap with other mesenchymal tumors. This study aimed to characterize the genomic landscape of MpBC using a nationwide Japanese database and to explore the molecular basis of its diagnostic ambiguities and therapeutic responses. Methods: We retrospectively analyzed genomic and clinical data from 123 MpBC cases registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. To evaluate diagnostic boundaries, genomic profiles of histological mimickers, including 19 cases of angiosarcoma and eight cases of myoepithelial carcinoma, were also examined. Furthermore, an exploratory single-cell RNA-sequencing analysis was performed on 3274 cells from independent MpBC datasets to investigate cellular heterogeneity and potential lineage plasticity. Results: TP53 (73.2%) and PIK3CA (46.0%) were the most prevalent genomic alterations in the MpBC cohort. Exploratory analysis suggested that PIK3CA mutations may be associated with an improved disease control rate in patients receiving taxane-based therapy (p = 0.028). Comparisons with mimickers identified distinctive molecular signatures, such as MED12 and HRAS hotspot mutations, across entities. Single-cell transcriptomics identified a distinct subpopulation (7.02% of malignant cells) co-expressing epithelial and phyllodes-like signatures. Conclusions: These findings suggest that MpBC harbors hybrid malignant cell populations that may contribute to its complex morphological diversity. While the therapeutic associations are based on a limited cohort and require prospective validation, the integration of comprehensive genomic and single-cell profiling provides an exploratory framework that may potentially enhance diagnostic accuracy in the future. However, these associations remain preliminary and require prospective validation to confirm their clinical utility.