Background:KDM1B, a flavin-dependent histone demethylase, is an epigenetic regulator implicated in tumorigenesis; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to explore the biological role of KDM1B in ESCC and, on this basis, to develop a prognostic prediction model incorporating KDM1B. Methods:Public transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO; GSE26886 and GSE161533) were analyzed to assess KDM1B expression, prognostic relevance, pathway enrichment, and immune infiltration in ESCC. KDM1B genomic alterations were further examined in 52 ESCC specimens from our center. Functional assays were performed in ESCC cell lines to evaluate the effects of KDM1B on proliferation, migration, and apoptosis. Overall survival (OS) was the primary prognostic outcome. Univariable and multivariable Cox regression analyses were performed to construct a prognostic prediction model for estimating 1-, 3-, and 5-year OS. Results:KDM1B was significantly upregulated in ESCC compared with normal esophageal epithelium and was associated with a higher response rate to systemic therapy. In our cohort, intronic variants and copy-number alterations of KDM1B were detected in a subset of tumors. Functional enrichment analyses suggested that KDM1B may be involved in cell-cycle regulation and apoptosis, and its expression was associated with immune infiltration. Survival analyses showed that elevated KDM1B expression was associated with longer OS. A prognostic prediction model incorporating KDM1B expression, pathologic node stage (N stage), pathologic metastasis stage (M stage), overall pathologic stage, gender, and histologic grade was developed to estimate 1-, 3-, and 5-year OS in patients with ESCC. In vitro experiments showed that KDM1B promoted ESCC cell proliferation and migration while inhibiting apoptosis, suggesting a context-dependent role in ESCC biology, potentially influenced by treatment and the immune microenvironment. Conclusions:KDM1B is upregulated in ESCC and may influence tumor behavior through regulation of the cell cycle, apoptosis, and the tumor immune microenvironment. KDM1B was also incorporated into a prognostic prediction model for OS estimation in ESCC, supporting its potential value in prognostic stratification.

Aim To evaluate the prognostic value of Noggin expression and develop a clinically applicable prediction model for patients with advanced gastric cancer receiving first-line chemotherapy. Methods Noggin expression was analysed using the GTEx and TCGA databases and further assessed by immunohistochemistry in 217 gastric cancer tissue specimens. Associations between Noggin expression and clinicopathological characteristics were evaluated. In patients receiving first-line chemotherapy, independent prognostic factors for overall survival were identified using multivariable Cox regression. A nomogram incorporating these factors was developed and internally validated in terms of discrimination, calibration, and clinical utility. Results Noggin expression was significantly higher in gastric cancer tissues than in normal tissues (46.1% vs 15.1%, p < 0.001) and was associated with tumour differentiation and primary tumour location. Among 165 patients who received first-line chemotherapy, six independent prognostic factors for overall survival were identified: malignant ascites, history of gastrectomy, HER2 status, liver metastasis, mismatch repair status, and Noggin expression. A nomogram based on these variables showed good discriminative ability, calibration, and clinical utility after internal validation. Conclusion Noggin expression is an independent prognostic factor in advanced gastric cancer. The Noggin-based nomogram may serve as a practical tool for survival prediction and risk stratification in patients receiving first-line chemotherapy.

