bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characterization of luminal breast tumors in African American women.
Authors: Simons Yael , Hassan Mohamed , Chlipala George , Danciu Oana Cristina , Gadi Vijayakrishna K. , Singh Manmeet , Mohapatra Gayatry , Hoskins Kent 
Published: June 2021

550 Background: Racial disparities in breast cancer (BC) mortality are attributed to later stage diagnoses and a higher incidence of triple-negative BC among African American (AA) women. In previous work, we showed that AA women with ER+ BC are more likely to develop biologically aggressive disease and are more likely to die from early stage, ER+ BC than non-Hispanic White women (Hoskins et al, JAMA Oncol, 2021). The underlying molecular drivers of this disparity are unknown. Here we report the molecular characterization of a series of luminal BC from AA women. Methods: Consecutive breast tumor specimens received in the Pathology Department underwent next generation sequencing (NGS). Unstained FFPE tissue sections were macro-dissected to isolate tumor cells, and nucleic acids were extracted using commercially available kits. DNA and RNA sequencing libraries were prepared with the Oncomine Comprehensive Assay v3 (OCAv3) (Thermo Fisher), which includes 161 driver genes and detects SNVs, CNVs, INDELs and gene fusions. Sequencing was performed on the Ion S5XL sequencer. Sequencing reads were mapped to the UCSC human genome build GRCh37/hg19 using Torrent Suite™ software (version 5.10; Thermo Fisher). Data analysis and variant calling was performed using the Ion Reporter analysis tool. Results: We identified 60 somatic driver gene alterations in luminal tumors from 35 AA patients (primary tumors, n = 26; metastatic tumors, n = 9). Recurrently altered genes identified in > 5% of tumors are listed in the Table. The most frequently altered gene was PIK3CA (42% of tumors). ESR1 gene fusions were seen in 25% of tumors. Interestingly, an equal frequency of ESR1 fusions were detected in primary (27%) and metastatic (22%) tumors, in contrast to activating mutations which are found in recurrent tumors following treatment with aromatase inhibitors. ARID1A alterations were identified in 17% of primary tumors. ARID1A encodes a subunit of the SWI/SNF chromatin remodeling complex. Alterations in ARID1A confer endocrine resistance, and are enriched in recurrent tumors in the literature. We also found a high number of CNVs in members of the FGF gene family (36% of tumors), which are also associated with resistance to endocrine therapy. An in silico analysis comparing our findings with publicly available datasets will be presented. Conclusions: This study of somatic driver gene alterations in a consecutive series of luminal breast tumors from AA patients found a higher than expected frequency of alterations in genes associated with endocrine resistance in untreated primary tumors, suggesting a partial explanation for racial disparities in survival.[Table: see text]
Pertuzumab plus trastuzumab (P+T) in patients (Pts) with uterine cancer (UC) with ERBB2 or ERBB3 amplification, overexpression or mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Ali-Ahmad Hussein Moustapha , Rothe Michael , Mangat Pam K. , Garrett-Mayer Liz , Ahn Eugene , Chan John , Maitland Michael L. , Balmanoukian Ani Sarkis , Patel Sapna R. , Reese Zachary , Drescher Charles W. , Leath Charles A. , Li Rui , Tsimberidou Apostolia Maria , Schilsky Richard L. 
