High-grade Tumors Research Articles

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2's protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

Clinicopathological and molecular genetic analysis of 13 cases of primary retroperitoneal Ewing sarcoma

Retroperitoneal Ewing sarcomas (RES) are very rare and mostly described in case reports. The purpose of this study was to retrospectively analyze the clinicopathology, molecular characteristics, biological behavior, and therapeutic information of 13 cases of primary RES with immunohistochemical staining, fluorescence in situ hybridization, RT-PCR and NGS sequencing detection techniques. The thirteen patients included eight males and five females with a mean age of 34 years. Morphologically, the tumors were comprised of small round or epithelial-like cells with vacuolated cytoplasm (6/13,46 %) arranged in diffuse, nested (8/13,62 %) and perivascular (7/13,54 %) patterns. Unusual morphologic patterns, such as meningioma-like swirling structures and sieve-like structures were relatively novel findings. Immunohistochemical studies showed CD99 (12/13; 92 %), CD56 (11/13; 85 %), NKX2.2 (9/13; 69 %), PAX7 (10/11;91 %) and CD117(6/9;67 %) to be positive.12 cases (92 %) demonstrated EWSR1 rearrangement and 3 cases displayed EWSR1::FLI1 fusion by FISH. ERCC4 splice-site variant, a novel pathogenic variant, was discovered for the first time via RNA sequencing. With a median follow-up duration of 14 months (6 to 79 months), 8/13 (62 %) patients died, while 5/13(38 %) survived. Three cases recurred, and five patients developed metastasis to the liver (2 cases), lung (2 cases) and bone (1 case). RES is an aggressive, high-grade tumor, prone to multiple recurrences and metastases, with distinctive morphologic, immunohistochemical, and molecular genetic features. ERCC4 splicing mutation, which is a novel pathogenic variant discovered for the first time, with possible significance for understanding the disease, as well as the development of targeted drugs.

Risk factors for lymph node metastasis in T2 colorectal cancer: a systematic review and meta-analysis.

Lymph node metastasis (LNM) occurs in 20-25% of patients with T2 colorectal cancer (CRC). Identification of risk factors for LNM in T2 CRC may help identify patients who are at low risk and thereby potential candidates for endoscopic full-thickness resection. We examined risk factors for LNM in T2 CRC with the goal of establishing further criteria of the indications for endoscopic resection. MEDLINE, CENTRAL, and EMBASE were systematically searched from inception to November 2023. Studies that investigated the association between the presence of LNM and the clinical and pathological factors of T2 CRC were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Certainty of evidence (CoE) was assessed using the GRADE approach. Fourteen studies (8349 patients) were included. Overall, the proportion of LNM was 22%. The meta-analysis revealed that the presence of lymphovascular invasion (OR, 5.5; 95% CI 3.7-8.3; high CoE), high-grade tumor budding (OR, 2.4; 95% CI 1.5-3.7; moderate CoE), poor differentiation (OR, 2.2; 95% CI 1.8-2.7; moderate CoE), and female sex (OR, 1.3; 95% CI 1.1-1.7; high CoE) were associated with LNM in T2 CRC. Lymphatic invasion (OR, 5.0; 95% CI 3.3-7.6) was a stronger predictor of LNM than vascular invasion (OR, 2.4; 95% CI 2.1-2.8). Lymphovascular invasion, high-grade tumor budding, poor differentiation, and female sex were risk factors for LNM in T2 CRC. Endoscopic resection of T2 CRC in patients with very low risk for LNM may become an alternative to conventional surgical resection. PROSPERO, CRD42022316545.

Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.

Abstract PO4-16-01: EZH2 is Overexpressed in Invasive Carcinoma and DCIS in both BRCA1 and BRCA2 Mutation Carriers

Abstract Background The transcriptional repressor EZH2 (Polycomb Group Protein Enhancer of Zeste Homologue 2) is overexpressed in multiple neoplasms including breast cancer where it associates with high proliferation, aggressive features and poor prognosis and is of interest as a potential therapeutic target. EZH2 nuclear expression in breast cancer has been shown to correlate specifically with high tumor grade and basal-like histologic features but has not been well studied in cancers from BRCA carriers. Here we evaluate the expression of EZH2 protein in BRCA-associated invasive breast carcinomas and precursor lesions. Methods Eighteen cases of invasive breast cancer in consented BRCA carriers (8 BRCA1 and 10 BRCA2) treated at Dana Farber Cancer Institute from 2001-2019 were reviewed by two pathologists (TAD and RBPP). Histopathologic features (histologic subtype, nuclear grade, mitotic score) and presence of precursor lesions were recorded. Immunohistochemistry for EZH2 was performed on freshly cut formalin-fixed paraffin-embedded tissue sections (1-3 sections/case) using a monoclonal antibody against EZH2 (D2C9, Cell Signaling). Nuclear EZH2 expression was scored as negative (score=1, no staining); weak (score 2, &amp;lt; 25%); moderate (score=3, 25–75%); and strong (score=4, &amp;gt;75%), of any intensity following published criteria. EZH2 overexpression was defined as scores 3 and 4. Results The majority of the invasive carcinomas showed grade III histology (13/18, 72%), as expected. Of 8 BRCA1 cases, 6 were classified as grade III (75%), 1 as grade II, and 1 as grade I (7 cases of invasive ductal carcinoma and 1 case of invasive tubular carcinoma). Of 10 BRCA2 cases, 7 were classified as grade III (70%) and 3 as grade II (30%) (5 cases of invasive ductal carcinoma and 5 cases of invasive carcinoma with ductal and lobular features). The majority of cases (13 of 18, 72%) showed high expression of EZH2 in the invasive carcinoma (6 BRCA1 and 7 BRCA2 cases; 2 grade II and 11 grade III). Of 13 cases with EZH2 overexpression, 6 were ER+/PR+/HER2- and 7 were triple negative, with 9 invasive ductal carcinomas and 4 invasive carcinomas with ductal and lobular features. Of 5 cases with no/low EZH2 overexpression, 1 was ER+/PR+/HER2-, 3 were ER+/PR-/HER2- and 1 was triple negative, with 3 invasive ductal carcinomas, 1 invasive carcinoma with ductal and lobular features and 1 invasive tubular carcinoma. In all cases with adjacent ductal carcinoma in situ (DCIS) (n=14), the pattern of EZH2 expression in the DCIS was identical to that seen in the invasive carcinoma (11 high and 3 low expression). Overexpression of EZH2 was not observed in any other precursor lesions (LCIS, ADH, ALH) or in normal tissue. Conclusion EZH2 protein overexpression is seen in the majority of invasive carcinomas in BRCA carriers, both in BRCA1 and in BRCA2. In all cases, the associated DCIS shows the same pattern of expression as the invasive carcinoma, suggesting that overexpression occurs early in tumorigenesis, while tumor cells are still confined within the ducts. The high rate of overexpression of EZH2 in BRCA1- and BRCA2-associated tumors suggests a potential role for EZH2 as a target and/or a biomarker in these cancers. Citation Format: Tabata Alves Domingos, Roberto Bonfim Pimenta Peixoto, Rodrigo Fonseca Abreu, Ashka Patel, Krishan Taneja, McKenna Moore, Celina Kleer, Deborah Dillon. EZH2 is Overexpressed in Invasive Carcinoma and DCIS in both BRCA1 and BRCA2 Mutation Carriers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-01.