BackgroundImmune checkpoint inhibitor (ICI)-based induction therapy followed by definitive radiotherapy has emerged as a promising treatment strategy for patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, many patients still experience disease progression and poor clinical outcomes. Although longitudinal circulating biomarkers may provide valuable prognostic information, their dynamic predictive value in this treatment setting remains largely unexplored.Materials and methodsWe retrospectively enrolled patients with unresectable LA-ESCC from a single medical center who received PD-1inhibitor-based induction therapy followed by definitive radiotherapy. In addition to baseline clinical and histopathological characteristics, 110 circulating biomarkers were serially collected throughout treatment to characterize longitudinal changes. A Bayesian joint model integrating baseline predictors with longitudinal biomarker trajectories was developed for dynamic survival prediction. Model discrimination and calibration were evaluated using time-dependent area under the receiver operating characteristic curve (AUCs) and Brier scores, respectively.ResultsA total of 376 patients were included, comprising a training cohort (n = 221) and an independent temporal test cohort (n = 155), yielding 328,104 longitudinal biomarker measurements. Following multistage variable selection procedure, latent class growth analysis identified distinct longitudinal trajectories of the albumin-to-globulin ratio (AGR) that are significantly associated with survival outcomes. Dynamic AGR value and trajectory emerged as the most informative longitudinal predictors among all candidate biomarkers. In the training cohort, the 12-, 24-, and 36-month AUCs were 0.85 (95% CI, 0.82-0.89), 0.92 (95% CI, 0.90-0.94), and 0.87 (95% CI, 0.84-0.91), respectively. In the test cohort, the corresponding 12- and 24-month AUCs were 0.80 (95% CI, 0.75-0.85) and 0.82 (95% CI, 0.78-0.86), respectively.ConclusionBy integrating longitudinal AGR trajectories with baseline clinical information, the Bayesian joint model enables individualized, real-time prognostic updating and may facilitate dynamic risk stratification and risk-adapted management for patients with unresectable LA-ESCC.

Carcinoma of unknown primary (CUP) is a rare malignancy characterized by metastatic disease without an identifiable primary tumor, even after extensive diagnostic evaluation. This case report described a 70-year-old female patient with squamous cell CUP (SCCUP) who initially presented with elevated carbohydrate antigen 19-9 and a diaphragmatic mass. Despite comprehensive workup, including 18F-fluorodeoxyglucose positron emission tomography-computed tomography and a 90-gene expression assay, the primary site remained unclear. The patient underwent surgical resection followed by two cycles of systematic therapy and achieved a disease-free survival of 14 months. This case underscores the limitations of the current diagnostic tools and the potential role of multimodal therapy in the management of CUP. The discordance between molecular testing and the clinical findings further emphasizes the perplexing nature of CUP. This report also reviews the literature on diagnosis and therapeutic options. Due to the absence of standardized regimens, future international collaboration and comprehensive genomic profiling are warranted to advance the understanding of this heterogeneous disease.

Background: HER2-positive breast cancer (BC) requires anti-HER2 therapy. We aimed to determine whether the expression of the HER2/centromeric probe for chromosome 17 (CEP17) ratio is associated with prognosis in patients with HER2-positive non-metastatic BC. Methods: 267 HER2-positive BC were enrolled between January 2010 and December 2011. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline characteristics. Real-world disease-free survival (DFS) and overall survival (OS) was analyzed. Results: The median follow-up time was 10.3 years (interquartile range: 9.4-10.8 years). HER2/CEP17 ratio of > 7.0 was defined as the HER2 ultra-positive group; a HER2/CEP17 ratio of ≤ 7.0 was defined as the HER2 normal-positive group. After sIPTW adjustment, no differences were observed in DFS and OS when anti-HER2 therapy was unclear, and so was in the patients who did not receive trastuzumab (all p > 0.05). Interestingly, HER2 ultra-positive group had a worse DFS than the normal-positive group (hazard ratio [HR] = 2.72, p = 0.02), but there was no difference in OS (p = 0.30) in patients receiving trastuzumab. The multivariate Cox models also showed that the HER2 ultra-positive have worse DFS than HER2 normal-positive patients (HR = 3.71; p < 0.01). Conclusion: For non-metastatic HER2-positive BC with or without trastuzumab treatment, the HER2/CEP17 ratio did not predict the survival time. However, our study supports that HER2 ultra-positive group had a worse DFS than the normal-positive group among non-metastatic HER2-positive BC patients receiving trastuzumab; therefore, this could be a potential predictor of DFS in these patients. Citation Format: Fangchao Zheng, Feng Du, Zixuan Yang, Xue Wan, Jian Yue, Yun Ling, Peng Yuan. Potential prognostic Value of HER2/CEP17 FISH ratio in HER2-positive non-metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-01-23.