Published: June 2021

5508 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of UC pts with ERBB2 or ERBB3 amplification , overexpression or mutation treated with P+T are reported. Methods: Eligible pts had advanced UC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts matched to P+T had UC with ERBB2 or ERBB3 amplification or overexpression or a pre-specified ERBB2 mutation. Recommended dosing was P at an initial dose of 840 mg intravenously (IV) over 60 minutes (m), then 420 mg IV over 30-60 m every 3 weeks (wks), and T at an initial dose of 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m every 3 wks until disease progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female pts were enrolled from August 2017 to November 2019; all pts were evaluable for efficacy and toxicity. Demographics and outcomes are summarized in Table. Twenty-two pts had tumors with ERBB2 amplification (21) or overexpression (1); 4 tumors had ERBB2 mutations; 1 tumor had ERBB3 amplification; 1 tumor had both an ERBB2 amplification and mutation. Two PR and 7 SD16+ were observed in pts with ERBB2 amplification, and 1 SD16+ was observed in a pt with ERBB2 V8421 mutation only (no amplification) for DC and objective response (OR) rates of 37% (95% CI, 21% to 50%) and 7.1% (95% CI, 0.8% to 24%), respectively. One pt experienced grade 3 muscle weakness at least possibly related to P+T. Conclusions: P+T demonstrated evidence of anti-tumor activity in heavily pre-treated UC pts with ERBB2 amplification or certain mutations. Additional study is warranted to confirm the efficacy of P+T in this pt population. Clinical trial information: NCT02693535. [Table: see text]
Phase IIa study of BVAC-C in HPV type 16 or 18 positive recurrent cervical carcinoma.
Authors: Choi Chel Hun , Kim Byoung-Gie , Lee Jeong-Won , Bae Duk-Soo , Kang Eun-Suk , Kim Yong-Man , Kim Kidong , Kim Jae-Weon , Kim Young-Tae , Lim Myong Cheol , Oh Taegwon , Kang Chang-Yuil , Cho Duck , LEE JUNG-YUN , Kim Hee Seung 
Published: June 2021

5512 Background: BVAC-C is a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, which was well tolerated in HPV positive recurrent cervical carcinoma in phase I study (J Clin Med. 2020 Jan 5;9(1):147). This phase IIa study sought to determine the antitumor activity of BVAC-C. Methods: Twenty-one patients with HPV 16 or 18 positive recurrent cervical cancer who had experienced recurrence after one prior platinum-based combination chemotherapy were enrolled. They were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks (1x108 cells/dose); Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose); Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose) with topotecan at 2, 6, 10, 14 weeks (0.75 mg/m2 for 3 days). Results: The overall response rate was 21% (Arm 1: 29% (2/7), Arm 2: 25% (1/4), Arm 3 : 0 % (0/3)) among the evaluable patients (N = 14), and the median duration of response was 18 months (range, 9 – 26 months). The disease control rate was 43% (Arm 1: 29% (2/7), Arm 2: 50% (2/4), Arm 3 : 67 % (2/3)) and the median duration of stable disease were 12 months (range, 6 - 26 months). The median progression-free survival in all patients was 4 months (95% CI, 2 to Infinite months). Immune responses of patients after vaccination were shown to be correlated with clinical responses of them. Consistent with Phase I study, all evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α), which might be mediated by the activation of natural killer cells and natural killer T cells, but also potent E6/E7-specific T cell responses upon vaccinations. Conclusions: BVAC-C demonstrated a durable antitumor activity with an immune response in HPV 16- or 18-positive recurrent cervical carcinoma patients who failed 1st line platinum based chemotherapy. Clinical trial information: NCT02866006.
Defective mismatch repair associated mutational signatures, a prognostic and predictive biomarker in endometrial cancer.