Abstract PO4-25-04: MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance)

Abstract Background: Tertiary lymphoid structure (TLS) is an organized form of ectopic lymphoid aggregates (LA) with secondary lymphoid organ structure. Several studies showed that the presence of TLS associates with improved outcomes in multiple cancers when treated with immune checkpoint inhibitors. However, data is currently limited regarding TLS and outcomes in HER2+ breast cancer patients (pts) treated with adjuvant trastuzumab. Furthermore, distinguishing TLS and simple LA is challenging in standard hematoxylin and eosin (H&amp;E) staining, particularly when the germinal center is absent. Emerging studies also showed the prognostic value of MHC expression in breast cancer but mainly in triple-negative breast cancer. In this study, we evaluated integrated pathological quantification and genomic data to assess functional TLS in association with MHC expression and outcomes in the N9831 trial. Methods: Pathological evaluation of LA in H&amp;E slides from pts treated in Arm A (chemotherapy alone) and Arm C (chemotherapy with concurrent trastuzumab) in N9831 was performed. NanoString was used to quantify mRNA of MHC class I and II expression as well as TLS-related immune genes, including IFNG, ICOSLG, CXCL13, CXCR3, BCL6, IL21R, ICOS, PDCD1, CXCR5, CXCL9, TBX21, CD38, CXCL10, CLXCL11, IL21, CD200, CD19, MS4S1. Wilcoxon rank sum test, Chi-squared test, Kaplan-Meier method, and Cox regression model were used to evaluate the association between LA and baseline characteristics, MHC expression, and outcomes. Results: LA was evaluated in 526 pts in Arm A and 485 in Arm C. Greater number of LA was significantly associated with stromal tumor-infiltrating lymphocytes (sTILs), hormone receptor negative, and higher tumor grade, but not stage and age. Using multivariable Cox regression analysis, increasing numbers of LA were associated with improved recurrence-free survival in both arms combined (RFS, p 0.028). However, when evaluating each arm separately, LA was associated with improved RFS only in Arm A (HR 0.6, 95%CI 0.43-0.84, p 0.003) but not in Arm C (HR 0.72, 95%CI 0.47-1.1, p 0.134). We further evaluated TLS-related immune genes in 252 pts in Arm C with LA ≥ 1. As a continuous variable, higher expression of BCL6 (HR 0.61, 95%CI 0.41-0.92, p 0.019) and IL21R (HR 0.78, 95%CI 0.62-0.98, p 0.03) were associated with improved RFS in Arm C pts with LA ≥ 1. However, these genes were not significantly associated with outcomes in Arm C pts without LA with BCL6 (HR1.07, 95%CI 0.67-1.71, p 0.776) and IL21R (HR 0.96, 95%CI 0.71-1.29, p 0.775). Moreover, we evaluated differential gene expression between tumors with LA ≥ 1 with high BCL6 vs. LA 0. All MHC class I and II (HLA A, B, C, E, DQ, DM, DO, DP, and DQ) were significantly higher in tumors with LA ≥ 1 with high BCL6 (p &amp;lt; 0.001). Conclusion: A greater number of LA was associated with improved outcomes in pts with early-stage HER2+ breast cancer, particularly when treated with chemotherapy alone. Using histologic and genomic integration with the combination of pathological LA and TLS-related immune genes, we identified that pts with functional TLS with LA ≥ 1 and higher expression of BCL6 or IL21R had significantly improved outcomes when treated with trastuzumab. High MHC class I and II expressions are associated with the presence of functional TLS, underscoring the crucial role of antigen presentation in the generation of an effective adaptive immune response. Support: U10 CA180821, U10 CA180882, U24 CA196171, https://acknowledgments.alliancefound.org; Genentech; Clinicaltrials.gov Id: NCT00005970 Citation Format: Saranya Chumsri, Tracy Shachner, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith Perez, Aziza Nassar, E. Thompson, Keith Knutson. MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-04.

