Citations

TPS624 Background: Abemaciclib (LY2835219), a cell cycle inhibitor of CDK4/CDK6, demonstrated a clinically manageable safety profile and single-agent anti-tumor activity in MBC; all tumor responses were observed in hormone receptor positive (HR+) disease (Tolaney SM, Rosen LS, Beeram M, et al. San Antonio Breast Cancer Symposium, 2014, Abstract P5-19-13). Non-steroidal aromatase inhibitors (NSAI, letrozole and anastrazole), approved in the first-line setting for postmenopausal women with HR+ MBC, are being evaluated in combination with abemaciclib for safety and tolerability in a phase Ib study (NCT02057133) and in the present study (NCT02246621) to assess clinical efficacy. Methods: MONARCH 3 is a randomized, double-blind, placebo-controlled, phase III study of abemaciclib + NSAI vs placebo + NSAI in locoregionally recurrent (not amenable to curative treatment) breast cancer or MBC, with no prior systemic therapy in this disease setting. Patients will be randomized 2:1, and stratified by nature of disease (visceral vs bone-only metastases vs other) and prior (neo)adjuvant endocrine therapy (aromatase inhibitor vs other vs none). Abemaciclib 150 mg or placebo will be given continuously PO every 12 hours until progression, along with anastrozole 1 mg or letrozole 2.5 mg once daily at the investigator’s discretion, and assessments will occur every 28 days. Postmenopausal women with HR+, HER2- disease, a disease-free interval > 12 mos after completion of (neo)adjuvant endocrine therapy, ECOG PS ≤ 1, adequate organ function, and measurable disease or nonmeasurable bone-only disease (RECIST v1.1) are eligible. The primary endpoint is progression-free survival (PFS); a key secondary endpoint is overall survival (OS). The study has 80% power to detect an increase in PFS of approximately 40% (hazard ratio = 0.714). Assuming a median PFS of 10 mos in the control arm, this corresponds to a 4-mo increase in the median PFS. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%. Enrollment began November 2014; planned enrollment is 450 patients. Clinical trial information: NCT02246621.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disorder which leads to progressive fibrosis and lung failure within 2-5 years1,2. Approximately 30% of IPF patients develop Chronic Kidney Disease (CKD) with renal dysfunction and fibrosis3. The treatment options for IPF are still limited and the disease is an unmet clinical need. The only animal model for IPF is represented by mice treated with bleomycin, a compound used for chemotherapy which has lung toxicity as its major adverse effect, that develop progressive fibrosis. Recent data indicate that bleomycin triggers lung fibrosis by increasing the release of the pro-inflammatory cytokine TGF-β by the resident megakaryocytes (MK)4. Using these observations as foundation, we investigated whetherGata1lowmice, a model for myelofibrosis induced by a TGF-β/P-selectin (P-sel) circuitry established by the abnormal MK5, includes fibrosis in lungs and kidney and whether these traits are rescued by genetic ablation (P-selnullmutation) and antibody neutralization (by RB40.34) of P-sel. MK were observed in lungs from wild-type (WT, n=9),Gata1low(n=22),P-selnull(n=4) andP-selnullGata1low(n=10) littermates. In frequency, MK were significantly lower inGata1low andP-selnullGata1lowthan in WT andP-selnulllittermates (median=1.3-1.5 vs 3-3.7/0.144mm2, p<0.003) and mostly immature. In addition, lungs and kidney fromGata1low mice, but not those from the other experimental groups, contained great levels of TGF- β (Fig.1). Interstitial pneumonia was observed in lungs from WT (n=12, age=3-13 months, males=8, females=4),P-selnull(n=9, age=3-16 months, males=4, females=5),Gata1low(n=29, age=2-24 months, males=16, females=13) andGata1lowP-selnull(n=18, age=3-16 months, males=7, females=11) mice while nephritis was observed only in kidneys fromGata1low mice. Controlling for the effects of sex, there are statistically significant differences in severity of inflammation in kidney (p=0.001) but not in lungs (p=0.86) betweenGata1low and WT mice. These results indicate that lung inflammation is a baseline condition of the CD1 background used for the study while kidney inflammation is a trait exclusive toGata1low mutants independently from their gender. Great levels of fibrosis were observed in lungs and kidney