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Abstract Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Abstract Hematological malignancies are associated with an increased risk of complications during SARS-CoV-2 infections. Primary series or monovalent booster vaccines reduce disease severity, hospitalization, and death among multiple myeloma patients. We characterized virus-neutralizing and spike-binding antibody profiles following monovalent (WA1) or bivalent (WA1/BA.5) SARS-CoV-2 booster vaccination in MM patients. Bivalent vaccination improved the breadth of binding antibodies but not neutralization activity against contemporary variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Abstract Resistance to radiotherapy is a major barrier during cancer treatment. Here using genome-scale CRISPR/Cas9 screening, we identify CD274 gene, which encodes PD-L1, to confer lung cancer cell resistance to ionizing radiation (IR). Depletion of endogenous PD-L1 delays the repair of IR-induced DNA double-strand breaks (DSBs) and PD-L1 loss downregulates non-homologous end joining (NHEJ) while overexpression of PD-L1 upregulates NHEJ. IR induces translocation of PD-L1 from the membrane into nucleus dependent on deglycosylation of PD-L1 at N219 and CMTM6 and leads to PD-L1 recruitment to DSBs foci. PD-L1 interacts with Ku in the nucleus and enhances Ku binding to DSB DNA. The interaction between the IgC domain of PD-L1 and the core domain of Ku is required for PD-L1 to accelerate NHEJ-mediated DSB repair and produce radioresistance. Thus, PD-L1, in addition to its immune inhibitory activity, acts as mechanistic driver for NHEJ-mediated DSB repair in cancer.

Objective Immune checkpoint inhibitors (ICI) that block the programmed cell death 1 (PD-1) pathway have shown promise with limited benefit. We and others have shown in small patient cohorts that an early proliferative CD8 T-cell response in the blood may be predictive of clinical response. However, these studies lack detailed analyses and comparisons between monotherapy and combination therapies.Methods and analysis We analysed longitudinal blood samples from 103 patients with cancer who received αPD-1 monotherapy or combined with anti-cytotoxic T lymphocyte-associated protein 4 (αCTLA-4) or chemotherapy. Transcriptional analysis of CD8 T cells after the first treatment cycle with effector cells generated following yellow fever virus (YFV-17D) vaccine-induced infection was also compared.Results An early proliferative (Ki-67+) CD8 T-cell response was observed after cycle 1 in 60 patients (58.3%). Patients with early-and-sustained proliferative responses (cycle 1 and beyond) had better clinical responses and survival than patients with an early-but-limited response (p=0.02). The proliferating cells had an effector-like phenotype. The transcriptional profiles of the effector-like CD8 T cells were similar irrespective of treatment type or clinical response but distinct from that of YFV-specific effector CD8 T cells.Conclusions Our data suggest that early proliferative CD8 T-cell response in the blood is predictive, and that an early-and-sustained proliferative response may further identify patients with prolonged survival. The ICI-induced effector-like CD8 T cells are transcriptionally distinct from highly functional YFV-specific cells, suggesting opportunities for improved T-cell effector function with combination therapies for better clinical outcome.

IntroductionPost-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening malignancy that arises in the setting of immunosuppression (IS) after solid organ transplant. IS regimens containing belatacept have been associated with an increased risk of PTLD in Epstein–Barr virus (EBV)-seronegative renal transplant recipients, and the use of belatacept is contraindicated in this population. However, the impact of belatacept-based regimens on PTLD risk and outcomes in EBV-seropositive renal transplant recipients is less well characterized.MethodsA case-control study was conducted to investigate how combinatorial IS regimens impact the risk of PTLD and survival outcomes in renal transplant recipients at a large transplant center between 2010 and 2019. In total, 17 cases of PTLD were identified and matched 1:2 to controls without PTLD by age, sex, and transplanted organ(s). We compared baseline clinical characteristics, examined changes in IS regimen, viral loads, and renal function over time, and evaluated time-to-event analyses, including graft rejection and survival.ResultsCases of PTLD largely resembled matched controls in terms of baseline characteristics, although expected differences in EBV serostatus trended toward significance (42.9% of PTLD cases were donor-positive/recipient-negative vs. 8.3% controls, p = 0.063). PTLD cases were not more likely to have received belatacept than controls. Belatacept was not associated with graft rejection or failure, re-transplant, hospitalization, or decreased survival.ConclusionsBelatacept was not associated with an increased risk of PTLD, and was not associated with decreased survival in either PTLD cases or in the entire cohort. Our case-control study supports the concept that belatacept remains a safe and effective option for IS in EBV-seropositive renal transplant patients.