Abstract PO5-23-04: Clinical utility of sentinel lymph node biopsy in women ≥ 70 years with early breast cancer – an international, retrospective multi-center cohort study

Abstract Introduction Traditionally, sentinel lymph node biopsy (SLNB) has been used to stage the axilla in early breast cancer (EBC) to guide adjuvant treatment recommendations. Following advances in tumor biology understanding, targeted systemic therapies and genomic testing, with increasing de-escalation of axillary surgery, its role may be less critical especially in selected groups of women. Aims Evaluate clinical utility of SLNB in adjuvant treatment recommendations for women ≥ 70 years with EBC. Methods Retrospective cohort study of women ≥ 70 years with cT1-2N0 EBC undergoing primary surgery and SLNB between 01/2017-12/2022 at The Royal Marsden Hospital (RMH), University Hospital Zurich (USZ) and Seoul National University Hospital (SNUH) in the United Kingdom, Switzerland and South Korea respectively. Simple descriptive statistics and non-parametric tests were performed as appropriate. Results A total of 884 patients were included in the analysis, with 584 patients from RMH, 148 from USZ and 152 from SNUH. The median age was 75 (IQR 72-79) years. Most cancers were invasive ductal (82.9%), grade 2 (61.4%), hormone receptor (HR) positive/HER2 negative (82.9%) with a median tumor size of 17 (IQR 4-50) mm. SLNB was positive in 116 (13.1%) patients. Of these 116 patients, 20 (17.2%) had completion ALND; 7/20 had further RT up to levels 3&amp;4 of the axilla. Of these 116 patients, 96 patients (82.8%) avoided ALND; 25/96 had no further treatment, and 71/96 patients had loco-regional axillary RT (8/71 had RT to levels 1&amp;2 and 63/71 had RT up to levels 3&amp;4). As per international guidelines for patients with EBC with 1-2 positive macrometastases on SLNB treated with breast conserving surgery and breast RT, 5/20 could have been spared ALND, and 50/71 axillary RT. Completion ALND was more likely to be performed at SNUH compared to the other 2 units (p&amp;lt; 0.0001). Axillary RT was more likely to be administered at SNUH and less likely at RMH (p&amp;lt; 0.0001). The multidisciplinary team (MDT) recommended adjuvant chemotherapy (AC) in 146 (16.5%) patients and 100 received it. Of those with a positive SLNB (n=116), AC was recommended in 35, and received by 29. Recommendation for AC was significantly associated with younger age (p=0.021), fewer comorbidities (p=0.003), higher tumor grade (p&amp;lt; 0.0001), increased tumor size (p&amp;lt; 0.0001), HR negative status (p&amp;lt; 0.0001), high genomic risk profile (p&amp;lt; 0.0001) and positive SLNB status (p&amp;lt; 0.0001), but not center (p=0.497). A subgroup analysis of 505 patients with cT1N0, HR+/HER2- EBC, representing a more favorable prognosis group, was performed. Here, 52/505 (10.3%) patients had positive SLNB, of whom 11 had no further axillary treatment, 9 underwent ALND and 32 axillary RT, where 4/9 could have been spared ALND and 28/32 axillary RT as per international guidelines mentioned above. AC was recommended in 26/505 (5.15%) women and 23 received it. AC was not recommended in 39/52 (75%) cases, despite a positive SLNB. MDT recommendation for AC was associated with grade 3 (p&amp;lt; 0.0001), multifocal disease (p=0.021), positive SLNB status (p&amp;lt; 0.0001), high genomic risk profile (p&amp;lt; 0.0001), lower age (p=0.044), fewer co-morbidities (p=0.001) and center (p=0.007) with SNUH being more likely than the other 2, but not ethnicity (p=0.130); AC receipt was associated with the same factors except age (p=0.347). Conclusions Real-world data demonstrates axillary overtreatment despite evidence of the safety of de-escalation of axillary management in EBC. Only a small proportion of women ≥ 70 years with EBC had positive SLNB that may influence adjuvant treatment recommendations, especially with favorable prognosis tumors. In such cases, where clinical morbidity and financial burden of SLNB may outweigh the benefits, a nuanced discussion for opting in SLNB rather than routine performance should be considered. Citation Format: Radhika Merh, Denise Vorburger, Ji-Jung Jung, Han-Byoel Lee, Marios Tasoulis. Clinical utility of sentinel lymph node biopsy in women ≥ 70 years with early breast cancer – an international, retrospective multi-center cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-23-04.

Abstract PO3-16-08: Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early Breast Cancer

Abstract Background: As the treatment landscape of human epidermal growth factor receptor 2-negative (HER2–) early breast cancer (BC) evolves, an understanding of treatments given in real-world settings to elderly patients with HER2– early BC is needed to gain insight into the potential unmet needs of this population for whom clinical data are limited. This study described demographics, clinical characteristics, and neoadjuvant and adjuvant treatment patterns in elderly patients with HER2– early BC in the United States. Methods: This retrospective study used SEER-Medicare data (2010–2019) to identify patients aged ≥66 years with HER2– early (Stage I–III) BC receiving primary surgery. Patient characteristics were evaluated at primary surgery or at BC diagnosis. Neoadjuvant and adjuvant therapies were defined as any National Comprehensive Cancer Network-recommended regimens received between BC diagnosis and primary surgery, and during the 180-day period following primary surgery, respectively. Patient characteristics were described using means and standard deviations (SDs) for continuous characteristics, and frequencies and proportions for categorical characteristics. Neoadjuvant and adjuvant therapies were summarized using frequencies and proportions. All analyses were conducted for the overall population and stratified by breast cancer subtype (hormone receptor-positive [HR+]/HER2– vs. triple negative BC [TNBC]) and stage at diagnosis (Stage I vs. Stage II/III). Results: Of 28,655 eligible patients, 25,899 (90.4%) had HR+/HER2– BC and 2,756 (9.6%) had TNBC; 17,961 (62.7%) had Stage I BC and 10,694 (37.3%) had Stage II/III BC. Mean (SD) age at diagnosis was 75.8 (6.4) years, mean (SD) National Cancer Institute comorbidity index was 1.9 (2.1), and 23.7% received single or multi-gene testing for a breast cancer gene 1 and/or 2 (BRCA1/2) mutation (HR+/HER2– BC: 24.6%; TNBC: 15.5%), with most (86.3%) testing occurring after primary surgery. Relative to HR+/HER2– BC patients, TNBC patients were less likely to present with Stage I disease (46.7% vs. 64.4%), had a larger mean tumor size at diagnosis (2.6 cm vs. 1.9 cm), and higher-grade tumors (Grade III or IV: 70.6% vs. 14.6%). TNBC patients were also more likely to receive neoadjuvant chemotherapy (90.9% vs. 35.3%) and adjuvant radiation therapy (81.2% vs. 66.4%) than HR+/HER2– BC patients (Table 1). By BC stage, neoadjuvant therapy was more common among Stage II/III patients relative to Stage I patients (12.3% vs. 2.7%), with most (90.4%) neoadjuvant chemotherapy use observed among Stage II/III patients. Adjuvant therapy use was similar between Stage I and Stage II/III patients (87.4% vs. 88.1%) and the most common adjuvant therapies across both subgroups were endocrine therapy (85.2% vs. 82.2%) and radiation therapy (68.5% vs. 66.1%). Conclusion: In elderly patients with HER2– early BC, treatment with adjuvant therapy was common, while neoadjuvant therapy was limited. Moreover, one in four HER2– early BC patients were tested for a BRCA1/2 mutation in real-world clinical practice. Our findings highlight the need for a better understanding of the role of increased and timely BRCA1/2 testing to inform optimal treatment strategies across neoadjuvant and adjuvant settings in this population. Table 1. Treatment Patterns Among Patients with TNBC and HR+/HER2– Early Breast Cancer Citation Format: Jagadeswara Earla, Allison Kurian, Kalé Kponee-Shovein, Ambika Satija, Yan Song, Nathaniel Downes, Malena Mahendran, Qi Hua, Arun Kumar, Jaime Mejia. Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-08.