fromGata1low mice but not in those from WT littermates. There are statistically significant differences in lung (p=0.01) and kidney (p<0.001) fibrosis between the two groups; these differences remained after adjusting for age or sex. By contrast, there is insufficient evidence to conclude there exists a relationship between age and fibrosis grade in the other experimental groups. Age was found to be a statistically significant effect modifier on the relationship between genotype and fibrosis in lung (p=0.024) and kidney (0.004). In addition, although there is insufficient evidence for a relationship between sex and fibrosis grade in lung (p=0.62), there is a statistically significant effect of gender in kidney fibrosis inGata1low mice (p<0.001). These results indicate that fibrosis in lung and nephritis and fibrosis in kidney are novel traits ofGata1low mice developed independently from the underlying state of inflammation and which are rescued by ablation ofP-sel. To further clarify the role of P-sel in lung and kidney fibrosis, 14Gata1lowmice (7 males, 7 females) were treated with either vehicle (8 mice) or RB40.34 (30 μg/mouse/day per 3 days/week by tail vein injection as described6). Mice were sacrificed on day 5 (males) and 12 (females) and histopathology, inflammation, fibrosis and TGF-β content in lungs and kidney analyzed. Treatment with RB40.34 restored the morphology and reduced inflammation, fibrosis and TGF-β content in the lungs and in kidney with respect to vehicle (Fig.1). In conclusion, Gata1low mice are a novel animal model for IPF with CKD. The phenotype is associated with highTGF-βcontent in lung and kidney and is rescued by targeting P-sel, suggesting that treatment with antibodies against P-sel may cure IPF in man. REF: 1Richeldi et al.Lancet389: 1941, 2017; 2Hutchinson et al.EurRespirJ46, 795, 2015; 3Ikezoeet al.Respiration94: 346, 2017; 4Zhouet al.CellDeathDis10:648, 2019: 5Spangrudeet al.StemCells34: 67, 2016; 6Emburyet al.Blood104: 3378, 2004. Disclosures Migliaccio: Novartis:Research Funding.

Background The importance of the immune system in modulating the trajectory of lymphoma outcomes has been increasingly recognized. We recently showed that CD4+ cells are associated with clinical outcomes in a prospective cohort of almost 500 patients with follicular lymphoma (FL). Specifically, we showed that the absence of CD4+ cells inside follicles was independently associated with increased risk of early clinical failure. These data suggest that the composition, as well as the spatial distribution of immune cells within the tumor microenvironment (TME), play an important role in FL. To further define the architecture of the TME in FL we analyzed a FL tumor section using the Co-Detection by Indexing (CODEX) multiplex immunofluorescence system. Methods An 8-micron section from a formalin-fixed paraffin-embedded block containing a lymph node specimen from a patient with FL was stained with a cocktail of 15 CODEX antibodies. Five regions of interest (ROIs) were imaged using a 20X air objective. Images underwent single-cell segmentation using a Unet neural network, trained on manually segmented cells (Fig 1A). Cell type assignment was done after scaling marker expression and clustering using Phenograph. Each ROI was manually masked to indicate areas inside follicles (IF) and outside follicles (OF). Relative and absolute frequencies of cell types were calculated for each region. Cellular contacts were measured as number and types of cell-cell contacts within two cellular diameters. To identify proximity communities, we clustered cells based on number and type of neighboring masks using Phenograph. The number of cell types and cellular communities were calculated inside and outside follicles after adjustment for total IF and OF areas. The significance of cell contact was measured using a random permutation test. Results We identified 13 unique cell subsets (11 immune, 1 endothelial, 1 unclassified) in the TME of our FL section (Fig. 1A). The unique phenotype of each subset was confirmed using a dimensionality reduction tool (t-SNE). The global composition of the TME varied minimally across ROIs and consisted primarily of B cells, T cells, and macrophages subsets - in decreasing order of frequency. Higher spatial heterogeneity across ROIs was observed in the frequency of T cell subsets in comparison to