Faculty Bibliography

Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.

PURPOSE/OBJECTIVE:This prospective, non-randomized phase II single-arm pilot trial aimed to explore favorable mid-treatment nodal response (FMNR) through CT imaging to guide de-escalated chemoradiation therapy (CRT) in patients with favorable risk, node-positive HPV-associated oropharyngeal cancer (OPC). MATERIALS AND METHODS/METHODS:. At week 4, CT imaging evaluated nodal response: ≥40% reduction warranted de-escalation to 60 Gy, while <40% reduction continued standard CRT. Primary endpoint was 2-year PFS from initiation of dose de-escalated CRT. Tissue tumor modified viral (TTMV) HPV DNA samples and DW-MRI were collected at baseline and week 4. MDADI questionnaires were collected at baseline, 1, 3, 6, 12, and 24 months. RESULTS:Of 39 patients, 26 had FMNR and underwent de-escalated treatment. 13 pts had slow mid-treatment nodal shrinkage and received standard dose. At a median follow-up of 47.4 months, the 2-year PFS was 92.1% (95% CI: 0.72-0.98) for the deescalated dose group and 92.3% for the standard dose patients (95% CI: 0.57-0.99), p=0.96. With a median survival follow up of 48.9 months (range: 16.7-77.8 months), there were no deaths or distant failures. FMNR was associated with rapid TTMV HPV DNA clearance, reduced TTMV HPV DNA flare, lower baseline and week 4 MRI diffusivity, and higher baseline and week 4 MRI diffusional kurtosis. No differences in acute or late maximum grade 3-4 toxicity by patient were noted. MDADI composite scores showed minimal clinical important difference (MCID) in the de-escalated group at 1-month post-treatment while the standard group had MCID up to 1-year post-treatment. No patients required feeding tube placement. CONCLUSIONS:De-escalated CRT using CT-based mid-treatment nodal response in favorable risk, node-positive HPV-associated OPC achieved excellent 2-year PFS and OS rates and represents a potential approach in better selecting patients for treatment de-escalation.

BACKGROUND:Clinical trials suggest that adjuvant radiotherapy (RT) may be omitted in women aged 65 or older with early-stage, hormone-receptor (HR) positive breast cancer provided completion of 5 years of endocrine therapy (ET). However, at the time of RT consult, it is often unknown whether the patient will start ET or will start but not complete 5 years, either of which, if known in advance, would alter RT recommendations. We studied a cohort of patients who would have been eligible for RT omission to examine factors associated with declining or discontinuing ET. METHODS:Using a prospectively maintained institutional database, we identified patients age ≥65 who underwent surgery from 2010 to 2017 with stage I HR-positive breast cancer. Patients were classified as having osteopenia or osteoporosis based on the lowest T-score on DEXA. Missing data were replaced using multiple imputation. Recurrence and survival statistics were calculated using Kaplan-Meier analysis. Univariate and multivariate logistic regression was used to assess factors associated with not starting or discontinuing ET. RESULTS:We identified 590 eligible patients. Of these, 453 (76.8%) started ET. Patients who did not start ET were older (mean age 77.02 vs. 72.46, p < 0.001), had lower BMI (mean 25.36 vs. 26.78, p = 0.008), and lower DEXA scores (mean score -1.92 vs. -1.58, p = 0.056), and were less likely to undergo axillary surgery (64.2% vs. 86.8%, p < 0.001). Of the 453 patients who started ET, 315 (69.5%) completed at least 5 years. Discontinuation of ET was associated with older age (HR 1.082, 95% CI 1.033-1.133, p = 0.001), not undergoing axillary surgery (HR 0.365, 95% CI 0.146-0.915, p = 0.032) and smoking (HR 1.636, 95% CI 1.001-2.676, p = 0.05). Patients who were single or never married were less likely to discontinue ET (HR 0.281, 95% CI 0.096-0.821, p = 0.020). Patients who completed 5 years ET had significantly better local recurrence-free survival (96.8%) compared to those who stopped early (87.7%, p=0.01) or did not start ET (88.7%, p < 0.001). CONCLUSIONS:Older age, osteopenia, and lower BMI were associated with not starting ET, while older age, marital status, axillary surgery, and smoking history predicted discontinuation of ET. These factors may guide discussions regarding the omission of adjuvant radiotherapy.