HER2-positive breast cancer (BC) requires anti-HER2 therapy. We aimed to determine whether the expression of the HER2/centromeric probe for chromosome 17 (CEP17) ratio was associated with prognosis in patients with HER2-positive non-metastatic BC. 267 HER2-positive BC were enrolled between January 2010 and December 2011. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline characteristics. Real-world disease-free survival (DFS) and overall survival (OS) was analyzed. The median follow-up time was 10.3 years (interquartile range: 9.4–10.8 years). HER2/CEP17 ratio of > 7.0 was defined as the HER2 ultra-positive group; a HER2/CEP17 ratio of ≤ 7.0 was defined as the HER2 normal-positive group. After sIPTW adjustment, no differences were observed in DFS and OS when anti-HER2 therapy was unknown, and similarly in the patients who were recorded as not receive trastuzumab (all p > 0.05). Interestingly, HER2 ultra-positive group had a worse DFS than the normal-positive group (hazard ratio [HR] = 2.72, p = 0.02), but there was no difference in OS (p = 0.30) in patients did receive trastuzumab. The multivariate Cox models also showed that the HER2 ultra-positive had worse DFS than HER2 normal-positive patients (HR = 3.71; p < 0.01). For non-metastatic HER2-positive BC with or without trastuzumab treatment, the HER2/CEP17 ratio did not predict DFS and OS. However, our study supported that HER2 ultra-positive group had a worse DFS than the normal-positive group among non-metastatic HER2-positive BC patients receiving trastuzumab; therefore, this could be a potential predictor of DFS in these patients.

NDC80, a crucial component of the kinetochore, plays a pivotal role in regulating cell mitosis. Recent studies reported that NDC80 regulates the proliferation of cancer cells and may be related to poor prognosis in cancer. However, the biological function and mechanism of NDC80 in esophageal squamous cell carcinoma (ESCC) have not yet been elucidated. In this study, we analyzed the expression and mutation of NDC80 in ESCC tissue and assessed its impact on ESCC cells in vitro. A total of 52 ESCC tissues samples were collected and NDC80 gene status was analyzed by whole exome sequence. shRNA was used to knockdown NDC80 expression in two ESCC cell lines TE1 and ECA109 by targeting silence NDC80 gene. Cellular proliferation, apoptosis, migration, and invasion were examined. Copy number variants (CNVs) of NDC80 were detected in 40.4

We aimed to evaluate the efficacy and safety of adding apatinib, to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer (TNBC). In the phase 2 NeoSAC trial, patients with early TNBC received six cycles of apatinib, sintilimab, nab-paclitaxel, and carboplatin followed by surgery. The primary endpoint was pathological complete response (pCR) rate. Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment. Among 34 enrolled patients, 24 achieved pCR (70.6%; 95% confidence interval (CI), 53.0-85.3), and 79.4% (95% CI, 65.1-93.7) had residual cancer burden 0-I. Imaging evaluation showed 21 complete responses (61.8%) and 13 partial responses (38.2%). The most common grade 3-4 adverse events were leukopenia (47%), neutropenia (36%), and thrombocytopenia (24%). The 36-month disease-free survival rate stood at 94.1% with a median follow-up of 39.1 months. Notably, baseline high ImmuneScore, immune cell infiltration, and enrichment of interferon-related pathways correlated with pCR. Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets, thereby activating the tumor microenvironment. Moreover, higher oxeiptosis scores were associated with an increased likelihood of achieving pCR. Following neoadjuvant therapy, the pCR group showed a decrease in oxeiptosis score, whereas the non-pCR group exhibited an increase. Our study suggests that apatinib, sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study. ClinicalTrials.gov registration: NCT04722718.

