Bagaria, Sanjay P.

Abstract Background The current definition, prognosis, and optimal treatment (tx) for oligometastatic breast cancer (OMBC) are not fully known. With advances in multimodality breast cancer (BC) tx and overall improvement in patient (pt) outcomes, it is important to identify baseline pt factors that confer better prognosis in OMBC and assess the impact of local/regional tx and metastasis (mets)-directed tx on survival outcomes. Methods We reviewed 105 Mayo Clinic pts with OMBC (up to 5 mets) from 2003 to 2021. Pts were excluded from analysis if they were misidentified as having OMBC (n=6), did not have a primary breast mass (n=1), developed de novo BC during tx (n=1), or were lost to follow up (n=2). Categorical variables were summarized as counts. Continuous variables were reported as medians. Kaplan-Meier method was used to estimate survival and the time from diagnosis to next tx at 1, 3, and 5 years. Log-rank test was used to compare survival rates between baseline factors. Univariate Cox proportional hazards models were performed on both baseline and time-dependent factors. All tests were two-sided with p-value < 0.05 considered statistically significant. Results Total pts included were 95. Median age was 49 (range, 26-86), most (93.6%) pts were White, and 46.8% were postmenopausal. Invasive ductal carcinoma (89.5%) was the most common BC type. Median survival was 10.8 years; 1-, 3-, and 5-year survival rates were 98.9%, 87.7%, and 81%, respectively. 58 pts (61.1%) required a change in tx due to disease progression. No significant survival difference was observed in pre- vs. postmenopausal pts (p=0.71) or in groups based on hormone receptor and/or human epidermal growth factor receptor 2 status. 47 pts (49.5%) received local/regional tx; no significant difference in survival (HR 0.57, 95% CI 0.23-1.40; p=0.217) or time to next tx (HR 0.67, 95% CI 0.39-1.15; p=0.144) was seen in this subgroup. Of these pts, 36 (76.6%) received neoadjuvant chemotherapy and/or immunotherapy, 5 of whom (10.6%) also started endocrine tx preoperatively. Overall, 11/47 pts (23.4%) received neoadjuvant endocrine tx. 20 pts received systemic tx without eventual surgery, and 5 pts got palliative radiation (RT). Biopsy-confirmed mets were noted in 76 pts (80%), with bone-only mets in 50%, 30 pts (31.6%) with viscera-only mets and 7 pts (7.4%) with both bone and visceral mets. 18 pts had suspected mets on imaging but did not undergo biopsy. The hazard of death was 6.34 times higher in pts with both bone and visceral mets than those with bone-only mets (p=0.008). Pts with viscera-only mets had higher survival at 2 and 3 years than pts with bone-only or both bone and visceral mets (p=0.093). Pts with 3 mets (7/76, 7.4%) had decreased survival at 1, 2, and 3 years compared to pts with 1-2 (65/76, 85.5%) mets (p=0.6). 67 pts (70.5%) received mets-directed tx; RT alone was the most common modality (52/67, 77.6%), followed by surgery (6/67, 9%), RT plus surgery (5/67, 7.5%), and ablation alone (3/67, 4.5%). There was no significant difference in survival (HR 1.27, 95% CI (0.53, 3.07), p=0.589) or time to next tx (HR 0.95, 95% CI (0.56, 1.63), p=0.856) in pts who received mets-directed tx. Multivariate analysis was not performed because most findings were not statistically significant in univariate analysis. Conclusions We did not find any significant differences in survival based on characteristics like menopausal status or site or number of mets in pts with OMBC. There was a trend toward improved survival in pts with viscera-only mets, but this finding requires validation. Local/regional and mets-directed tx did not improve survival; however, survival at 1, 3, and 5 years was excellent in this OMBC pt population. Our study was limited by low pt numbers and heterogeneity in the pt population. Findings need validation in larger studies. Citation Format: Tanmayi Pai, Raza Zarrar, Zhongwei Peng, Zhuo Li, Lauren Cornell, Kostandinos Sideras, Rohit Rao, Alvaro Moreno-Aspitia, Saranya Chumsri, Sarah McLaughlin, James Jakub, Emmanuel gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Features and Survival Outcomes of Oligometastatic Breast Cancer Patients: The Mayo Clinic Experience [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 PO3-06-04.