Abstract PO2-16-11: Real-World Data of Neuroendocrine Neoplasms of Breast

Abstract Background: Primary neuroendocrine neoplasms (NEN) of breast are rare and heterogeneous. WHO has classified NENs of non-endocrine organs into three distinct categories in 2022, however real-world data on outcomes of patients with NENs of non-endocrine organs under this new classification system are still sparse. Real world experience regarding demography, clinical presentation, treatment response, and prognosis can help identify potential areas of improvement in the management of breast NEN. Methods: Here, we present our findings from patients with NEN of breast in the Cleveland Clinic Foundation between 2000 and 2023. Pathology reports were reviewed to confirm NEN of breast origin. Neuroendocrine differentiation was determined by tumor histology and immunohistochemistry (IHC). For metastatic tumors at presentation, primary organ was determined by IHC and clinical presentation. Overall survival (OS) was from date of diagnosis of NEN. Recurrence is redemonstration of tumor following curative intent therapy, and progression is increase in tumor burden. T-test and log-rank test were used in statistical analyses. Results: Total of 97 patients were identified. Of these, 79 presented with localized disease, 18 were metastatic at presentation. 88 (91%) were invasive ductal carcinoma (IDC), and 64 (81%) were local disease at presentation and rest were metastatic. Gender spread was 92:5 (F:M). Patients with ER + disease was 84/96, PR + disease was 71, and 4/93 patients had overexpression of HER2. Median age was 70 at diagnosis. 11 patients underwent neoadjuvant chemotherapy, 15 patients underwent adjuvant chemotherapy (AC), and 58/84 patients underwent hormonal adjuvant therapy. For localized disease, median recurrence free survival (RFS) was 165 months (144-NA), and recurrence rate was 8/79 (10%). Recurrence rate for local IDC was 10% (6/64). Patients with metastatic disease at presentation had a median progression free survival (PFS) of 30 months, and progression rate was 7/18 (39%). For patients with metastatic disease, median lines of palliative therapy used was 2, with median duration of first line treatment being 3.5 months, and 10 months for second line. Most common surgical procedure was mastectomy, with 37% of patients undergoing management. Median duration from diagnostic biopsy to definitive surgery was 1 month. Median follow up was 28 months. Most common hormonal adjuvant option was anastrozole (58%), most common AC regimen was docetaxel and cyclophosphamide (39%), and most common first line palliative agent was letrozole (42%). Patients who underwent AC did not reach median OS, and patients who did not receive AC had a median OS of 148 months (p=0.8). Patients with grade 3 tumors had a median OS of 58.6 months, and grade 1 and 2 had a median OS of 148.1 months (p=0.5). Discussion: Current treatment strategies for NEN of breast mirror those of non-NEN of breast with similar histology and stage based on extrapolation of data. Recurrence rate was similar between IDC and SPC. In our cohort, survival was not significantly dependent on grade and use of AC. This might be due to the number of patients included in our study, as there was a non-significant trend towards lower OS in patients with high-grade neoplasms, and further limitations from retrospective design of study. Further research towards benefit of AC in NEN of breast and prognostic value of grading is necessary to explore management options in comparison to non-NEN of the breast. Citation Format: Serhan Unlu, Olisaemeka Ogbue, Gloria Lewis, Abdo Haddad, Hamed Daw, Baidehi Maiti. Real-World Data of Neuroendocrine Neoplasms of Breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-11.