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell–rich and T cell–sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC–mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A–positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1–positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.

Abstract Background Previously, we showed that chemotherapy terminology is difficult for patients to understand. Therefore, we developed short videos explaining key terminology and though proven effective, they will only be helpful if appropriately disseminated. Therefore, we aimed to determine the best dissemination method at three different healthcare settings. Methods With consent, we interviewed healthcare workers from (1) an academic cancer center, Winship Cancer Institute (Winship) serving higher SES patients, (2) an inner‐city, safety‐net hospital Grady Memorial (GMH), (3) clinics serving rural Georgia, from the Winship Community Network (Network). All interviews were transcribed and analyzed using a semantic content analysis method. Suggested dissemination plans were then implemented. Results Twenty‐two Winship, 11 GMH, and 4 Network healthcare workers were interviewed. Seventy‐two percent (n = 8) of the GMH and 100% (n = 4) of Network healthcare workers felt that the best place for patients to view the videos was in the clinic, compared to 27% (n = 6) of the Winship clinicians. 68% (n = 15) of the Winship clinicians stated an app would be the most useful format, compared to 27% (n = 3) at GMH, and 0% at Network sites. Video viewing increased after dissemination plans were implemented. CONCLUSION Educational materials explaining oncology treatment terminology enhance patient understanding, yet without proper dissemination, these tools may never reach the intended patient population. Our study shows that dissemination plans need to be tailored to each individual patient population, with rural and lower SES patients needing to view the videos during clinic visits, and patients of more means viewing them using technology at home.

IntroductionAs immunotherapy has improved distant metastasis-free survival (DMFS) in Non-Small Cell Lung Cancer (NSCLC), isolated locoregional recurrences have increased. However, management of locoregional recurrences can be challenging. We report our institutional experience with definitive intent re-irradiation using Intensity Modulated Proton Therapy (IMPT).MethodRetrospective cohort study of recurrent or second primary NSCLC or LS-SCLC treated with IMPT. Kaplan-Meier method and log-rank test were used for time-to-event analyses.Results22 patients were treated from 2019 to 2021. After first course of radiation (median 60 Gy, range 45-70 Gy), 45% received adjuvant immunotherapy. IMPT re-irradiation began a median of 28.2 months (8.8-172.9 months) after initial radiotherapy. The median IMPT dose was 60 GyE (44-60 GyE). 36% received concurrent chemotherapy with IMPT and 18% received immunotherapy after IMPT. The median patient’s IMPT lung mean dose was 5.3 GyE (0.9-13.9 GyE) and 5 patients had cumulative esophagus max dose >100 GyE with 1-year overall survival (OS) 68%, 1-year local control 80%, 1-year progression free survival 45%, and 1-year DMFS 60%. Higher IMPT (HR 1.4; 95% CI 1.1-1.7, p=0.01) and initial radiotherapy mean lung doses (HR 1.3; 95% CI 1.0-1.6, p=0.04) were associated with worse OS. Two patients developed Grade 3 pneumonitis or dermatitis, one patient developed Grade 2 pneumonitis, and seven patients developed Grade 1 toxicity. There were no Grade 4 or 5 toxicities.DiscussionDefinitive IMPT re-irradiation for lung cancer can prolong disease control with limited toxicity, particularly in the immunotherapy era.

Purpose/Objective: Given the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients’ symptom burden from radiotherapy (RT) are lacking. Materials/Methods: This multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded. Results: Forty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %). Conclusion: RT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

Abstract Background The management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis. Methods A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured. Results 63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07–0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits. Conclusions Outcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context.

Abstract Background Ultrahypofractionation using stereotactic body radiotherapy (SBRT) is an increasingly utilized technique for men with prostate cancer (PC). The comparative efficacy of SBRT plus androgen deprivation therapy (ADT) compared to fractionated radiotherapy (EBRT) plus ADT in higher-risk prostate cancer is unknown. Methods Men > 40 years old with localized PC treated with external beam radiation and concomitant ADT for curative intent between 2004 and 2016 were analyzed from the National Cancer Database. Patients who lacked ADT or risk stratification data were excluded. 558 men treated with SBRT versus 40,797 men treated with conventional or moderately hypofractionated EBRT were included. Patients were stratified by unfavorable intermediate (UIR) and high (HR) risk using NCCN criteria. Kaplan Meier and Cox proportional hazards were used to compare overall survival (OS) between RT modality, adjusting for age, race, and comorbidity index. Results With a median follow up of 74 months, there was no difference in estimated 6-year OS between men treated with SBRT versus EBRT regardless of risk group. On multivariable analysis, there was no difference in risk of death for men treated with SBRT compared to EBRT (UIR: adjusted HR 1.09, 95% CI 0.68–1.74, p = .72; HR: adjusted HR 0.93, 95% CI 0.76–1.14, p = .51). On sensitivity analyses, when confining the cohort to men treated with NCCN-preferred dose fractionations, with no comorbidities, or