B cells subsets. Inspecting the spatial distribution of T cell subsets (Fig. 1B), we observed that cytotoxic T cells were primarily located in OF areas, whereas CD4+ T cells were found in both IF and OF areas. Notably, the majority of CD4+ T cells inside the follicles expressed CD45RO (memory phenotype), while most of the CD4+ T cells outside the follicles did not. Statistical analysis of the spatial distribution of CD4+ memory T cell subsets confirmed a significant increase in their frequency inside follicles compared to outside (20.4% vs 11.2%, p < 0.001; Fig. 1D). Cell-cell contact analysis (Fig 1C) showed increased homotypic contact for all cell types. We also found a higher frequency of heterotypic contact between Ki-67+CD4+ memory T cells and Ki-67+ B cells. Pairwise analysis showed these findings were statistically significant, indicating these cells are organized in niches rather than randomly distributed across image. Analysis of cellular communities (Fig. 1C) identified 13 niches, named according to the most frequent type of cell-cell contact. All CD4+ memory T cell subsets were found to belong to the same neighborhood (CD4 Memory community). Analysis of the spatial distribution of this community confirmed that these niches were more frequently located inside follicles rather than outside (26.3±4% vs 0.004%, p < 0.001, Fig. 1D). Conclusions Analysis of the TME using CODEX provides insights on the complex composition and unique architecture of this FL case. Cells were organized in a pattern characterized by (1) high degree of homotypic contact and (2) increased heterotypic interaction between activated B cells and activated CD4+ memory T cells. Spatial analysis of both individual cell subsets and cellular neighborhoods demonstrate a statistically significant increase in CD4+ memory T cells inside malignant follicles. This emerging knowledge about the specific immune-architecture of FL adds mechanistic details to our initial observation around the prognostic value of the TME in this disease. These data support future studies using modulation of the TME as a therapeutic target in FL. Figure 1 Disclosures Galkin: BostonGene: Current Employment, Patents & Royalties. Svekolkin:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Postovalova:BostonGene: Current Employment, Current equity holder in private company. Bagaev:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Ovcharov:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Varlamova:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Novak:Celgene/BMS: Research Funding. Witzig:AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Ansell:Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

Abstract Aim Female urethral stricture disease is rare and has several surgical approaches including endoscopic dilations (ENDO), urethroplasty with local vaginal tissue flap (ULT) or urethroplasty with free graft (UFG). This study aims to describe the contemporary management of female urethral stricture disease and to evaluate the outcomes of these three surgical approaches. Methods This is a multi‐institutional, retrospective cohort study evaluating operative treatment for female urethral stricture. Surgeries were grouped into three categories: ENDO, ULT, and UFG. Time from surgery to stricture recurrence by surgery type was analyzed using a Kaplan–Meier time to event analysis. To adjust for confounders, a Cox proportional hazard model was fit for time to stricture recurrence. Results Two‐hundred and ten patients met the inclusion criteria across 23 sites. Overall, 64% ( n = 115/180) of women remained recurrence free at median follow‐up of 14.6 months (IQR, 3–37). In unadjusted analysis, recurrence‐free rates differed between surgery categories with 68% ENDO, 77% UFG and 83% ULT patients being recurrence free at 12 months. In the Cox model, recurrence rates also differed between surgery categories; women undergoing ULT and UFG having had 66% and 49% less risk of recurrence, respectively, compared to those undergoing ENDO. When comparing ULT to UFG directly, there was no significant difference of recurrence. Conclusion This retrospective multi‐institutional study of female urethral stricture demonstrates that patients undergoing endoscopic management have a higher risk of recurrence compared to those undergoing either urethroplasty with local flap or free graft.