Abstract PO2-15-05: Mesenchymal-like immune-activated: the 4th robust triple-negative breast cancer molecular subtype

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of primary BC. This heterogeneous disease is the most aggressive BC subtype. TNBC is characterized by young age at onset, high-grade tumors, high risk of early recurrence and poor prognosis. Until recently, TNBC patients were considered as one group and all patients were treated with conventional chemotherapy. With the emergence of new therapies targeting distinct biological pathways, personalized medicine is now accessible by defining finer TNBC subtypes, e.g. molecular subtypes, and identifying their specific targetable pathways. Several studies based on transcriptomics have identified three to six TNBC molecular subtypes. Today, there is a clear consensus on three TNBC robust subtypes: luminal androgen receptor (LAR), basal-like immune-activated (BLIA) and basal-like immune-suppressed (BLIS). The debate about the robustness of other subtypes is still open, notably mesenchymal-like (M) and mesenchymal stem-like (MSL or MES). The goal of this study was to establish a robust molecular classification of TNBC that allow to determine the best treatment options. To optimize this process, we harvested as much transcriptomic data as possible. Available clinicopathological data linked to these data were also imported. To our knowledge, this is the largest study aimed at subtyping TNBC; it exploits a total of 1942 TNBC patient data collected from 19 datasets: 1243 samples from microarray technology (14 datasets) and 699 from RNAseq technology (five datasets including a new one from our institution [GSE225002]). We performed independent unsupervised analyses on these two large cohorts with consensus k-means clustering including selection of optimal number of clusters and optimal number of variables. Both consensus clustering analyses separated TNBC microarray and RNAseq TNBC cohorts into four optimal clusters. These clusters were then characterized using clinicopathological features, gene ontology enrichment analyses (GOEA), gene set enrichment analysis (GSEA), 70 gene expression signatures (GES) and expression of 47 immune checkpoint genes. We concluded that TNBC are composed of four robust subtypes: LAR, mesenchymal-like immune-activated (MLIA), BLIA and BLIS. Importantly, we propose that MLIA acronym should replace M or MSL, because it highlights the two main biological characteristics of this subtype, i.e. mesenchymal-like features and a high IR comparable to that of BLIA. Furthermore, we showed that each subtype shares common biological characteristics with another one: LAR and MLIA (androgen receptor pathway activation); MLIA and BLIA (immune activation, notably high levels of immune checkpoints); BLIA and BLIS (basal-like features); BLIS and LAR (immune suppression). As regards microarray cohort, LAR included 19.23% (n = 239) of TNBC, MLIA 17.38% (n = 216), BLIA 32.50% (n = 404) and BLIS 30.89% (n = 384). Concerning RNAseq cohort, LAR included 19.60% (n = 137) of TNBC, MLIA 17.31% (n = 121), BLIA 28.47% (n = 199) and BLIS 34.62% (n = 242). Distributions of patients among the four clusters in the two cohorts were similar (p = 0.3583). Distributions were also similar between studies for microarray cohort (p = 0.2479) and RNAseq cohort (p = 0.1775). Pooled data (n = 1942 patients) gave the following distribution: 19.36% for LAR; 17.35% for MLIA; 31.06% for BLIA; 32.23% for BLIS, confirming that TNBC are largely but not exclusively basal-like (63.29%). In brief, according to the TNBC subtype molecular characterisation, anti-androgen therapy could be prescribed for LAR, immune checkpoint inhibitors for MLIA and BLIA, alone or in combination, and TAM-focused and antineurogenic therapies for BLIS. As an extension of this work, TNBC transcriptomic data associated with their clinicopathological features and TNBC subtype annotations were included in bc-GenExMiner v5.0 web tool (http://bcgenex.ico.unicancer.fr). Citation Format: Mario Campone, Pascal Jézéquel, Fadoua Ben Azzouz, Wilfried Gouraud, Agnes Bassevile, Bertrand Michel, Hamza Lasla, Jean Sebastien FRENEL. Mesenchymal-like immune-activated: the 4th robust triple-negative breast cancer molecular subtype [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-05.

Abstract PO3-02-13: Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes

Abstract Background: Breast cancer (BC) is the most common malignancy among women in Saudi Arabia. Noticeably, it shows a higher incidence in younger age groups than what is reported from Western countries. Age 35 years and less is an applied cut-off age for clinically defining BC in very young women (BCVY). This study describes characteristics, survival and risk of death associated factors in this rare subset of patients. Methods: A retrospective cohort study included females &amp;gt; 18 and &amp;lt; 35 years with histologically confirmed primary non-metastatic breast cancer from an academic hospital in Jeddah, Saudi Arabia between the years 2009-2019. Demographic data, tumor clinicopathological features, and outcomes were obtained. Survival and potential associated factors were examined. A p-value of less than 0.05 was regarded as statistically significant. Results: 204 female patients with a confirmed breast cancer diagnosis were included. The mean age at diagnosis was 31.43 ± 2.94 years. Fifty-three percent of the patients had a left-sided tumor with the majority being IDC (92%) and one-third with positive axillary lymph nodes (N+) and multifocal disease in 17%. One-quarter of the tumors showed LVI, 45% revealed associated DCIS and 26% showed tumor necrosis on histopathology examination. The presence of tumor-infiltrating lymphocytes (TILs) was reported in 23% of TNBC cases. Tubular differentiation score 3 was reported in 79.4%, nuclear pleomorphism score 3 in 79% and mitosis activity score 3 in 19% while the most reported overall grade was II in 48.5% followed by grade III in 34%. HER2-positive in 33.8 %, HR-positive in 34.3 %, TNBC in 24% and unknown in 8% of the patients. Thirty percent had a distant recurrence and 15% were deceased. The mean survival time was 4.61 years with a maximum of 6.54 years and a minimum of 3.67 years. Table 1 shows the multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Conclusions: The current study describes the clinicopathological characteristic, survival and related factors of breast cancer in very young patients &amp;lt; 35 years, which is considered an uncommon presentation. Large, high-grade tumors and a high frequency of HER2 and TNBC were observed in BCVY patients. Involvement of the regional lymph nodes and the development of distant recurrence were associated significantly with an increased risk of death. The presence or absence of TILs, LVI and tumor necrosis on histopathological examination did not influence the risk of recurrence or death in this cohort. Table 1. The multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Citation Format: Atlal Abusanad, Rana Ajabnoor, Aydah Al-Awadhi, Omalkhair Abualkhair. Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-13.