Abstract Background Immunotherapy terminology is complex and can be difficult for patients to understand, threatening informed consent. The aims of this exploratory study are to determine whether patients understand immunotherapy terminology and if the provider defining the term improves patient understanding. Good patient/provider communication is important for good informed consent, patient adherence to treatment and patient outcomes. Methods Conversations between oncology providers and patients discussing immunotherapy were observed (n = 39), and technical terms used were noted. With consent, patients were interviewed post‐conversation to assess their understanding of these terms (n = 39). Comparisons of the terms were conducted using chi‐square tests, Fisher's exact tests, or ANOVA where appropriate. Results “Immunotherapy” was the most difficult for participants to understand with 48.7% (19/39) correctly defining immunotherapy. “Immunotherapy agents” was understood 53.8% (14/26) of the time. “Immune system” was well understood 88.5% (23/26). Providers defined immunotherapy in 97.4% of conversations. There was no correlation between having immunotherapy defined in the conversation, and the likelihood of a correct definition (p = 0.487). “Immune system” was defined in 92.3% of conversations (n = 26), and defining it in the conversation was correlated with increased patient understanding (p = 0.009). Conclusion Our results indicate that patients have difficulty understanding some immunotherapy terminology. Since patient understanding of key terminology is crucial for informed consent and patient care, it is essential to implement interventions to improve understanding.

# Background Aerial images are being used more often to map residential structures on the ground in a study area (the sample frame). However, non-coverage bias associated with overhead imagery has not been fully explored. Non-coverage occurs when residential structures are not included in a particular sampling frame. Our study aimed to evaluate non-coverage bias and sensitivity of an aerial photograph methodology in Nueva Santa Rosa, Guatemala, which was used to generate the sampling frame for a larger cross-sectional survey of sanitation, disease, and water quality. # Methods High-resolution aerial photographs of Nueva Santa Rosa were overlaid with a grid, and roof images were geo-located within randomly sampled cells, dichotomized by population as very high-density (VHD) or non-VHD. Roofs found on-site were compared to roofs found in photographs to evaluate the numbers and sizes of residences excluded from the sampling frame. Non-coverage proportions were estimated, and sensitivity and specificity were assessed. # Results There was no statistically significant difference (1.2%; 95% confidence interval, CI= -12.1-14.6) in non-coverage proportion between VHD segments (39.6%) and non-VHD cells (38.4%). Roof-size range sensitivity and specificity were 66.4% (95% CI=57.6–74.2) and 69.4% (95% CI=54.4–81.3). # Conclusions Approximately one-third of residential roofs were missed, perhaps due to outdated photographs. No substantial bias concerning population density appeared to influence our sampling frame. Further assessment of non-coverage bias, possibly expanding the roof size range to modify sensitivity and specificity, should be performed to generate geographically based best practices for overhead-image use.

For a typical medical research project based on observational data, sequential routine analyses are often essential to comprehend the data on hand and to draw valid conclusions. However, generating reports in SAS ® for routine analyses can be a time-consuming and tedious process, especially when dealing with large databases with a massive number of variables in an iterative and collaborative research environment. In this work, we present a general workflow of research based on an observational database and a series of SAS ® macros that fits this framework, which covers a streamlined data analyses and produces journal-quality summary tables. The system is generic enough to fit a variety of research projects and enables researchers to build a highly organized and concise coding for quick updates as research evolves. The result reports promote communication in collaborations and will escort the research with ease and efficiency.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8+, CD3+ and FOXP3+ T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.

For a typical medical research project based on observational data, sequential routine analyses are often essential to comprehend the data on hand and to draw valid conclusions. However, generating reports in SAS® for routine analyses can be a time-consuming and tedious process, especially when dealing with large databases with a massive number of variables in an iterative and collaborative research environment. In this work, we present a general workflow of research based on an observational database and a series of SAS® macros that fits this framework, which covers a streamlined data analyses and produces journal-quality summary tables. The system is generic enough to fit a variety of research projects and enables researchers to build a highly organized and concise coding for quick updates as research evolves. The result reports promote communication in collaborations and will escort the research with ease and efficiency.