PURPOSE/OBJECTIVE:The recently published results of the National Surgical Adjuvant Breast and Bowel Project B51 trial suggest that regional nodal irradiation may be safely omitted in patients with cT1-3N1 breast cancer treated with either lumpectomy or mastectomy, and achieve a pathologic complete response (pCR) in the regional nodes. Of note, almost 80% of patients on the trial demonstrated breast pCR. The goal of our study was to compare clinical outcomes between patients with breast pCR versus not. METHODS AND MATERIALS/METHODS:We included all patients treated at a single institution between 2010 and 2021 with cT1-3N1 breast cancer (pathologically proven via fine needle aspiration) who completed neoadjuvant chemotherapy and had axillary nodal pCR. Patients could undergo breast-conserving surgery or mastectomy. Univariate and multivariate logistic models were used to identify factors associated with breast pCR. Cox proportional hazard model was used to find independent prognostic variables associated with disease-free survival (DFS). RESULTS:We identified 124 patients meeting eligibility criteria. Of those, 72 patients (58%) achieved a breast pCR. On multivariate analysis, patients with human epidermal growth factor receptor (HER2)-positive breast cancer were more likely to develop breast pCR than patients with HER2-negative disease (odds ratio = 15.3; CI, 2.9-156.6; P = .001). At a median follow-up of 5 years, our study showed an overall low rate of local recurrence or distant metastasis with 5-year DFS of 92.3%. There was a numerically higher disease recurrence rate in patients without a breast pCR compared to those with a breast pCR, though this difference was not statistically significant (4.2% vs 12%; hazard ratio = 3.41; 95% CI, 0.53-22.1; P = .2). CONCLUSIONS:Our study showed that of the 124 patients who had pCR in the nodes, only 58% had a pCR in the breast, which is lower than the 80% rate seen in National Surgical Adjuvant Breast and Bowel Project B51. While our study found no significant difference in 5-year DFS between those with breast pCR versus not, given that patients with ER/PR+/HER2- disease are less likely to achieve breast pCR and tend to recur at later timepoints, further research is needed to evaluate the benefit of regional nodal irradiation in patients with a pCR in the axilla without a pCR in the breast.

Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from nonplatelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with nonplatelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.

OBJECTIVES/OBJECTIVE:Lacrimal gland cancer is a rare malignancy with little data known about its pathologic characteristics or optimal management. We performed a large database analysis using the National Cancer Database (NCDB) to elucidate this unusual condition. METHODS:Patients with lacrimal gland cancer diagnosed between 2004 and 2018 were included in the analysis. Using available clinical data, we excluded all patients with histologies likely reflective of lacrimal sac or duct cancer, which are coded similarly to lacrimal gland cancer in the NCDB. Kaplan-Meier analysis was used to estimate overall survival (OS), and Cox proportional hazards models were used to indicate covariates associated with survival. RESULTS:A total of 440 cases of lacrimal gland cancer were included in the analysis, with a median follow-up of 52.9 months. The five-year OS for the entire cohort was 65.0%. Adenoid cystic carcinoma was the predominant histology (47.3%). Cox models showed that improved OS was associated with surgical resection (UVA: p < 0.001; MVA: p = 0.035). A detriment in OS was associated with increasing age, Charlson-Deyo score of 1, T4 stage, and positive margins and on UVA for adenocarcinoma and malignant mixed tumor histology. CONCLUSION/CONCLUSIONS:Adenoid cystic carcinoma comprises the plurality of lacrimal gland cancers. About half of patients with lacrimal gland carcinoma will live beyond 10 years, underscoring the importance of reduced morbidity of treatment. Surgical management is associated with improved prognosis. Further study will elucidate the role of surgical excision and radiotherapy in lacrimal gland cancer.

BACKGROUND/PURPOSE/UNASSIGNED:The optimal management of residual micrometastases and isolated tumor cells (ITC) in patients with invasive breast cancer who undergo neoadjuvant chemotherapy (NAC) followed by definitive surgery is not well-studied. We evaluated the role of regional nodal irradiation (RNI) in clinically node-positive (cN1) breast cancer patients with residual low-volume nodal disease following NAC. METHODS/MATERIALS/UNASSIGNED:We queried the National Cancer Database (NCDB) and included patients with cN1 invasive breast cancer diagnosed from 2004 to 2016 who were treated with NAC and definitive surgery and had residual micrometastases (ypN1mi) or ITC (ypN0i+). We used univariable (UVA) and multivariable (MVA) Cox regression analyses to determine prognostic factors and Kaplan-Meier (KM) methods to evaluate overall survival (OS). We used inverse probability treatment weighting (IPTW) to reweight data to account for confounding factors. RESULTS/UNASSIGNED:Our final cohort included 1980 patients, including 527 patients with ypN0i + disease and 1453 patients with ypN1mi disease. 1101 patients (45.0%) received RNI in the overall cohort with a higher proportion of ypN1mi patients receiving RNI (56.5%) compared to 53.1% of ypN0i + patients. There was no significant difference in OS between ypN0i + and ypN1mi patients. RNI had no significant effect on OS in the overall cohort using Cox MVA and KM methods. With separate subset analysis of ypN0i + and ypN1mi patients, there was no significant effect of RNI on OS. This was confirmed with IPTW. CONCLUSIONS/UNASSIGNED:In a national hospital-based study of cN1 invasive breast cancer patients with residual ITC or micrometastases after NAC, RNI did not have a significant effect on OS.