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms

BackgroundAdvancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs.MethodsThe expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored.ResultsTumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively).ConclusionsLNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

Abstract PO4-13-10: The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer

Abstract We have previously identified a role for bone morphogenic protein 4 (BMP4) in reducing distant relapse risk after early breast cancer (BrCa) (1). We therefore set out to identify mechanisms underlying the protective effect of BMP4, looking to translate this finding for patient benefit. A highly metastatic variant of the triple negative MDA-MB-231 human BrCa line (231-HM-turboGFP) was transduced with BMP4, leading to sustained BMP4 secretion. These modified tumours were established in NSG mice, resected at a given size and turboGFP-positive cancer cells were recovered from primary tumours for RNA sequencing analysis. Gene set enrichment analysis (GSEA) was completed to identify signalling pathways that were significantly modulated by BMP4. The four most significantly downregulated gene sets were associated with cholesterol synthesis, with the overwhelming majority of genes in this pathway being downregulated. BMP4 downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1, involved in cholesterol biosynthesis) was confirmed at the protein level by western blotting on whole tumour lysates. Forced expression of BMP4 also led to a significant reduction in the levels of free and total cholesterol. In a confirmatory analysis of the METABRIC human BrCa dataset, the expression of cholesterol biosynthesis-related genes inversely correlated with the expression of BMP4. Further, for the majority of these genes, expression was elevated in high-grade breast tumours, and predicted worse overall survival of patients. Finally, we tested the effect of a lipophilic statin, lovastatin, on the growth and metastasis of 231-HM-turboGFP tumours. Treatment did not affect the growth of primary tumours but significantly less metastases were observed in the lungs of treated mice, at least partially replicating the anti-metastatic effect of BMP4. Having identified inhibition of cholesterol biosynthesis as a potential mechanism of protective BMP4 action we then asked if BMP4 status interacted with any protective effect of co-administered statins. We therefore returned to the cohort initially employed to demonstrate BMP4 benefit (1) and looked at the interaction between BMP4 protein levels and statin usage with regards to recurrence. BMP4 protein and statin usage data were available on a cohort of 417 patients with early BrCa. Statin use compared to none led to a reduced risk of distant relapse (8 v 22%, 0.0029) at 15 years. BMP4 led to borderline reduction in distant relapse (16 v 24%, p=0.052). In BMP4 negative tumours, statin protected against any relapse (p=0.0025) whereas in BMP4 positive disease no significant risk reduction was not significant (p=0.074). Absence of BMP4 expression may be a biomarker of both higher relapse risk and statin benefit in early BrCa. 1. Eckhardt et al, Cancer Res. 2020;80(6):1304-1315 Citation Format: Lap Hing Chi, Andrew Redfern, Allan Burrows, Suraya Roslan, Leone Oh, Lisa Spalding, Robin Anderson. The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-10.

Abstract PO1-22-03: Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy

Abstract Introduction: Previous studies have shown that ATM (ataxia-telangiectasia mutated) mutations may be associated with increased radiation sensitivity and altered treatment response. However, there is a limited understanding of the clinical implications and optimal management strategies for breast cancer patients with ATM mutations receiving radiotherapy (RT). The aim of our study is to assess the impact of ATM mutations on radiation response and treatment outcomes in breast cancer patients undergoing RT. Material and Methods: A total of 79 female patients diagnosed with breast cancer were included in the study, with 31 (39.3%) having pathogenic (P) and likely pathogenic (LP) variants (all of the variants were heterozygous) and 48 (60.8%) having VUS variants detected through whole ATM gene sequencing screening for patients in accordance with NCCN clinical practice guideline. Statistical analysis, including descriptive, graphical, and inferential methods, such as the Kolmogorov-Smirnov test, Mann-Whitney U Test, and Chi-square tests, was conducted using SPSS version 25.0 to evaluate the normal distribution of continuous variable scores and perform quantitative and qualitative comparisons between groups at a 95% confidence level (p &amp;lt; 0.05). Results: The median age of the patients was 44 years (range: 24-74), with 75% of them being 50 years old or younger .The rate of breast cancer in patients with VUS variants was significantly higher in those aged 50 and below compared to those with P/LP variants (83% vs. 61%, p=0.028). There was no statistically significant difference in clinical stage, tumour histological type, and molecular subtype classification based on ATM gene variant type (P/LP vs. VUS) among the patients (p&amp;gt;0.05), but the rate of high tumour grade was significantly higher in the VUS variant group (65% vs. 40%, p=0.034). The rate of patients who received RT was 87%, with 26 patients receiving radiation to the breast or chest wall and 43 patients receiving additional regional lymph node irradiation. There were no statistically significant differences in surgical and systemic treatment types and RT dose based on ATM gene variant type (P/LP vs. VUS) (p&amp;gt;0.05). Among the patients who received RT, 33 (48%) experienced early-stage skin reactions, and 15 (22%) experienced late-stage skin reactions according to Common Terminology Criteria for Adverse Events (CTCAE) v5. No Grade 3, 4 and 5 early and late toxicity were observed . The rate of early (83% vs. 23%; p&amp;lt; 0.001) and late (35% vs. 13%; p=0.029) skin reactions was significantly higher in the P/LP variant group compared to the VUS variant group. Grade I lymphedema was observed in 2 (2.5%) patients, 1 (3.2%) in the P/LP group and 1 (2.1%) in the VUS group (p&amp;gt;0.05). Among the 23 patients who underwent breast reconstruction, 1 (4%) had implant revision and 1 (4%) experienced implant loss, both of which were observed in the pathogenic variant group (p&amp;gt;0.05). Conclusion: Limited clinical data exists on RT toxicity in breast cancer patients with ATM gene mutations, and clear guidelines for decision-making are lacking. Our study revealed higher rates of acute and chronic skin reactions in the P/LP variant group, highlighting the need for further investigation into the impact of these variants on treatment outcomes and patient management. However, it is crucial to manage these reactions effectively and not allow them to hinder treatment. Additional research and interventions are warranted to better understand and address these reactions, aiming to enhance the overall treatment experience and outcomes for patients with ATM gene mutations. Citation Format: Evrim Tezcanli, Seda Eroz, Ugur Ozbek, Ahmet Yesilyurt, CIHAN URAS, Nuran Bese. Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-03.