Background:Breast cancer is a highly heterogeneous disease, characterized by tumor and nontumor cells at various cell states. Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironment and delineates the tumor ecosystem, demonstrating clinical significance. However, further validation is needed in breast cancer. Methods:Ecotyper was applied to identify multiple cellular states and tumor ecotypes using large-scale breast cancer bulk sequencing data, followed by a detailed analysis of their associations with clinical classification, molecular subtypes, survival prognosis, and immunotherapy response. Identified subtypes were further characterized using single-cell and spatial data sets to reveal molecular profiles. Results:In a comprehensive analysis of 6578 breast cancer samples from four data sets, Ecotyper identified 69 cellular states and 10 tumor ecotypes. Of these, 37 cellular states significantly correlated with overall survival. Notably, specific states within epithelial cells, macrophages/monocytes, and fibroblasts were linked to a worse prognosis. CE2 abundance was identified as the most significant marker indicating unfavorable prognosis and was further validated in an additional data set of 116 HER2-negative patients. These biomarkers also indicated the efficacy of neoadjuvant immunotherapy in breast cancer. CE2-high cancers were characterized by an abundance of basal-like epithelial cells, scant lymphocytic infiltration, and activation of hypoxia signaling. Single-cell analysis showed that CE2-high areas were rich in SPP1-positive tumor-associated macrophages(TAM), basal-like epithelial cells, and hypoxic cancer-associated fibroblasts(CAF). Spatially, these regions were often peripheral in triple-negative breast cancer, adjacent to fibrotic/necrotic zones. Multiplex immunofluorescence confirmed the enrichment of SPP1+CD68+TAM and HIF1A+SMA+CAF in hypoxic triple-negative breast cancer (TNBC) regions. Conclusions:Ecotyper identified novel biomarkers for breast cancer prognosis and treatment prediction. The CE2-high region may represent a hypoxic immune-suppressive niche.

Family with sequence similarity 135 member B (FAM135B) is a novel driver gene in esophageal squamous cell carcinoma (ESCC). However, little is known regarding its biological functions and mechanisms in ESCC. Here, we identified that the high expression of FAM135B was associated with lymph node metastasis and infiltrating development of ESCC. Elevated FAM135B expression promoted ESCC migration and invasion in vitro and lung metastasis in vivo. Furthermore, epithelial-mesenchymal transition (EMT)-related pathways were enriched in ESCC samples with high levels of FAM135B and FAM135B positively regulated EMT markers. Mechanistically, we observed that FAM135B interacted with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), activating the Wnt/β-catenin signaling pathway. The facilitation of TNIK on ESCC migration and invasion was reversed by FAM135B siRNA. In addition, the N6-methyladenosine (m6A) modification positively regulated FAM135B expression, with methyltransferase like 3 (METTL3) acting as its substantial m6A writer. The pro-EMT effects of METTL3 overexpression were reversed by silencing FAM135B. Collectively, these findings illustrate the critical role of ABCDE in ESCC progression and provide new insights into the upstream and downstream mechanisms of FAM135B.NEW & NOTEWORTHY This study reveals for the first time that the novel cancer-related gene, FAM135B, promotes ESCC metastasis both in vitro and in vivo. Besides, we substantiate FAM135B's action on the β-catenin pathway through interacting with TNIK, thereby elucidating the promotional effect of FAM135B on ESCC EMT. Furthermore, we provide initial evidence demonstrating that METTL3-mediated m6A modification upregulates the expression of FAM135B in ESCC cells.

Objective: The choice of chemotherapeutic regimen for triple-negative breast cancer (TNBC) remains controversial. Homologous recombination deficiency (HRD) has attracted increasing attention in informing chemotherapy treatment. This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods: Chinese patients with TNBC who received chemotherapy between May 1, 2008 and March 31, 2020 were retrospectively analyzed with a customized 3D-HRD panel. HRD positivity was defined by an HRD score ≥ 30 or deleterious BRCA1/2 mutation. A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort (NCT01150513) and a metastatic cohort, and 189 patients with available clinical and tumor sequencing data were included. Results: In the entire cohort, 49.2％ (93/189) of patients were identified as HRD positive (40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of ≥ 30). In the first-line metastatic setting, platinum therapy was associated with longer median progression-free survival (mPFS) than platinum-free therapy [9.1 vs. 3.0 months; hazard ratio (HR), 0.43; 95％ confidence interval 0.22–0.84; P = 0.01]. Among HRD-positive patients, the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy (13.6 vs. 2.0 months; HR, 0.11; P = 0.001). Among patients administered a platinum-free regimen, HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients (P = 0.02; treatment-biomarker P-interaction = 0.001). Similar results were observed in the BRCA1/2-intact subset. In the adjuvant setting, HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy (P = 0.05, P-interaction = 0.02). Conclusions: HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.