e20535 Background: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 600 new cases per million people diagnosed annually in the U.S. High incidence of germline mutations has been reported in MPM patients (pts) without asbestos exposure. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in MPM pts. Methods: Using the Mayo Clinic Cancer Registry, we identified 64 pts who were treated for MPM from January 2002-December 2022 with updated follow-up data until 01/15/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 25 pts were male, and 39 pts were female. 14/64 (22%) pts were found to have at least one additional malignancy, including breast cancer (4/14, 29%), colon cancer (3/14, 21%), lymphoma (3/14, 21%), ovarian cancer (2/14, 14%), melanoma (2/14, 14%), anal squamous cell carcinoma (1/14, 7%), papillary thyroid cancer (1/14, 7%), Chronic lymphocytic leukemia (1/14, 7%), renal cell carcinoma (1/14, 7%), squamous cell carcinoma of tongue (1/14, 7%), hepatocellular carcinoma (1/14, 7%) and pituitary macroadenoma (1/14, 7%). 4/14 (29%) pts had more than one (2-4) non-MPM malignancies. The median age at diagnosis of MPM was 65 years (44-82). The median age at diagnosis of non-MPM malignancies was 66 years (18-81). Most of the patients (11/14) were diagnosed with non-MPM malignancy within 12 months of diagnosis of MPM. Most pts (11/14, 78%) were diagnosed with non-MPM malignancy first, among which 5 pts (45%) were found to have MPM on surveillance scans. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and Li-Fraumeni syndrome. FH was available in 29 pts, out of which 28 pts had FH of cancer identified in first-degree relatives. Among the 14 pts with additional malignancies, 9 pts had FH of cancer in first-degree relatives. Among all pts, 15 (18%) pts had a history of asbestos exposure. Among pts who also had non-MPM malignancies, 3/14 (21%) pts had a history of asbestos exposure. Among the 21 non-MPM cancers, 1/21 (5%), 11/21(52%), 1/21(5%), 3/21(14%), and 5/21(24%) non-MPM malignancies were stage 0, stage I, II, and III, or unknown at the diagnosis respectively. All except 1 pt underwent curative treatment for their non-MPM malignancies, and 12 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of multiple primary malignancies in pts with MPM is high, indicating possible genetic predisposition associated with this disease. Early genetic consultation and evaluation for germline mutations may need to be considered for these pts to improve long-term outcomes.

Abstract Surgical resection of early stage soft-tissue sarcomas (STS) is a potentially curative treatment; however, many STS tumors will recur. Predicting recurrence and survival outcomes for patients with early stage STS remains a challenge. In this study, we identify prognostic biomarkers from clinical and transcriptomic data form a large set of early stage STS. Primary tumor samples from 69 subjects with STS were sequenced using the Tempus xT targeted DNA and whole transcriptome next-generation sequencing platforms. The most common histologies included were liposarcoma (n=22), gastrointestinal stromal tumor (n=19), and leiomyosarcoma (n=12). As expected, high-grade tumors were associated with decreased DFS and OS times while tumor histology was only correlated with OS. Single sample gene set enrichment analysis (ssGSEA) values for seven Hallmark genesets were correlated with both DFS and OS; including pro-tumor survival pathways (p53, Apoptosis, TNF-α via NF-κB), tumor proliferation pathways (MTORC1, MYC Targets, Mitotic Spindle), and UV Response signaling. These pathways are associated with tumor proliferation as well as an immunosuppressive tumor microenvironment (TME). To assess the TME of these tumors we estimated immune cell infiltration using CIBERSORTx. Of the 22 cell types accounted for by CIBERSORTx, only elevated infiltration of M2 Macrophages were associated with poor DFS and OS. To further determine TME activation we assessed the expression of 74 known immune response associated genes. Only PDCD1 (PD-1) was associated with reduced DFS and OS times. Clustering on the nine variables identified here to correlate with both DFS and OS revealed two distinct clusters demonstrating similar histologies. While histologies were similar across clusters, cluster 2 exclusively included high-grade tumors while cluster 1 was made up of 57.4% high-grade tumors. Sub-classifying cluster 1 into low and high-grade subgroups demonstrated a stepped biomarker expression pattern associated with both tumor grade and cluster membership. Using established TME genesets, high-grade tumors demonstrated higher tumor proliferative scores than low-grade tumors, while cluster 2 tumors demonstrated increased tumor associated macrophage signaling. In a multivariable model, cluster membership outperformed tumor grade and histology as the only significant predictor of DFS or OS. Taken together, while tumor grade is a strong predictor of clinical outcomes following surgical resection in STS, immunosuppressive signaling patters may help to identify patients at the highest risk. Citation Format: Nathan David Seligson, Yan W. Asmann, Tariq Almerey, Steven Attia, Sanjay P. Bagaria. Immune-suppressive tumor microenvironment leads to poor survival following curative intent surgical resection in soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 990.