Abstract PO1-12-07: Denosumab vs. Pamidronate in the Management of Osteolytic Bone Metastases Secondary to Breast Cancer, a Multi-Institutional Analysis

Abstract Breast cancer is one of the most common cancers in women and is associated with poor outcomes due to the metastatic potential of high-grade tumors. One common site of breast cancer metastasis is to the bone, leading to serious adverse effects such as bone pain, bone fracture, and spinal cord compression. Denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappa-b (RANK) ligand (RANKL), and Pamidronate, a bisphosphonate, are two pharmacologic agents offered for the treatment of these adverse complications. The goal of this study was to conduct a retrospective cohort analysis across multiple institutions to compare the efficacy of Denosumab vs. Pamidronate in the management of osteolytic bone metastases secondary to breast cancer by evaluating the risk of adverse events. TriNetX, an online network that provides access to anonymized medical records for more than 108 million patients in 72 large healthcare organizations, was used in this study. Two cohorts, consisting of 847 patients with a diagnosis of bone metastases and breast cancer, were created and subsequently matched for age, race, gender, and ethnicity. One cohort was given Denosumab while the other was given Pamidronate, and each cohort was excluded from receiving the other medication. The occurrence of pathologic fracture in each arm, spinal cord compression, and overall five-year survival rate was measured and analyzed. The results of this study showed that Denosumab had a statistically insignificant risk reduction in both pathological fracture (2.7% vs. 2.8%, p = 0.88) and spinal cord compression (2.6% vs. 2.7%, p = 0.88) and a statistically insignificant difference in the overall five-year survival rate (45.5% vs. 52.4%, p = 0.78) when compared to Pamidronate. As a result, additional factors such as financial cost, route of administration, dosing schedule, and potential adverse side effects should be discussed with each individual who requires pharmacological therapy for bone metastases secondary to breast cancer. Citation Format: Megan Bradley, Mabry Nichols, Brittany Miles. Denosumab vs. Pamidronate in the Management of Osteolytic Bone Metastases Secondary to Breast Cancer, a Multi-Institutional Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-07.

The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

Parenchymal obliteration by renal masses: Functional and oncologic implications

ObjectivesMost renal tumors merely displace nephrons while others can obliterate parenchyma in an invasive manner. Substantial parenchymal volume replacement (PVR) by renal cell carcinoma (RCC) may have oncologic implications; however, studies regarding PVR remain limited. Our objective was to evaluate the oncologic implications associated with PVR using improved methodology including more accurate and objective tools. Patients/MethodsA total of 1,222 patients with non-metastatic renal tumors managed with partial nephrectomy (PN) or radical nephrectomy (RN) at Cleveland Clinic (2011-2014) with necessary studies were retrospectively evaluated. Parenchymal volume analysis via semiautomated software was used to estimate split renal function and preoperative parenchymal volumes. Using the contralateral kidney as a control, %PVR was defined: (parenchymal volumecontralateral–parenchymal volumeipsilateral) normalized by parenchymal volumecontralateral x100%. PVR was determined preoperatively and not altered by management. Patients were grouped by degree of PVR: minimal (<5%, N = 566), modest (5%-25%, N = 414), and prominent (≥25%, N = 142). Kaplan-Meier was used to evaluate survival outcomes relative to degree of PVR. Multivariable Cox-regression models evaluated predictors of recurrence-free survival (RFS). ResultsOf 1,122 patients, 801 (71%) were selected for PN and 321 (29%) for RN. Overall, median tumor size was 3.1 cm and 6.8 cm for PN and RN, respectively, and median follow-up was 8.6 years. Median %PVR was 15% (IQR = 6%-29%) for patients selected for RN and negligible for those selected for PN. %PVR correlated inversely with preoperative ipsilateral GFR (r = -0.49, P < 0.01) and directly with advanced pathologic stage, high tumor grade, clear cell histology, and sarcomatoid features (all P < 0.01). PVR≥25% associated with shortened recurrence-free, cancer-specific, and overall survival (all P < 0.01). Male sex, ≥pT3a, tumor grade 4, positive surgical margins, and PVR≥25% independently associated with reduced RFS (all P < 0.02). ConclusionsObliteration of normal parenchyma by RCC substantially impacts preoperative renal function and patient selection. Our data suggests that increased PVR is primarily driven by aggressive tumor characteristics and independently associates with reduced RFS, although further studies will be needed to substantiate our findings.

Radiologic tumor border can further stratify prognosis in patients with pancreatic neuroendocrine tumor

Background and objectivesPancreatic neuroendocrine tumor (PanNET), although rare in incidence, is increasing in recent years. Several clinicopathologic and molecular factors have been suggested for patient stratification due to the extensive heterogeneity of PanNETs. We aimed to discover the prognostic role of assessing the tumor border of PanNETs with pre-operative computed tomography (CT) images and correlate them with other clinicopathologic factors. MethodsThe radiologic, macroscopic, and microscopic tumor border of 183 surgically resected PanNET cases was evaluated using preoperative CT images (well defined vs. poorly defined), gross images (expansile vs. infiltrative), and hematoxylin and eosin-stained slides (pushing vs. infiltrative). The clinicopathologic and prognostic significance of the tumor border status was compared with other clinicopathologic factors. ResultsA poorly defined radiologic tumor border was observed in 65 PanNET cases (35.5 %), and were more frequent in male patients (P = 0.031), and tumor with larger size, infiltrative macroscopic growth pattern, infiltrative microscopic tumor border, higher tumor grade, higher pT category, lymph node metastasis, lymphovascular and perineural invasions (all, P < 0.001). Patients with PanNET with a poorly defined radiologic tumor border had significantly worse overall survival (OS) and recurrence-free survival (RFS; both, P < 0.001). Multivariable analysis revealed that PanNET with a poorly defined radiologic border is an independent poor prognostic factor for both OS (P = 0.049) and RFS (P = 0.027). ConclusionPre-operative CT-based tumor border evaluation can provide additional information regarding survival and recurrence in patients with PanNET.