Abstract Background: Racial disparities in breast cancer outcomes persist in the US, in which black women are more likely to die from breast cancer than white women. Despite levels of mammographic screening comparable to the US, Atlanta has a disproportionate burden of late-stage breast tumors and higher mortality rates, especially among black women. To better understand this disparity, we sought to identify tumor, treatment, and patient characteristics that may contribute to the observed differences in breast cancer mortality between black and white women in the metropolitan Atlanta area. Methods: In this study, patients were identified from the Georgia Cancer Registry. We included 4943 non-Hispanic white and 3580 non-Hispanic black women with an initial diagnosis of stage I-IV primary breast cancer between January 2010 and December 2014 in Atlanta. Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare black vs. white breast cancer mortality by tumor (stage, grade, ER status, and molecular subtype), treatment (surgery type, receipt of chemotherapy, radiation, hormone therapy, and trastuzumab), and patient (insurance, marital status, SES, and location of service) characteristics. We performed a mediation analysis to evaluate the contribution of subtype, stage, and socioeconomic status (SES) as mediators on the path between race and breast cancer mortality. Results: Compared with white breast cancer patients, black women were younger with tumors that were higher stage, higher grade, and more likely to be larger, node positive and triple negative. In fully adjusted models, black women diagnosed with Luminal A subtype were 58% more likely to die of breast cancer compared to their white counterparts (HR=1.58, 95%CI 1.31-2.00). Similarly, black women with private insurance were 60% more likely to die of breast cancer (HR=1.61, 95%CI 1.25-1.98), and black women in the highest SES group were more than twice as likely to die from breast cancer (HR=2.26, 95%CI 1.26-4.06) than white women with comparable SES. The smallest disparities in breast cancer mortality by race were observed among women without insurance, in the lowest SES index, or those diagnosed with triple-negative breast cancer. The mediation analysis showed 84.8% of the effect between race and breast cancer mortality was through stage, subtype, and SES. Conclusion: Our results indicate variation in racial disparities in breast cancer mortality by tumor and patient characteristics. Consistent with previous reports, our mediation results suggest that later stage and triple-negative subtype among black women are major contributors of the observed disparity. However, our results also shed new light on the disparity, suggesting that the largest disparities are observed among women with ER+ tumors amenable to adjuvant therapies and are most pronounced among women of high SES. More research is needed to understand the drivers of disparities in these treatable tumors. Citation Format: Lindsay J. Collin, Renjian Jiang, Kevin C. Ward, Keerthi Gogineni, Preeti D. Subhedar, Mark Sherman, Mia M. Gaudet, Carmen Radecki Breitkopf, Olivia D'Angelo, Sheryl Gabram-Mendola, Jolie Siegel, Rana Aneja, Anne Gaglioti, Lauren E. McCullough. Identification of factors contributing to breast cancer mortality disparities in the metropolitan Atlanta area [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C053.

AbstractUtility of adjuvant chemotherapy for stage II cancer remains a matter of debate. Clinical guidelines suggest adjuvant chemotherapy for stage II tumors with high‐risk features, in particular T4 tumors. However, limited consensus exists regarding the importance of other high‐risk features (lymphovascular or perineural invasion, microsatellite instability). Our study aimed to investigate the impact of adjuvant chemotherapy for stage IIA (T3N0) colon cancer patients. Patients who underwent colectomy for stage IIA colon adenocarcinoma (2010‐2015) were identified in the National Cancer Database (NCDB) and divided in two groups based on receipt of adjuvant chemotherapy vs observation. Inverse probability of treatment weighting (IPTW)‐adjusted Kaplan‐Meier and Cox proportional hazards regression analyses were performed to compare overall survival between the two groups. Subgroup analysis of patients with specific high‐risk features LVI, PNI and MSI was performed. Among 46 688 surgical patients with stage IIA colon adenocarcinoma 5937 (12.7%) received adjuvant chemotherapy, while 40 751 (87.3%) were observed. Five‐year IPTW‐adjusted survival was higher in the adjuvant chemotherapy group (79.7% [95% CI 79.1, 80.2]) compared to the observation group (70.3% [95% CI 69.7, 70.9]). Patients with high‐risk pathological features showed an estimated 5‐year survival benefit of 11.3% (78.2% [95% CI 77.4, 79.1] vs 66.9% [95% CI 65.9, 67.8]) when treated with adjuvant chemotherapy. This NCDB analysis revealed a survival benefit for patients with stage IIA colon adenocarcinoma and high‐risk features that were treated with adjuvant chemotherapy.

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.