Background: Chemotherapy is the most common treatment strategy for triple negative breast cancer (TNBC) patients. Nevertheless, due to adverse drug reactionsthe molecular high heterogeneity of TNBC and no appropriate meaningful efficacy markers, it is still difficult to establish preferred therapeutic strategies and predict the outcomes for TNBC. This study was to investigate the potential predictors and therapeutic targets based on genetic features. Methods: A total of 386 TNBC patients were randomized 1:1 to receive either six cycles of paclitaxel + cisplatin (TP) or four cycles of epirubicin + cyclophosphamide followed by four cycles of docetaxel (EC-T) adjuvant chemotherapy after surgery (NCT01150513), which were described previously. Finally, 149 TNBC patients with clinical and tumor sequencing data availability were retrospectively analysed by NGS for 733 cancer-related genes. All tumor samples were collected during the surgical operation and subjected to NGS for evaluating genomic mutations and the potential predictors. Cox regression model and Kaplan-Meier method were applied to evaluate disease-free survival (DFS). Results: In the surgical cohort receiving adjuvant chemotherapy, 74 patients received platinum and 75 received platinum-free chemotherapy as adjuvant chemotherapy. The most frequently mutated genes in this surgical TNBC cohort were TP53 (84%), BRCA1 (18%), BRCA2 (15%), POL1 (13%), PTEN (12%), REV3L (11%), FANCC (10%), and PARP4 (10%). We analyzed the associations between 733 cancer-related gene mutations and DFS after adjuvant chemotherapy. For the TP group, PIK3CA mutation (19%, 14/74) was discovered to correlate with poor DFS for patients treated with platinum-containing adjuvant therapy (HR=3.2, P=0.037), and KMT2D mutation (15%, 11/75) display worse DFS for patients treated with EC-T platinum-free group (HR=3.0, p=0.039). However, BRCA1/2 mutation (24%, 35/149) was found to be associated with poor prognosis (HR=2.1 (95% CI: 1-4.6), p=0.047), irrespective of therapeutic regimen. Conclusions: In this population of surgical TNBC patients, NGS analysis identified potential predictive markers. PIK3CA mutation in TP platinum-containing group and KMT2D mutation in EC-T platinum-free group were significantly associated to poor prognosis for adjuvant chemotherapy in triple negative breast cancer. Citation Format: Xue Wang, Feng Du, Jian Yue, Yiran Si, Lina Cui, Bei Zhang, Xiaochen Zhao, Binghe Xu, Peng Yuan. KMT2D and PIK3CA mutation as potential factors to predict adjuvant chemotherapy efficacy in surgical triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5084.

To the Editor: In the DESTINY-Breast03 trial, Cortes et al. (Mar. 24 issue)(1) found that trastuzumab deruxtecan therapy prolonged progression-free survival to a greater extent than trastuzumab emtansine therapy among patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The percentage of patients with an overall response (complete or partial response) increased from 60.9% in an earlier, phase 2, single-group study(2) to 79.7% in the phase 3 trial. Furthermore, in the trial, 58.2% of the patients in the trastuzumab deruxtecan group were Asian and 27.2% were White; in the trastuzumab . . .