Authors: Chang Yifan Emily , Adjei Naomi N , Khadraoui Wafa , Altwerger Gary 
Published: June 2021

5528 Background: Mismatch repair (MMR) deficiency is the distinguishing molecular feature of a significant portion of endometrial cancers (UCEC), and tumors with MMR deficiency have been identified as candidates for immune checkpoint blockade therapy. We studied MMR deficiency in UCEC using defective mismatch repair associated mutational signatures (MMRd-ams). Methods: WES-derived somatic mutation data of 531 UCEC samples from TCGA Pan-Cancer Atlas were analyzed. COSMIC mutational signatures for each sample were calculated using the R package deconstructSigs. MMRd-ams were correlated with clinical and molecular features for 507 TCGA samples (cBioPortal). Samples were divided into High MMRd-ams ( n = 192) and Low MMRd-ams ( n = 315) groups by the average of the representative MMRd-ams (0.2396). Fractions of tumor immune infiltrates were derived from CIBERSORT. Results: A significantly higher percentage of patients (47/192, 24.5%) in the High MMRd group had somatic putative driver mutations in at least 1 of the MMR genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and EPCAM), compared with patients in the Low MMRd group (37/315, 11.8%, p = 0.0003). 15% (54/359) of tumors in the non-MSI subtypes expressed significant MMRd-ams and were categorized in the High MMRd-ams group. Patients in the High MMRd-ams group had longer progression-free survival (PFS) ( p = 0.0457, log-rank). Analysis of the inferred composition of tumor immune infiltrates revealed that the High MMRd-ams group had significantly higher fraction of CD8+ T cells ( p < 0.0001), higher fraction of T follicular helper cells ( p < 0.0001) and lower fraction of M2 macrophages ( p < 0.001). Tumors in the High MMRd-ams group also displayed higher mRNA expression levels of immune checkpoint genes: PDCD1 ( p = 0.0013), and CTLA4 ( p = 0.0016). Conclusions: MMRd-ams may be a prognostic and predictive biomarker with significant clinical impact. High MMRd-ams patients prognostically demonstrated longer PFS. Predictively, high MMRd-ams was associated with increased tumor immune infiltrates and elevated expression levels of CTLA4 and PDCD1 , known immune checkpoint genes exploitable by immune checkpoint therapies. MMRd-ams importantly characterized a subset of patients that were non-MSI but fit the MMR deficient phenotype by mutational signature. Together these findings open an avenue for recognizing and treating a previously unidentifiable group of patients.
A phase I study of mirvetuximab soravtansine (MIRV) and gemcitabine (G) in patients (Pts) with selected frα-positive solid tumors: Results in the ovarian cancer (EC) cohort.
Authors: Cristea Mihaela C. , Ruel Nora H. , Frankel Paul Henry , Synold Timothy W. , Stewart Daphne B. , Wang Edward Wenge , Jung Alex , Wilczynski Sharon , Tran Michael , Konecny Gottfried E. , Eng Melissa , Kilpatrick Lindsay , Chen Yi-Jen , Glaser Scott , Dellinger Thanh Hue , Hakim Amy , Lee Stephen , Morgan Robert , Han Ernest Soyoung 
Published: June 2021

5542 Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. MIRV has promising single agent activity in FRα-positive medium/high expression epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. This study evaluated MIRV and G in recurrent EOC, endometrial and triple negative breast cancer. The recommended phase 2 dose (RP2D) was established at MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8 q21 days (J Clin Oncol 37, 2019, Abs. #3009). Here we report the results from the EOC cohort. Methods: Patients (pts) with FRα-positive platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, were eligible. FRα positivity was initially defined as ≥ 25% of cells with PS2+ staining intensity (low to high FRα expression) and was subsequently revised to require medium/high FRα expression (≥50%/ ≥75% of cells with PS2+ staining intensity). Results: From 10/2017 to 12/2020, 113 EOC pts underwent FRα screening, with 74 FRα-positive results. Thirty total EOC pts (with median 3 prior lines of therapy) were treated; 8 pts during dose escalation and 22 EOC pts at the RP2D (all evaluable for response). Fifteen (50%) pts had high FRα, 10 pts (33%) medium FRα, and 5 pts (17%) low FRα expression. Eleven (36%) of the 30 EOC pts achieved a partial response (PR), 15 pts (50%) had SD and 4 pts (13%) progressed. Among the 11 responders, 5 pts had high FRα, 4 pts medium FRα and 2 pts low FRα expression. Non-heme clinically significant adverse events (AEs) included: G2 sensory neuropathy (4 pts) G3 diarrhea (3 pts), G3 fatigue (2 pts), G3 pneumonitis (2 pts), and 1 pt with G5 respiratory failure (secondary to pneumonia but drug-induced pneumonitis could not be ruled out). Conclusions: MIRV in combination with G has promising clinical activity in late line platinum resistant FRα-positive EOC, with best responses observed in high FRα expression. The regimen is well tolerated with expected AEs based on the known toxicities of each agent. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825.