Abstract Background Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer (BC) defined by presence of both epithelial and mesenchymal components. Most are triple negative but are often chemo-refractory and associated with poor survival outcomes compared to non-metaplastic triple negative BC. Advances in therapy have led to improvements in survival outcomes of patients (pts) with BC over the last decade. Our multicenter retrospective study aims to assess (1) progression free survival (PFS) and overall survival (OS) (2) factors predictive of survival outcomes in MBC pts Methods We performed a retrospective analysis of pts diagnosed with MBC from 1997-2021 at Mayo Clinic (Florida, Arizona and Rochester) under IRB approval. Kaplan-Meier method was used to estimate OS and PFS at 1, 3 and 5 years. Cox regression models were used to examine the association between risk factors and survival outcomes. All tests were two-sided with p value < 0.05 considered statistically significant Results We evaluated 158 pts with MBC. Median age and tumor size was 61 (range: 20-91) years and 2.8 (range: 0.5-21) cm, respectively, with 80% of pts being postmenopausal. At diagnosis, 14.6% of pts had clinical T3/T4 disease, 16.4% were clinically node-positive, and 6.3% (10 pts) had distant metastases (DM). Spindle cell histology was seen in 36 pts. Most MBC pts were triple-negative (68.3%), high grade (77.2%) and high Ki-67 (36/47; 76.5%). Of the 61 pts tested for germline mutation, 8 (13.1%) were positive, with BRCA1/2, PTEN, NBN, CHEK2, and BARD1 mutations. Most pts had lumpectomy (53.8%), followed by simple mastectomy (38.5), and modified radical mastectomy (7.7%). Majority of pts had sentinel lymph node biopsy (71.8%). Adjuvant radiation therapy was performed in 65.6% of pts. Pathologic complete response (pCR) was noted in 4/38 (10.5%) evaluable pts who received neoadjuvant chemotherapy (NACT). Residual cancer burden (RCB) scores of 2 and 3 were seen in 76.2% of evaluable pts. Median follow-up time was 2.2 years (range: 6 days-24.6 years). Overall, 1-, 3-, and 5-year OS was 93.3%, 81.7%, and 76.0%, while PFS was 80.8%, 67.9%, and 60.9%, respectively. The presence of DM at diagnosis [HR 38.55 (11.18, 132.93), p < 0.001] and spindle cell histology (SC) [HR 2.57 (1.19, 5.53), p = 0.02] predicted worse OS in multivariable analysis. Inferior PFS was predicted by DM [HR 18.84 (6.53, 54.35), p < 0.001], SC [HR 2.46 (1.25, 4.86), p = 0.009], and node-positivity at diagnosis [HR 3.65 (1.5, 8.89), p = 0.004]. The 5-year OS and PFS were 22.2% and 0% for DM pts versus 80.0% and 65.6% for non-DM pts. The 5-year OS and PFS were 71.5% and 54.7% for SC pts versus 81% and 66.6% for non-SC pts. 5-year OS and PFS for NACT pts was 67.3% and 52.6% for NACT pts versus 78.2% and 62.8% for non-NACT pts. Age at diagnosis, menopausal status, family history of BC, grade, stage, tumor size, hormone-receptor and HER2 status, and use of NACT were not found to be significantly associated with OS or PFS in multivariate analysis. Conclusion This study is one of the largest and most recent review of institutional experiences with MBC. Overall, OS at 5 years was improved compared to prior older studies of MBC but still remains very low for those with DM, representing an area of unmet clinical need. SC and DM correlated with worse outcomes for both PFS and OS. Additionally, node positivity at diagnosis was a predictor of worse PFS. In contrast, no association was seen between survival and tumor size, stage, hormone receptor-positivity, HER2 receptor-positivity. The low pCR rates following NACT in our study are consistent with reported literature. Further, use of NACT does not impact survival, suggesting pts with resectable disease should proceed with surgery first. Citation Format: Siven Chinniah, Raza Zarrar, Zhuo Li, Kostandinos Sideras, Alvaro Moreno-Aspitia, Saranya Chumsri, Rohit Rao, Sarah McLaughlin, James Jakub, Emmanuel Gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Factors associated with Survival Outcomes in Patients with Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-25.

