Yulei Wang

Rationale: Triple-negative breast cancer (TNBC) with germline PALB2 (gPALB2 ) mutations represents a rare but actionable subset sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. However, clinical evidence supporting PARP inhibition combined with programmed cell death protein 1 (PD-1) blockade after progression on prior immunotherapy remains limited, particularly in central nervous system-involved disease. Patient concerns: A 61-year-old woman initially diagnosed with stage I TNBC developed chest wall recurrence and occipital bone metastasis after a 2-year disease-free interval. The disease subsequently progressed to spinal leptomeningeal metastasis, causing complete bilateral lower-limb paralysis. Diagnoses: Recurrent metastatic TNBC with programmed death-ligand 1 expression and leptomeningeal and multiple osseous metastases was diagnosed. Pharmacogenomic profiling identified a pathogenic gPALB2 p.L484* mutation. Interventions: First-line liposomal doxorubicin achieved 9 months of disease control. Second-line nab-paclitaxel plus tislelizumab, a PD-1 inhibitor, provided a progression-free survival of only 2 months. Third-line carboplatin plus tislelizumab induced rapid neurological improvement, but carboplatin was discontinued after 2 months due to hematologic toxicity. Maintenance tislelizumab monotherapy was continued for an additional 5 months until neurological deterioration and a new femoral metastasis indicated disease progression. Olaparib was subsequently added to continued tislelizumab. Outcomes: Following olaparib initiation, bilateral lower-limb muscle strength improved from Medical Research Council grade 0 to grade 2. Follow-up imaging demonstrated marked regression of the leptomeningeal and osseous lesions. The patient achieved a durable progression-free survival of approximately 40 months with acceptable tolerability. Lessons: Identification of a gPALB2 mutation informed the addition of olaparib to continued tislelizumab, leading to sustained disease control in this patient. Although the relative contributions of each component cannot be determined from a single case, this hypothesis-generating observation suggests that PARP inhibitor–based strategies and continuation of PD-1 blockade beyond progression warrant further investigation in carefully selected patients with gPALB2 -mutated TNBC with central nervous system involvement.

Background: Precise surgical excision of nonpalpable breast microcalcifications remains challenging when conventional localization equipment is limited or not routinely available across clinical settings, underscoring the need for an accessible and reproducible alternative approach. This study aimed to assess the feasibility and localization accuracy of a novel mammography-based localization strategy for guiding diagnostic surgical excision of nonpalpable breast microcalcifications. Methods: This multicenter retrospective study evaluated a mammography-based geometric localization approach termed mammogram geometric projection localization (MaGPL). The technique applies a boundary-defined, range-based “Maximal Width Crossing Criterion” to reconstruct a body-surface coordinated field from two standard mammographic projections, preferentially the craniocaudal (CC) and lateromedial (LM) views. By deliberately selecting the most geometrically stable boundary information from each projection, MaGPL defines axis-specific localization boundaries, forming the geometric basis for boundary-defined localization of nonpalpable calcifications. A total of 41 patients (45 lesions) underwent diagnostic excision guided by MaGPL. Localization accuracy was evaluated using the geometric offset (D_offset), defined as the linear distance between the radiographic center of the calcification cluster and the center of the excised specimen measured on intraoperative mammography. Results: The cohort had a median age of 48 years (range, 25–81 years) and a mean mammographically estimated breast volume of 370±158 mL. The mean linear extent of the target calcification clusters was 22.6±15.1 mm (range, 3.0–67.0 mm), and pathologic examination confirmed malignancy in 18 of 45 lesions (40.0%). All calcification clusters were successfully excised in a single operation, achieving a 100% intraoperative retrieval rate. The median D_offset was 9.7 mm [interquartile range (IQR), 8.3–13.0 mm], indicating a clinically acceptable level of geometric localization precision. Orthogonal CC + LM projections yielded smaller offsets than non-orthogonal combinations (P=0.003). Larger breast volumes were associated with greater D_offset (PConclusions: MaGPL represents a standardized, equipment-independent alternative for body-surface localization to guide surgical excision of nonpalpable breast microcalcifications, offering reproducible and clinically applicable localization accuracy without additional cost, with particular utility in community and resource-limited settings.

Lin X, et al. J Breast Cancer. 2023 Jul;26:e30. https://doi.org/10.4048/jbc.2023.26.e30

Purpose: Somatic alteration of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a crucial therapeutic target in breast cancer (BC) and PI3Kα-specific inhibitor Alpelisib has been used in clinics. This study investigates the PIK3CA alterations in Chinese and Caucasians BC patients for the purpose of selecting anti-PI3K therapy. Methods: The molecular profile of the PIK3CA gene was analyzed in 412 Chinese patients with untreated invasive BC using a 540 gene next-generation sequencing panel. The results were compared with data of the Caucasian BC patients in The Cancer Genome Atlas (TCGA-white). Results: PIK3CA alterations were frequently found in BC of estrogen receptor (ER) positive (49.3%, p = 0.024), low ki67 proliferation index (58.3%, p = 0.007) and low pathological grade (grade I/II/III 80%, 53.4%, 35.9%, p < 0.001). Compared to TCGA-white, Chinese BC patients had a higher alteration frequency (45.6% vs. 34.7%, p < 0.001) with larger proportion of p.H1047R mutation among three common mutation sites (p.E545K, p.E542K and p.H1047R) (66.1% vs. 43.7%, p = 0.01). Across four molecular subtypes, ER + /human epidermal growth factor receptor 2 positive (HER2 +) tumors harbored the most PIK3CA alterations (51.6%), while ER-/HER2- harbored the least alteration (30.0%) but the most copy number amplification (19.05%). Conclusion: PIK3CA alterations prevail in Chinese BC patients and have different molecular features compared to that of Caucasians. The results provide precise annotations of PIK3CA genomic alterations of Chinese in the context of application of PIK3CA inhibitor.