Elucidating activity for WNT signaling mediators in breast cancer and Paclitaxel chemoresistance

Breast cancer continues to be among the most common cancers found in patients worldwide with more than 300,000 new cases projected to be diagnosed in 2024 for women in the United States (Siegel et al. 2023). Metastatic breast cancer is heterogenous, which indicates both its complexity and the increased degree of chemotherapeutic intervention necessary for advanced or refractory cases. The development of chemoresistance further complicates intervention, as even previously effective therapeutics against early-stage cancers can develop resistance and generate refractory, high-grade tumors. Paclitaxel is a microtubule-stabilizing compound that remains of clinical importance due to its ongoing applications in early and metastatic disease. Studies in paclitaxel chemoresistance remain of critical consideration as even this promising therapeutic has been shown, like all compounds, to result in chemoresistance (Steding 2016). Studies have demonstrated pivotal roles for the WNT signaling pathway within tumor development, progression, and acquired chemoresistance (Zhong and Virshup 2019). The WNT signaling pathway has been implicated as a driving mechanism of chemoresistance in several cancer types, including both early and metastatic breast cancer. As WNT signaling can increase both as an immediate response to Paclitaxel treatment and as a potential mechanism of paclitaxel chemoresistance, it is important to elucidate further whether WNT signaling is actually a driving force of chemoresistance or merely a byproduct of its development. Furthermore, the widespread mechanisms and players involved in WNT signaling require further isolation and consideration to determine the most significant players in chemoresistance. Prior evidence has indicated that reductions in WNT signaling have the potential to restore sensitivity to treatment to a wide range of chemotherapeutics for some cancer types (Chikazawa 2010). These findings may be cell type specific or be a consequence of specific changes of WNT signaling mediators rather than global WNT signaling. Preliminary evidence observed in paclitaxel chemoresistant cell populations indicated a wide range of changes in WNT signaling mediators including both downregulation and upregulation of components within the same pathway. With the potential for conflicting results across cancers and these preliminary findings in mind, further investigation into the role of WNT signaling mediators in paclitaxel sensitivity and resistance remains of significant interest. In order to define actual mechanisms of action, roles for global WNT signaling as well as specific roles for key players within the pathway must be confirmed. We hypothesized that changes in global WNT signaling would significantly alter breast cancer sensitivity to paclitaxel through both canonical and noncanonical pathways via specific mediators. To begin to assess this hypothesis, breast cancer cells were treated with a global WNT inhibitor or an inhibitor targeting Beta-catenin (β-catenin). Treatment of cells with both inhibitors were found to suppress overall WNT activity to similar levels; however, the targeting of β-catenin altered paclitaxel effcacy compared to paclitaxel alone or in combination with the global inhibitor. Further analysis of specific changes following the combined treatment implicated the noncanonical pathway as playing a more substantial role in paclitaxel sensitivity. Although investigations remain ongoing, these findings indicate novel behaviors for WNT signaling in paclitaxel sensitivity and support further exploration into the complicated world of WNT signaling and its signaling mediators in chemoresistance. This research was supported in part by an Indiana Academy of Sciences Senior Research Grant (IASSG-S21-07) as well as a Marian University Faculty Research Development Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer: A Population-Based Assessment in the United States [ID 2693178

INTRODUCTION: The objective of this study was to assess population-level utilization and outcome of reproductive-aged patients with early epithelial ovarian cancer (EOC) who underwent fertility-sparing surgery (FSS) in the United States. METHODS: This population-based retrospective study queried the National Cancer Institute’s Surveillance, Epidemiology, and End Result Program. The study included 3,027 patients aged less than 50 years with stage I EOC receiving primary surgical therapy from 2007 to 2020. Fertility-sparing surgery was defined as preservation of one ovary and the uterus for unilateral lesion and preservation of the uterus for bilateral lesions. Temporal trend of FSS was assessed with linear segmented regression with log-transformation. Overall survival (OS) associated with FSS was assessed with Cox proportional hazard regression model. RESULTS: A total of 534 (17.6%) patients underwent FSS. At cohort level, the utilization of FSS was 13.4% in 2007 and 21.8% in 2020 (P-trend=.009). Non-Hispanic White individuals (2.8-fold), high-grade serous histology (2.2-fold), and stage IC disease (2.3-fold) had greater than 2-fold increase in FSS utilization during the study period (all, P-trend&lt;.05). After controlling for the measured clinico-pathological characteristics, patients who received FSS had OS comparable to those who had nonsparing surgery (5-year rates, 93.6% versus 92.1%; adjusted hazard ratio, 0.87; 95% CI, 0.57–1.35). This survival association was consistent in high-grade serous (5-year rates, 92.9% versus 92.4%), low-grade serous (100% versus 92.2%), clear cell (97.5% versus 86.1%), mucinous (92.1% versus 86.6%), low-grade endometrioid (95.7% versus 97.7%), and mixed histology (93.3% versus 83.7%) (all, P&gt;.05). In high-grade endometrioid tumor, FSS was associated with decreased OS (5-year rates, 71.9% versus 93.8%; adjusted-hazard ratio 2.90; 95% CI, 1.09–7.67). Among bilateral ovarian lesions, FSS was not associated with OS (5-year rates, 95.8% versus 92.5%; P=.364). CONCLUSION: Nearly one in five reproductive-aged patients with stage I EOC underwent FSS in recent years in the United States. The data suggest that FSS may not adversely affect OS, except for high-grade endometrioid tumors.