Introduction Contiguous non-mass enhancement (NME) often coexists with a solid tumor component on MRI, but it can be challenging to predict whether NME represents invasive breast cancer, ductal carcinoma in situ (DCIS), benign disease, or biopsy site reaction. The purpose of this study was to determine the association between the size/extent of NME and the presence of invasive cancer and/or DCIS on final pathology. Methods This was a single institution retrospective analysis of a prospectively maintained breast cancer registry (2010-2020). Female patients who underwent surgical resection were included if they had a diagnosis of invasive breast cancer (with or without DCIS) and had an MRI showing both a solid mass and contiguous NME. The size of NME on MRI was compared with the size of invasive cancer and/or DCIS on the final pathology. Results From a total of 3443 patients, 225 patients were included. 86.2% had invasive ductal carcinoma (IDC), and 12.0% had invasive lobular carcinoma 76.9% were ER+, 16.4% were HER2+, and 13.3% were triple negative breast cancer (TNBC). 18.7% received neoadjuvant chemotherapy (NCT) of whom 31% achieved a complete radiographic/pathologic response. Pearson correlation coefficients (r) between the size of NME and invasive cancer/DCIS showed a strong and positive correlation of MRI NME with DCIS on pathology in patients without NCT. Subgroup analysis showed the strongest correlations for NME and DCIS among non-white (r = .70) and HER2 + patients (r = .74) who did not receive NCT. Conclusions Strong correlations between NME and DCIS were found for HER2 + disease and non-white patients, but only modest correlations were found for other patient/disease characteristics. These correlations may impact decisions in surgical approach.

Abstract INTRODUCTION: Intratumoral phenylephrine (α1 vasoconstrictor) combined with chemotherapy has been used for cutaneous malignancies with modest local response. The purpose of this study was to improve the efficacy of intratumoral melphalan using sustained-release, liposomal nanoparticles containing phenylephrine in a mouse model of melanoma. METHODS: A modified ethanol injection method was used to develop the liposomal phenylephrine nanoparticles. These were injected peri-tumorally to generate a local vasoconstrictive effect intended to “entrap” intratumorally injected melphalan. Drug exposure/dwell time was measured with fluorescent imaging. Mice bearing B16 (subclone F10) melanoma tumors were treated with intratumoral melphalan (20 ug/50 ul) with or without peri-tumoral liposomal phenylephrine (10 ug/50-100 ul x 4-5 injections around the tumor periphery) twice weekly x 3 weeks. RESULTS: UV-Absorbance spectroscopy confirmed encapsulation of phenylephrine within the liposomal nanoparticles with an expected absorbance of 275 nm. The modified ethanol injection method produced liposomal phenylephrine encapsulation of approximately 25%. Peri-tumoral, liposomal phenylephrine caused vasoconstriction of normal surrounding vessels with an approximate 10% decrease in vessel diameter. Our liposomal phenylephrine nanoparticles also led to increased retention of intratumorally injected fluorescently-labeled (FITC) liposomes 24-48 hours after inoculation, using both melanoma (B16) and breast (TUBO/4T1) cell lines orthotopically grown within mice (C57Bl/6 and BALB/c, respectively). The combination of intratumoral melphalan with peri-tumoral phenylephrine resulted in more effective control of tumor growth and a complete tumor response rate of 44.4%, compared to phenylephrine/melphalan only controls (p < 0.01, n=18 per group). However, there was significant adverse reaction with the combination therapy, resulting in ulceration of the injection/tumor site. Ulcers healed about 14 days after completion of treatment. Immunohistochemistry demonstrated increased infiltration of CD11b+ cells into the tumors, suggesting an immune-mediated response in addition to direct chemotoxicity. CONCLUSIONS: Liposomal nanoparticles containing phenylephrine increased retention/dwell time of intratumorally administered melphalan and resulted in superior anti-tumor response. Our preclinical model holds innovative, translational promise for the clinical advancement of intralesional therapies in cutaneous/subcutaneous malignancies. Citation Format: Emmanuel M. Gabriel, Vijay Madamsetty, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Sanjay Bagaria, Keith Knutson, Debabrata Mukhopadhyay. Novel approach to intra- and peri-tumoral delivery of sustained-release chemotherapeutics [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 5071.