Role of CD10 expression in endometriosis-associated mesenchymal stem cells on the progression of endometriosis-associated carcinoma.
Authors: Atiya Huda , Orellana Taylor , Coffman Lan Gardner 
Published: June 2021

5561 Background: Endometriosis-associated carcinomas (EACs) such as ovarian clear cell cancer (OCCC) are rare, aggressive, chemo-resistant malignancies. While endometriosis is a known chronic inflammatory condition, the molecular mechanisms for the malignant transformation of endometriosis is unknown. Mesenchymal stem cells (MSC) are a critical component of the ovarian cancer microenvironment. Cancer cells reprogram MSCs to form carcinoma-associated MSCs (CAMSCs), which promote cancer growth, chemotherapy resistance, and metastases. MSCs are also found within the endometriotic microenvironment. CD10, a surface protein expressed by endometrial stromal cells, is also expressed on endometriosis-associated MSCs (enMSCs). Preliminary data demonstrate CD10 expression is lost in a subset of enMSCs and this loss is correlated with the acquisition of tumor-promoting properties. We hypothesized that the CD10 negative subset of enMSCs behave similarly to CAMSCs and support the growth of OCCC. Methods: EnMSCs were isolated from primary human benign endometriosis deposits involving the ovary or fallopian tubes. Flow cytometry was used to measure surface CD10 expression. We investigated the role of low CD10 enMSCs versus high CD10 enMSCs on OCCC tumor cell growth, chemotherapy resistance and stem-like cell properties in vitro and tumor cell engraftment, growth, and metastases in vivo. Luciferase-expressing OCCC cells were (1) used alone, (2) mixed with low CD10 enMSCs, or (3) mixed with high CD10 enMSCs and injected orthotopically into the ovarian bursa of NSG mice. In vivo imaging system was used to follow tumor progression and metastasis. Results: Our results demonstrated that enMSCs have variable CD10 expression. EnMSCs with low CD10 expression significantly enhanced OCCC proliferation, resistance to cisplatin, and sphere formation compared to OCCC alone. In contrast, high CD10 expressing enMSCs significantly reduce OCCC proliferation and sphere formation. Interestingly, low CD10 enMSCs selectively enhanced OCCC cell growth and had no effect on high grade serious ovarian cancer cell growth. Moreover, a reduction of CD10 expression was observed over time when high CD10 enMSCs were co-cultured with OCCC cells. Our results also showed enhanced tumor engraftment when OCCC cells were co-injected with low CD10 enMSCs to 100% one week post-injection, compared to 40% with OCCC and high CD10 enMSCs and 60% with OCCC alone. Further, mice co-injected with low CD10 enMSCs demonstrated increased metastasis and decreased survival compared to mice co-injected with high CD10 enMSCs. Conclusions: Our results indicate there is a sub population of enMSCs, marked by decreased CD10 expression, which selectively enhances OCCC growth. This highlights the existence of a tumor-promoting stromal cell within endometriosis which may be critical to the formation and propagation of EACs.
A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer.
Authors: Soliman Hatem Hussein , Han Hyo S. , Hogue Deanna , Mooney Blaise , Costa Ricardo L , Lee Marie Catherine , Niell Bethany , Williams Angela , Chau Alec , Falcon Shannon , Khakpour Nazanin , Soyano Aixa , Armaghani Avan J. , Weinfurtner Robert J , Hoover Susan , Kiluk John , Rosa Marilin , Fridley Brooke , Khong Hung T. , Czerniecki Brian J. 
