Cancer Consortium

High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is widely used for the treatment of malignant disease. CD34 selection of PBSC has been applied as a means of reducing contamination of the graft. Although CD34 selection results in a 2 to 3 log reduction in contaminating tumor cells without significantly delaying engraftment, many other types of cells are depleted from the CD34-enriched grafts and immune reconstitution may be impaired. In the present study, 31 cytomegalovirus (CMV)-seropositive patients who received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV disease in the first 100 days posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients (12.9%) died from complications of their infection. In a contemporaneous group of 237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10 patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate logistic regression analysis, the use of CD34-selected autologous PBSC after high-dose therapy was associated with a marked increase in the incidence of CMV disease and CMV-associated deaths.

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.

Tractable human tissue-engineered 3D models of cancer that enable fine control of tumor growth, metabolism, and reciprocal interactions between different cell types in the tumor microenvironment promise to accelerate cancer research and pharmacologic testing. Progress to date mostly reflects the use of immortalized cancer cell lines, and progression to primary patient-derived tumor cells is needed to realize the full potential of these platforms. For the first time, we report endothelial sprouting induced by primary patient tumor cells in a 3D microfluidic system. Specifically, we have combined primary human clear cell renal cell carcinoma (ccRCC) cells from six independent donors with human endothelial cells in a vascularized, flow-directed, 3D culture system ("ccRCC-on-a-chip"). The upregulation of key angiogenic factors in primary human ccRCC cells, which exhibited unique patterns of donor variation, was further enhanced when they were cultured in 3D clusters. When embedded in the matrix surrounding engineered human vessels, these ccRCC tumor clusters drove potent endothelial cell sprouting under continuous flow, thus recapitulating the critical angiogenic signaling axis between human ccRCC cells and endothelial cells. Importantly, this phenotype was driven by a primary tumor cell-derived biochemical gradient of angiogenic growth factor accumulation that was subject to pharmacological blockade. Our novel 3D system represents a vascularized tumor model that is easy to image and quantify and is fully tunable in terms of input cells, perfusate, and matrices. We envision that this ccRCC-on-a-chip will be valuable for mechanistic studies, for studying tumor-vascular cell interactions, and for developing novel and personalized antitumor therapies.

BACKGROUND: Although Latinos, African-Americans, and American Indians/Alaska Natives comprise 34% of Americans, these under-represented minorities (URMs) account for only 7% of US medical-school faculty. Even when URMs become faculty, they face many substantial challenges to success. Little has been published, however, on keys to academic success for URM young faculty investigators. METHODS: The Research in Academic Pediatrics Initiative on Diversity (RAPID) goal is to enhance the professional advancement of URM junior faculty pursuing research careers in general academic pediatrics. One important RAPID component is the annual mentoring/career-development conference, which targets URM residents, fellows, and junior faculty, and has included 62 URM participants since its 2013 inception. A conference highlight is the panel discussion on keys to academic success for URM young investigators, conducted by the RAPID National Advisory Committee, a diverse group of leading senior researchers. The article aim was to provide a guide to academic success for URM young investigators using the 2018 RAPID Conference panel discussion. A modified Delphi technique was used to provide a systematic approach to obtaining answers to six key questions using an expert panel: the single most important key to success for URM young investigators; ensuring optimal mentorship; how to respond when patients/families say, "I don't want you to see my child because you are ____"; best strategies for maximizing funding success; how to balance serving on time-consuming committees with enough time to advance research/career objectives; and the single thing you wish someone had told you which would have substantially enhanced your success early on. RESULTS/CONCLUSIONS: This is the first published practical guide on keys to academic success for URM young investigators. Identified keys to success included having multiple mentors, writing prolifically, being tenaciously persistent, having mentors who are invested in you, dealing with families who do not want you to care for their child because of your race/ethnicity by seeking to understand the reasons and debriefing with colleagues, seeking non-traditional funding streams, balancing committee work with having enough time to advance one's research and career by using these opportunities to generate scholarly products, and asking for all needed resources when negotiating for new jobs.

PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41-79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6-6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5-4.2). CONCLUSIONS: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

BACKGROUND: Rural populations experience a disproportionate cancer burden relative to urban populations. One possibility is that rural populations are more likely to hold counterproductive cancer beliefs such as fatalism and information overload that undermine prevention and screening behaviors. METHODS: = 6,541). All participants were 18 and older (M = 56.97, SD = 16.55), predominately non-Hispanic White (81%), and female (57%). Participants completed three items measuring cancer fatalism ("It seems like everything causes cancer," "There's not much you can do to lower your chances of getting cancer," and "When I think about cancer, I automatically think about death") and one item measuring cancer information overload ("There are so many different recommendations about preventing cancer, it's hard to know which ones to follow"). RESULTS: Compared with urban residents, rural residents were more likely to believe that (i) everything causes cancer (OR = 1.29; 95% CI, 1.17-1.43); (ii) prevention is not possible (OR = 1.34; 95% CI, 1.19-1.51); and (iii) there are too many different recommendations about cancer prevention (OR = 1.26; 95% CI, 1.13-1.41), and cancer is always fatal (OR = 1.21; 95% CI, 1.11-1.33). CONCLUSIONS: Compared with their urban counterparts, rural populations exhibited higher levels of cancer fatalism and cancer information overload. IMPACT: Future interventions targeting rural populations should account for higher levels of fatalism and information overload.

INTRODUCTION: Carbonic anhydrase IX (CAIX) is a hypoxia regulated metalloenzyme integral to maintaining cellular pH. Increased CAIX expression is associated with poor prognosis in breast cancer. To explore CAIX as a biomarker for breast cancer therapies, we measured plasma CAIX levels in healthy control subjects and in breast cancer patients. METHODS: In control subjects we evaluated plasma CAIX stability via commercially available ELISA. We then similarly quantified plasma CAIX levels in (1) locally advanced breast cancer (LABC) patients treated with neoadjuvant paclitaxel + sunitinib (T + S) followed by doxorubicin and cyclophosphamide (AC); (2) metastatic breast cancer (MBC) patients treated with systemic chemotherapy. RESULTS: Plasma CAIX levels were stable at room temperature for at least 48 hours in control subjects. Mean baseline plasma CAIX levels were lower in controls compared to patients with LABC or MBC. In LABC, CAIX levels rose significantly in response to administration of antiangiogenic therapy (T + S) (p = 0.02) but not AC (p = 0.37). In patients with MBC treated without an antiangiogenic agent CAIX levels did not change with therapy. CONCLUSIONS: Our results suggest that CAIX may be an easily obtained, stable measure of tumor associated hypoxia as well as a useful pharmacodynamic biomarker for antiangiogenic therapy.

Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. SIGNIFICANCE: T cell-engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors.

High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is widely used for the treatment of malignant disease. CD34 selection of PBSC has been applied as a means of reducing contamination of the graft. Although CD34 selection results in a 2 to 3 log reduction in contaminating tumor cells without significantly delaying engraftment, many other types of cells are depleted from the CD34-enriched grafts and immune reconstitution may be impaired. In the present study, 31 cytomegalovirus (CMV)-seropositive patients who received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV disease in the first 100 days posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients (12.9%) died from complications of their infection. In a contemporaneous group of 237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10 patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate logistic regression analysis, the use of CD34-selected autologous PBSC after high-dose therapy was associated with a marked increase in the incidence of CMV disease and CMV-associated deaths.