Taxanes plus carboplatin (TP) regimen may be an acceptable alternative adjuvant chemotherapy strategy in patients with triple-negative breast cancer (TNBC); however, the difference with the anthracycline-based regimen is yet to be clarified. Therefore, this study aimed to assess the difference between platinum-based and anthracycline-based regimens in prolonging the survival time in TNBC. Using exploratory landmark analysis, we found that the platinum-based TP regimen offers a longer disease-free survival (DFS) than the anthracycline-based regimen in TNBC patients with a DFS of > 4 years.

The optimal adjuvant systemic treatment and potential prognostic factors for patients with T1N0 HER2-positive breast cancer are still unclear. We conducted a real-world study in this relatively low-risk population to identify the clinical-pathological factors of potential prognostic value and to compare the efficacy of different adjuvant strategies. We included patients with HER2-positive T1N0 breast cancer of infiltrating ductal carcinoma (IDC) histology treated at the Cancer Hospital, Chinese Academy of Medical Sciences from April 2010 to April 2017. We performed Cox multivariate analysis to identify the potential prognostic factors for invasive disease-free survival (IDFS). We also compared survival outcomes of (1) patients treated with adjuvant chemotherapy alone, or chemotherapy plus trastuzumab, or observation; (2) patients receiving adjuvant anthracycline-based and non-anthracycline regimens, both combined with trastuzumab. Inverse probability of treatment weighting (IPTW) propensity score was used to reduce selection bias. Overall, 692 consecutive patients were included, with a median follow-up of 78.0 months for IDFS. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab were identified as independent prognostic factors. For adjuvant treatment, compared with observation and chemotherapy alone, chemotherapy plus trastuzumab could significantly benefit patients (HR = 2.70, P = 0.034; HR = 3.95, P < 0.001). Meanwhile, compared with observation, chemotherapy alone did not significantly benefit patients (HR = 1.37, P = 0.424). For the comparison of anthracycline-based versus non-anthracycline regimens when combined with trastuzumab, patients in both groups had similar IDFS (HR = 1.74, P = 0.242). HER2-positive T1N0 IDC patients could benefit from adjuvant chemotherapy plus trastuzumab. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab are independent prognostic factors for this population.

Background: Platinum-containing chemotherapy is treatment with high efficacy in homologous recombination (HR) deficient cancers that arise in carriers of mutations in the BRCA1/2 genes. However, previous reports have shown that TNBC patients carrying no BRCA1/2 mutations also could benefit from platinum therapy. This study aimed to explore the association between HR-related gene mutations and genomic instability, and further evaluate the effectiveness of platinum-containing chemotherapy preliminarily. Methods: A total of 386 TNBC patients were screened from a surgical cohort (NCT01150513) and a metastatic cohort. Finally, 189 TNBC patients with clinical and tumor sequencing data availability were included, including 149 patients treated with radical surgery and adjuvant chemotherapy. All tumor samples were collected during the surgical operation and subjected to NGS for evaluating homologous recombination deficiency (HRD) score and 15 HR-related gene pathogenic or likely pathogenic mutations (including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51D, RAD51C, RAD54L). HRD score was an algorithmic assessment of three biomarkers of genomic instability as loss of heterozygosity, telomeric-allelic imbalance, large-scale state transitions and based on over 10,000 single-nucleotide polymorphisms in the human genome. Results: In 189 TNBC cohort, 40 patients (21.1%) had BRCA1/2 deleterious mutations, with additional 26 patients (13.8%) carrying mutations in HR-related genes other than BRCA1/2. Compared with BRCA1/2-intact patients, those carrying BRCA1/2m displayed a significantly higher HRD score (median, 35.5 vs 20.0; P=0.02). However, patients with HRm obtained a similar HRD score with HRwt patients (median, 28.0 vs 21.0, P=0.83). TNBC patients with PALB2m (n=8) had a small trend higher HRD score compared with BRCA1/2m (median HRD score 39.0 and 35.5), and TNBC patients with RAD51 family (n=7), ATM (n=5) and other HR-related gene mutations had a numerical trend lower HRD score compared with BRCA1/2m (median HRD score 22.0, 4.0, 14.5 and 35.5). Of the 149 patients in surgical cohort, 74 received platinum-containing, and 75 underwent platinum-free adjuvant chemotherapy. We analyzed the associations between HR-related gene mutations and disease-free survival (DFS), and found that patients with RAD51Bm (n=3), RAD51Cm (n=1) or PPP2R2Am (n=1) displayed worse DFS for patients treated with adjuvant chemotherapy (P =0.012, P<0.0001 or P<0.0001, respectively). Conclusions: In this study, we found that different HR-related genes mutation subtypes may exert distinct effects on genomic instability, and mutations in HR-related genes beyond the context of BRCA1/2 may serve as a biomarker for platinum-based adjuvant therapy for TNBC patients, which warrants further studies. Citation Format: Xue Wang, Yimeng Chen, Feng Du, Jian Yue, Yiran Si, Xiaochen Zhao, Lina Cui, Bei Zhang, Ting Bei, Peng Yuan, Binghe Xu. Effects of homologous recombination-related gene mutation subtypes on gene instability and the efficacy of platinum-containing regiments in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5689.

BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly susceptible to recurrence and metastasis. The therapeutic drugs are limited due to the lack of effective biomarkers predicting the therapeutic efficacy and prognosis of disease. Previous studies have shown that platinum-containing regimens are effective for both early and advanced TNBC, therefore, it is particularly important to explore biomarkers for predicting the efficacy of platinum drugs and to screen the population sensitive to platinum drugs. Methods All patients with available tumor specimens from National Cancer Center in China were eligible for this prospective-retrospective study (n=189), including 149 patients with early TNBC (NCT01150513, CH-BC-007) and 40 patients with advanced TNBC (12-123/657, CH-BC-018) who are treated with or without platinum. The primary endpoint is disease-free survival (DFS) for early TNBC and progression free survival (PFS) for advanced TNBC. For HRD status and genomic signatures, indexed libraries were subjected to probe-based hybridization with a customized NGS panel targeting 733 cancer-related genes. 3DMed-HRD algorithm was evaluated based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) to characterize genomic instability using over 10,000 single-nucleotide polymorphisms distributed across human genome, adjusted by tumor ploidy and purity. HRD positive is defined by HRD score above the threshold (cut-off ≥30) and/or deleterious mutation in BRCA1/2. ResultsDeleterious BRCA1/2 mutations were detected in 21.2% (40/189) of TNBC patients and 48.1% (91/189) were defined as HRD positive. In advanced TNBC cohort, 21 patients received platinum-containing and 19 received platinum-free chemotherapy regimens for first-line chemotherapy. The progression-free survival (PFS) of the platinum-containing group was longer than that of the platinum-free group (median PFS 9.13 vs 2.97 months, HR 0.39, 95%CI, 0.19-0.81, P=0.011), and the PFS of patients with HRD positive was significantly longer than HRD negative patients (median PFS 13.6 vs 6.80 months, HR 0.38, 95%CI, 0.15-0.99, P=0.048) in platinum-containing group. Interestingly, HRD-positive patients have a significantly shorter PFS than HRD-negative in platinum-free group (median PFS 1.97 vs 4.52 months, HR 3.67, 95%CI, 1.20-11.22, P=0.023). For the HRD-positive patients, median PFS was significantly better in platinum-based group than platinum-free group (median PFS 13.6 vs 1.97 months, HR 0.12, 95%CI, 0.03-0.43, P=0.001). In early-stage TNBC cohort (n=149), 74 patients received platinum-containing and 75 received platinum-free chemotherapy regimens for adjuvant chemotherapy. In platinum-containing group, no statistically significant difference was found in DFS between HRD-positive and HRD-negative patients (P=0.118). High-risk TNBC group (Ki-67 ≥ 15%) analysis revealed that HRD-positive patients had a numerical better DFS than HRD-negative patients (HR 0.43, 95%CI, 0.12-1.50, P=0.180). Among patients with HRD-positive, patients in platinum-containing group had a tendency to benefit more than those in platinum-free group (HR 0.35, 95%CI, 0.11-1.10, P=0.062). Conclusions: We developed a novel algorithm to evaluate 3DMed-HRD status and highlights the potential utility of HRD in guiding chemotherapy for TNBC patients in this retrospective analysis. In comparison to platinum-free chemotherapy, the advanced TNBC HRD positive patients with advanced TNBC receiving platinum-based chemotherapy is a preferable regimen, and the HRD negative patients might be on the contrary. Prospective validation with larger sample size is needed. Citation Format: Yimeng Chen, Xue Wang, Feng Du, Jian Yue, Yiran Si, Lina Cui, Bei Zhang, Binghe Xu, Peng Yuan. The status of homologous recombination deficiency is a potential biomarker for platinum-based chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-12.