Background: Recent studies have shown that selenium-binding protein 1 (SELENBP1) is significantly down-regulated in a variety of solid tumors. Nevertheless, the clinical relevance of SELENBP1 in human bladder cancer has not been described in any detail, and the molecular mechanism underlying its inhibitory role in cancer cell growth is largely unknown. Methods: SELENBP1 expression levels in tumor tissues and adjacent normal tissues were evaluated using immunoblotting assay. The association of SELENBP1 expression, clinicopathological features, and clinical outcome was determined using publicly available dataset from The Cancer Genome Atlas bladder cancer (TCGA-BLCA) cohort. DNA methylation in SELENBP1 gene was assessed using online MEXPRESS tool. We generated stable SELENBP1-overexpression and their corresponding control cell lines to determine its potential effect on cell cycle and transcriptional activity of p21 by using flow cytometry and luciferase reporter assay, respectively. The dominant-negative mutant constructs, TAM67 and STAT1 Y701F, were employed to define the roles of c-Jun and STAT1 in the regulation of p21 protein. Results: Here, we report that the reduction of SELENBP1 is a frequent event and significantly correlates with tumor progression as well as unfavorable prognosis in human bladder cancer. By utilizing TCGA-BLCA cohort, DNA hypermethylation, especially in gene body, is shown to be likely to account for the reduction of SELENBP1 expression. However, an apparent paradox is observed in its 3′-UTR region, in which DNA methylation is positively related to SELENBP1 expression. More importantly, we verify the growth inhibitory role for SELENBP1 in human bladder cancer, and further report a novel function for SELENBP1 in transcriptionally modulating p21 expression through a p53-independent mechanism. Instead, ectopic expression of SELENBP1 pronouncedly attenuates the phosphorylation of c-Jun and STAT1, both of which are indispensable for SELENBP1-mediated transcriptional induction of p21, thereby resulting in the G₀/G₁ phase cell cycle arrest in bladder cancer cell. Conclusions: Taken together, our findings provide clinical and molecular insights into improved understanding of the tumor suppressive role for SELENBP1 in human bladder cancer, suggesting that SELENBP1 could potentially be utilized as a prognostic biomarker as well as a therapeutic target in future cancer therapy.

The complexity of breast cancer at the clinical, morphological and genomic levels has been extensively studied in the western population. However, the mutational genomic profiles in Chinese breast cancer patients have not been explored in any detail. We performed targeted sequencing using a panel consisting of 33 breast cancer-related genes to investigate the genomic landscape of 304 consecutive treatment-naïve Chinese breast cancer patients at Guangdong Provincial People's Hospital (GDPH), and further compared the results to those in 453 of Caucasian breast cancer patients from The Cancer Genome Atlas (TCGA). The most frequently mutated gene was TP53 (45%), followed by PIK3CA (44%), GATA3 (18%), MAP3K1 (10%), whereas the copy-number amplifications were frequently observed in genes of ERBB2 (24%), MYC (23%), FGFR1 (13%) and CCND1 (10%). Among the 8 most frequently mutated or amplified genes, at least one driver was identifiable in 87.5% (n=267) of our GDPH cohort, revealing the significant contribution of these known driver genes in the development of Chinese breast cancer. Compared to TCGA data, the median age at diagnosis in our cohort was significantly younger (48 vs. 58 years; P<0.001), while the distribution of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) statuses were similar. The largest difference occurred in HR+/HER2- subtype, where 8 of the 10 driver genes compared had statistically significant differences in their frequency, while there were differences in 2 of 10 driver genes among the TNBC and HR+/HER2+ group, but none in the HR-/HER2+ patients in our cohort compared to the TCGA data. Collectively, the most significant genomic difference was a significantly higher prevalence for TP53 and AKT1 in Chinese patients. Additionally, more than half of TP53-mutation HR+/HER2- Chinese patients (~60%) are likely to harbor more severe mutations in TP53, such as nonsense, indels, and splicing mutations. We elucidated the mutational landscape of cancer genes in Chinese breast cancer and further identified significant genomic differences between Asian and Caucasian patients. These results should improve our understanding of pathogenesis and/or metastatic behavior of breast cancer across races/ethnicities, including a better selection of targeted therapies.

Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

Emerging evidence from The Cancer Genome Atlas has revealed that nuclear factor κB2 (nfκb2) gene encoding p100 is genetically deleted or mutated in human cancers, implicating NFκB2 as a potential tumor suppressor. However, the molecular mechanism underlying the antitumorigenic action of p100 remains poorly understood. Here we report that p100 inhibits cancer cell anchorage-independent growth, a hallmark of cellular malignancy, by stabilizing the tumor-suppressor phosphatase and tensin homolog (PTEN) mRNA via a mechanism that is independent of p100’s inhibitory role in NFκB activation. We further demonstrate that the regulatory effect of p100 on PTEN expression is mediated by its downregulation of miR-494 as a result of the inactivation of extracellular signal–regulated kinase 2 (ERK2), in turn leading to inhibition of c-Jun/activator protein-1-dependent transcriptional activity. Furthermore, we identify that p100 specifically interacts with non-phosphorylated ERK2 and prevents ERK2 phosphorylation and nuclear translocation. Moreover, the death domain at C-terminal of p100 is identified as being crucial and sufficient for its interaction with ERK2. Taken together, our findings provide novel mechanistic insights into the understanding of the tumor-suppressive role for NFκB2 p100.