Abstract Background: The addition of CDK4/6, PI3K-α, or mTOR inhibitors to endocrine therapy (ET) improves progression free survival (PFS) in first and later lines of therapy for estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC). We hypothesized that simultaneous inhibition of these pathways would improve treatment efficacy. We conducted a phase Ib study of triplet therapy with gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6 inhibitor, and ET with letrozole (L) or fulvestrant (F) in women with ER+/HER2-negative MBC. Manageable toxicity and preliminary antitumor activity were observed in 35 patients enrolled on the dose escalation portion of the study (ASCO 2018). We now report results from the dose expansion study arms. Methods: Patients with ER+/HER2- MBC were treated in four-arms: A) G+P+L as first-line treatment, B) G+P+F as 2-line treatment in patients without prior CDK4/6 inhibitor therapy; C) G+P+F in patients with prior CDK4/6 inhibitor therapy; D) G+P+F in patients whose most recent regimen included a CDK4/6 inhibitor. Palbociclib, letrozole and fulvestrant were administered at standard doses. Gedatolisib 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. Pre-/peri-menopausal women received ovarian suppression. The primary endpoint was objective response assessed by the investigator. Secondary endpoints included safety, duration of response (DOR), and PFS.Results: A total of 103 patients were enrolled: Arm A (n=31); Arm B (n=13); Arm C (n=32); Arm D (n=27). Median age was 54, 62, 59.5, and 59 years in each arm respectively. Progressed on last line of endocrine therapy in < 6 months (refractory): Arms B: 4/13 (31%), Arm C: 15/32 (47%), Arm D: 7/27 (26%). ORR in evaluable patients, including unconfirmed responses: 84%; 75%, 33% and 64%. Median PFS (months) was not reached in Arm A, and for arms B, C and D was 11.9, 5.1, 12.9 respectively. Most common (≥50%), treatment emergent adverse events (TEAE) across all arms were: nausea 81.6% (all Gr1-2, no ≥Gr3), stomatitis 80.6% (27.2% Gr3), fatigue 79.6% (10.7% Gr3), vomiting 51.5 % (1% Gr3), neutropenia/neutrophil count decrease 79.6% (66.7% ≥Gr3). Most common (≥2%) treatment emergent SAEs were febrile neutropenia 4.9%, acute kidney injury and pyrexia 2.9% each. Hyperglycemia was reported in 26.2% (6.8% ≥Gr3) of patients regardless of relation to treatment. Most common reason for treatment discontinuation was disease progression.; 8.7% (9 out of 103) patients discontinued therapy due to a related AE across all arms. No treatment discontinuation due to TEAE and no SAE of stomatitis were observed in Arm D. Seventeen patients are continuing therapy at the time of data cut of May 10, 2021.Conclusions: The addition of Gedatolisib to palbociclib and endocrine therapy demonstrated promising antitumor activity in both first and later line settings for ER+ MBC that compared favorably to historical controls. Responses were also observed in patients refractory to the last treatment. Therapy was well tolerated with manageable toxicity and low number of treatment discontinuation due to related AE. The favorable safety profile and antitumor activity observed in patients treated with the three weeks on/one week off gedatolisib regimen supports use of this dosing schedule in future studies. A phase 3 study evaluating gedatolisib in patients with ER+/HER2- MBC is planned. Table 1.Arm A, n=31Arm B, n=13Arm C, n=32Arm D, n=27EfficacyEvaluable for response25122725ORR in evaluable patients84% (21/25)75% (9/12)33% (9/27)64% (16/25)DCR (CR, PR, SD)92%92%48%85%Treatment DiscontinuationAll64.5% (20/31)76.9% (10/13)100% (32/32)85.2% (23/27)PD/general deterioration38.7% (12/31)61.5% (8/13)75% (24/32)70.4% (19/27)TEAE (related)9.7% (3/31)7.7% (1/13)12.5% (4/32)3.7% (1/27)Stomatitis3.2% (1/31)7.7% (1/13)9.4% (3/32)0TEAE (not related)07.7% (1/13)00Withdrew9.7% (3/31)012.5% (4/32)0Other6.5% (2/31)0011.1% (3/27)Treatment Emergent SAEAll22.6% (7/31)30.8% (4/13)21.9% (7/32)14.8% (4/27)Stomatitis3.2% (1/31)000 Citation Format: Rachel Layman, Robert Wesolowski, Hyo Han, Jennifer M Specht, Erica M Stringer-Reasor, E. Claire Dees, Peter Kabos, Ingrid A Mayer, Ulka Vaishampayan, Janice Lu, Keerthi Gogineni, Aditya Bardia, Anne F Schott, Maysa Abu-Khalaf, Doug Howkins, Brian Sullivan, Igor Gorbatchevsky, Hope Rugo. Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-02.

PURPOSE: The purpose of this study was to establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance. EXPERIMENTAL DESIGN: We identified high-mobility group A2 (HMGA2) protein expression in basal PDAC cells in a single-cell RNA sequencing (RNA-seq) atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classic marker GATA-binding factor 6 (GATA6), in a cohort of 580 PDAC samples with multiplex IHC. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNA-seq databases. RESULTS: We found that expression of HMGA2, but not previously described basal markers cytokeratins 5 or 17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 statuses allowed for the identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n = 94, median survival = 11.2 months after surgery) and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n = 198, median survival = 21.7 months after surgery). HMGA2 was also prognostic for overall survival in RNA-seq from an independent cohort. CONCLUSIONS: IHC stratification of primary tumors by HMGA2 and GATA6 statuses in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.