Although platinum-based chemotherapy can improve pathologic complete response (pCR) in patients with triple-negative breast cancer (TNBC), the impact on survival of platinum-based neoadjuvant and adjuvant chemotherapy is still controversial. Our meta-analysis aimed at analyzing survival with platinum-based neoadjuvant and adjuvant chemotherapy in patients with TNBC. We searched PubMed, EMBASE, MEDLINE, Cochrane databases, and several major conferences up to January 2021. Fixed and random models were used for our meta-analysis. Disease-free survival (DFS), overall survival (OS), and side effects data were extracted from the included literature in addition to the corresponding pooled hazard ratio (HR) and odds ratio (OR) with 95

Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5–10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched subtype in patients with HR+/HER2+ breast cancer. First of all, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n = 141) and METABRIC (n = 104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. From this, we constructed a novel marker termed rH/E, which was calculated as ERBB2 expression quantity/(ESR1 expression quantity + 1). Secondly, we performed multiplex immunofluorescence (mIF) to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). When using mIF, rH/E was adjusted to prH/E, which was calculated as HER2-positive cells%/(ER-positive cells + 1)%. All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal B subtype was the most common, followed by the HER2-enriched and luminal A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2−, ER+/HER2+, ER−/HER2+, and ER−/HER2−. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, prH/E showed a significant prognostic association in the CAMS cohort. This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+ breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

Paclitaxel/docetaxel after doxorubicin plus cyclophosphamide (ECT) is considered as an adjuvant chemotherapy and improves the survival of early triple-negative breast cancer (TNBC) patients. We aim to assess whether carboplatin plus taxanes (TP) is non-inferior to ECT in prolonging the survival time. TNBC patients were randomized (1:1) to receive ECT (90 mg/m2 epirubicin + 600 mg/m2 cyclophosphamide followed by 75 mg/m2 docetaxel or 175 mg/m2 paclitaxel every 3 weeks, n = 154) or TP (75 mg/m2 docetaxel or 175 mg/m2 paclitaxel + carboplatin AUC 5 every 3 weeks, n = 154). These expression of SPARC, PD-L1, and BRCA were studied. Patients were followed up for disease-free survival (DFS), overall survival (OS), and safety. We recruited 308 TNBC patients (median follow-up of 97.6 months). The median DFS and OS were not reached; the 8-year DFS rate of ECT and TP arms was 78.4% and 81.7%, respectively, while the 8-year OS rate were 87.2% and 89.1%, respectively. In the SPARC (> 50%) subgroup analysis, the TP arm had longer DFS (P = 0.049) and a tendency with better OS (P = 0.06) than ECT arm. No significant differences were observed in the DFS and OS between the ECT arm and TP arm in TNBC with SPARC (≤ 50%), PD-L1 (−) PD-L1 (+), and BRCA mutation or BRCA wild (all P values > 0.05). TP showed non-inferiority for DFS and OS compared with ECT in early TNBC. TP may be an effective alternative chemotherapy for TNBC patients whom the standard ECT regimen is not being used. ClinicalTrials.gov identifier NCT01150513