Published: June 2021

578 Background: TVEC is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of unresectable cutaneous and nodal melanoma. TVEC is designed to preferentially lyse tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report results of a phase 2 trial combining NAC with TVEC in stage 2-3 TNBC. Methods: Stage II-III TNBC pts (N = 37) were to be enrolled into a single arm, optimal Simon 2 stage phase 2 trial with TVEC (10^6 PFU 1st dose then 10^8 PFU x 4 doses) weeks 1,4,6,8,10 + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone given preoperatively. Primary endpoint was residual cancer burden 0 rate (RCB0). Trial meets primary endpoint with ≥15 RCB0 responses out of 37 evaluable pts, assuming p1 = 45% vs. p0 = 30% with one sided type I error rate at 0.10 and power at 70%. Results: Forty pts were enrolled at Moffitt (5/2018 – 4/2020) and evaluable for safety with 3 pts non-evaluable for efficacy due to incomplete treatment. Study demographics: median age 49 (27-66), 67.5% White, 10% Black, 15% Hispanic, clinical stage II 83% and III 17%, node + 42%. The RCB0 rate = 16/37 (43%, 95% CI 27-61%) and additional 9 pts with RCB-1 (RCB0/1 rate 68%, 95% CI 50-82%). Toxicities did not differ significantly from expected NAC toxicities except for increased brief G1-2 fevers, chills, injection site pains. Four pts had G2-3 thromboembolic events (10%) slightly greater than expected 6% rate on NAC. Conclusions: Addition of TVEC to NAC increased RCB0 rates with manageable toxicities and warrants additional investigation in TNBC. Immune correlates and updated survival data will be presented at the meeting. Clinical trial information: NCT02779855.
Does timing of chemotherapy impact breast satisfaction after breast conservation therapy and mastectomy with immediate reconstruction?
Authors: Pawloski Kate R. , Moo Tracy-Ann , Sevilimedu Varadan , Nelson Jonas A. , Garcia Paula , Kirstein Laurie J. , Morrow Monica , Tadros Audree B. 
Published: June 2021

589 Background: Receipt of chemotherapy is associated with decreased postoperative breast satisfaction, but whether timing as neoadjuvant (NAC) versus adjuvant (AC) affects this outcome after breast conservation therapy (BCT) and mastectomy with immediate reconstruction (M-IR) is unclear. Methods: We retrospectively identified patients treated with chemotherapy and breast surgery (BCT and M-IR), from 1/2017-12/2019, who completed ≥ 1 BREAST-Q survey through 12/2020. Mean (standard deviation [SD]) Q-scores for satisfaction with breasts (SATBR) were compared between NAC versus AC groups in BCT and M-IR cohorts, respectively. Higher Q-scores on a 0-100 scale indicate superior satisfaction. A minimum 4-point difference was considered clinically important. Chemotherapy timing and significant covariates on univariate analyses were entered in multivariable linear regressions of 1- and 2-year SABTR. Results: 640 patients had BCT and 602 had M-IR; 210 (33%) BCT patients and 294 (49%) M-IR patients had NAC. Compared with M-IR, SATBR was higher after BCT in both NAC and AC groups, at all postoperative timepoints (Table). Following BCT, SABTR was highest in both NAC and AC groups at 6 months and returned to baseline in the NAC group by year 3. In the M-IR cohort, 331 (55%) patients had radiation and 120 (20%) had complications requiring re-operation or hospitalization. Compared with baseline, mean (SD) Q-scores were substantially lower at 6 months but improved to near baseline at 3 years in both NAC and AC groups. On multivariable analysis, radiation was associated with decreased SABTR at 1 year (Beta, -11; 95% CI, -17, -5.0; p<0.001) and 2 years (Beta, -12; 95% CI, -19, -5.5; p<0.001), as were complications at 1 year (Beta, -6.1; 95% CI, -12, -0.34; p=0.038) but not 2 years (Beta, -5.5; 95% CI, -12, 0.92; p=0.09). After multivariable adjustment, NAC was not significantly associated with 1- or 2-year SABTR after M-IR or BCT. Conclusions: SABTR was higher in BCT compared with M-IR cohorts, independent of chemotherapy timing. Following BCT, SABTR was lower in the NAC group at years 2-3 but remained at baseline or higher at all timepoints. In the M-IR cohort, both groups endorsed lower than baseline SABTR in years 0-2 but returned to near baseline at 3 years. Radiation and complications were independent predictors of decreased SABTR, but our findings suggest that patients who experience complications after M-IR can expect return to baseline breast satisfaction by 2 years.[Table: see text]