For a typical medical research project based on observational data, sequential routine analyses are often essential to comprehend the data on hand and to draw valid conclusions. However, generating reports in SAS ® for routine analyses can be a time-consuming and tedious process, especially when dealing with large databases with a massive number of variables in an iterative and collaborative research environment. In this work, we present a general workflow of research based on an observational database and a series of SAS ® macros that fits this framework, which covers a streamlined data analyses and produces journal-quality summary tables. The system is generic enough to fit a variety of research projects and enables researchers to build a highly organized and concise coding for quick updates as research evolves. The result reports promote communication in collaborations and will escort the research with ease and efficiency.

Background: With increasing numbers of oncology biosimilars in the approval pipeline, it is important to investigate oncology clinicians’ understanding of biosimilars and what information they need prior to adoption. Methods: Between January and May 2018, 77 oncology clinicians (52 physicians, 16 pharmacists, and 9 advanced practice providers) completed a survey covering three domains: clinician understanding, prescription preferences, and patient involvement. An in-depth interview was designed based on themes identified in the first 50 surveys: cost, safety and efficacy, patient preference, and disease stage. Participants were chosen to participate in the interview based on outlying responses to survey questions. Results: When asked to define a biosimilar, 74% (57/77) of respondents could not give a satisfactory definition, and 40.3% (31/77) considered a biosimilar the same as a generic drug. The most important factor in biosimilar prescription was safety and efficacy (4.51 out of 5) followed closely by cost differences (4.34 out of 5). A 40% increase (53.2–94.8%) in clinicians’ prescribing likelihood was seen after a biosimilar is designated as interchangeable. Participants in this study were split regarding the importance of shared decision-making with patients [50.7% (39/77) important or extremely important, 39.0% (30/77) somewhat or not at all important]. Clinicians were also split concerning the role that pharmacists should play in the decision to prescribe or substitute biosimilars. Conclusion: Understanding of biosimilars is low, and educational needs are high. The information that clinicians deem important to assess, such as safety, efficacy and cost, will need to be provided before they are comfortable prescribing biosimilars.

BackgroundRandomized clinical trials compare participants receiving an experimental intervention to participants receiving standard of care (SOC). If one could predict the outcome for participants receiving SOC, a trial could be designed where all participants received the experimental intervention, with the observed outcome of the experimental group compared to the prediction for those individuals.MethodsWe used the CancerMath calculator to predict outcomes for participants in two large clinical trials of adjuvant chemotherapy for breast cancer: NSABPB15 and CALGB9344. NSABPB15 was the training set, and we used the modified algorithm to predict outcomes for two groups from CALGB9344: one which received standard of care (SOC) chemotherapy and one which received paclitaxel in addition. We made a prediction for each individual CALGB9344 participant, assuming each received only SOC.ResultsThe predicted outcome for the group which received only SOC matched what was observed in the CALGB9344 trial. In contrast, the predicted outcome for the group also receiving paclitaxel was significantly worse than what was observed for this group. This matches the conclusion of CALGB9344 that adding paclitaxel to SOC improves survival.ConclusionThis project proves that a statistical model can predict the outcome of clinical trial participants treated with SOC. In some circumstances, a predictive model could be used instead of a control arm, allowing all participants to receive experimental treatment. Predictive models for cancer and other diseases could be constructed using the vast amount of outcomes data available to the federal government, and made available for public use.

Failure to achieve pathologic complete response is associated with poor prognosis in breast cancer patients following neoadjuvant chemotherapy (NACT). However, prognostic biomarkers for clinical outcome are unclear in this patient population. Cyclin-dependent kinase 9 (CDK9) is often dysregulated in breast cancer, and its deficiency results in genomic instability. We reviewed the records of 84 breast cancer patients from Emory University’s Winship Cancer Institute who had undergone surgical resection after NACT and had tissue available for tissue microarray analysis (TMA). Data recorded included disease presentation, treatment, pathologic response, overall survival (OS), locoregional recurrence free survival (LRRFS), distant-failure free survival (DFFS), recurrence-free survival (RFS), and event-free survival (EFS). Immunohistochemistry was performed on patient samples to determine CDK9 expression levels after NACT. Protein expression was linked with clinical data to determine significance. In a Cox proportional hazards model, using a time-dependent covariate to evaluate the risk of death between groups beyond 3 years, high CDK9 expression was significantly associated with an increase in OS (HR: 0.26, 95% CI: 0.07-0.98, p=0.046). However, Kaplan-Meier curves for OS, LRRFS, DFFS, RFS, and EFS did not reach statistical significance. The results of this study indicate that CDK9 may have a potential role as a prognostic biomarker in patients with breast cancer following NACT. However, further validation studies with increased sample sizes are needed to help elucidate the prognostic role for CDK9 in the management of these patients.