PURPOSE: Patients with Kirsten rat sarcoma viral oncogene (KRAS)-mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on the activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated, advanced KRAS-mutant NSCLC. PATIENTS AND METHODS: The primary outcomes of this multicenter phase I/II dose-escalation trial of selinexor plus docetaxel were safety and tolerability. Selinexor was started 1 week before docetaxel to permit monotherapy pharmacodynamic assessment. RESULTS: Among 40 enrolled patients, the median age was 66 years, 55% were female, and 85% were White. The MTD was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every 3 weeks. The most common adverse events were nausea (73%, 8% grade ≥3), fatigue (70%, 5% grade ≥3), neutropenia (65%, 60% grade ≥3), and diarrhea (58%, 10% grade ≥3). Of 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild-type TP53 (42%), including response and disease control rates (27% and 80% vs. 9% and 27%, respectively; P = 0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% confidence interval, 0.07-0.67; P = 0.003). After selinexor initiation and prior to docetaxel administration, serum lactate dehydrogenase levels increased an average of 51 U/L in TP53-altered cases and decreased an average of 48 U/L in TP53 wild-type cases (P = 0.06). CONCLUSIONS: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS-mutant NSCLC. The regimen has promising efficacy in TP53 wild-type cases, in which selinexor monotherapy may also have activity.

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. SIGNIFICANCE: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. Although HER2-directed therapies like fam-trastuzumab deruxtecan are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer and urothelial carcinoma remains inadequately characterized. We evaluated HER2 protein expression in metastatic prostate cancer and urothelial carcinoma using a validated IHC assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the prostate cancer cohort (n = 52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only five (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy-number gains were observed in some tumors but did not correlate with HER2 protein expression (P = 0.2). In urothelial carcinoma (n = 20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in six (30%) cases and 3+ expression observed in three (15%) cases in at least one tumor. Urothelial carcinoma samples showed less heterogeneity, with more consistent expression across metastases. HER2 overexpression is rare and heterogeneous in metastatic prostate cancer, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in urothelial carcinoma. These findings underscore the importance of comprehensive HER2 assessment in advanced urothelial carcinoma and suggest that success of HER2-directed therapies in prostate cancer will require careful case selection. SIGNIFICANCE: This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer and suggest that HER2-targeted therapies in prostate cancer will require careful patient selection.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTA) are first-line chemotherapies for TNBC; however, the molecular mechanisms that underlie TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent with the mitotic stress caused by PTPN12 inactivation in TNBC cell lines, tumors harboring loss of PTPN12 exhibit heightened sensitivity to taxane chemotherapy. Collectively, these data suggests that PTPN12 inactivation may drive chromosomal instability and favorable MTA response in TNBC-two prominent features of the disease with unclear mechanistic etiology. SIGNIFICANCE: Many TNBCs respond to MTAs, but the underlying cause(s) of this sensitivity remain poorly understood. Herein, we discover that the tumor suppressor PTPN12 regulates mitotic fidelity and MTA sensitivity in a large subset of patients with TNBC, which has significant implications for the use of MTAs in breast cancer.

BACKGROUND: FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to FXIIa (activated factor XII) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii ) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKS (kallikrein-kinin system) and to determine the downstream consequences on thromboinflammatory responses. METHODS: The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA. RESULTS: We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture. CONCLUSIONS: These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and kallikrein-kinin pathways and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

The ability to serially monitor tumor-derived cell-free DNA (cfDNA) brings with it the potential to measure response to anticancer therapies and detect minimal residual disease (MRD). This report describes a patient with HER2-positive metastatic breast cancer with an exceptional response to trastuzumab and nab-paclitaxel who remains in complete remission several years after cessation of therapy. Next-generation sequencing of the patient's primary tumor tissue showed several mutations, including an oncogenic hotspot PIK3CA mutation. A sample of cfDNA was collected 6 years after her last therapy and then analyzed for mutant PIK3CA using digital PCR. No detectable mutations associated with the primary tumor were found despite assaying >10,000 genome equivalents, suggesting that the patient had achieved a molecular remission. Results of this case study suggest that serial monitoring of MRD using liquid biopsies could provide a useful method for individualizing treatment plans for patients with metastatic disease with extreme responses to therapy. However, large-scale clinical studies are needed to validate and implement these techniques for patient care.

This cohort study examines whether any sociodemographic characteristics or screening modalities are associated with adherence to guideline-based cervical cancer screening.