Research Spotlight

Miles, D., J. Gligorov, F. André, D. Cameron, A. Schneeweiss, C. Barrios, B. Xu, A. Wardley, D. Kaen, L. Andrade, V. Semiglazov, M. Reinisch, S. Patel, M. Patre, L. Morales, S. L. Patel, M. Kaul, T. Barata and J. O’Shaughnessy (2021). “Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.” Ann Oncol 32(8): 994-1004.

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BACKGROUND: In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. PATIENTS AND METHODS: Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m(2) (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. RESULTS: Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. CONCLUSION: Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.

Fernandes, L. E., C. G. Epstein, A. M. Bobe, J. S. K. Bell, M. C. Stumpe, M. E. Salazar, A. A. Salahudeen, R. A. Pe Benito, C. McCarter, B. D. Leibowitz, M. Kase, C. Igartua, R. Huether, A. Hafez, N. Beaubier, M. D. Axelson, M. D. Pegram, S. L. Sammons, J. A. O’Shaughnessy and G. A. Palmer (2021). “Real-world Evidence of Diagnostic Testing and Treatment Patterns in US Patients With Breast Cancer With Implications for Treatment Biomarkers From RNA Sequencing Data.” Clin Breast Cancer 21(4): e340-e361.

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OBJECTIVE/BACKGROUND: We performed a retrospective analysis of longitudinal real-world data (RWD) from patients with breast cancer to replicate results from clinical studies and demonstrate the feasibility of generating real-world evidence. We also assessed the value of transcriptome profiling as a complementary tool for determining molecular subtypes. METHODS: De-identified, longitudinal data were analyzed after abstraction from records of patients with breast cancer in the United States (US) structured and stored in the Tempus database. Demographics, clinical characteristics, molecular subtype, treatment history, and survival outcomes were assessed according to strict qualitative criteria. RNA sequencing and clinical data were used to predict molecular subtypes and signaling pathway enrichment. RESULTS: The clinical abstraction cohort (n = 4000) mirrored the demographics and clinical characteristics of patients with breast cancer in the US, indicating feasibility for RWE generation. Among patients who were human epidermal growth factor receptor 2-positive (HER2(+)), 74.2% received anti-HER2 therapy, with ∼70% starting within 3 months of a positive test result. Most non-treated patients were early stage. In this RWD set, 31.7% of patients with HER2(+) immunohistochemistry (IHC) had discordant fluorescence in situ hybridization results recorded. Among patients with multiple HER2 IHC results at diagnosis, 18.6% exhibited intra-test discordance. Through development of a whole-transcriptome model to predict IHC receptor status in the molecular sequenced cohort (n = 400), molecular subtypes were resolved for all patients (n = 36) with equivocal HER2 statuses from abstracted test results. Receptor-related signaling pathways were differentially enriched between clinical molecular subtypes. CONCLUSIONS: RWD in the Tempus database mirrors the overall population of patients with breast cancer in the US. These results suggest that real-time, RWD analyses are feasible in a large, highly heterogeneous database. Furthermore, molecular data may aid deficiencies and discrepancies observed from breast cancer RWD.

Mattke, J., S. Vasu, C. M. Darden, K. Kumano, M. C. Lawrence and B. Naziruddin (2021). “Role of Exosomes in Islet Transplantation.” Front Endocrinol (Lausanne) 12: 681600.

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Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

Hendrick, R. E., D. L. Monticciolo, K. W. Biggs and S. F. Malak (2021). “Age distributions of breast cancer diagnosis and mortality by race and ethnicity in US women.” Cancer Aug 24. [Epub ahead of print].

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BACKGROUND: Surveillance, Epidemiology, and End Results (SEER) data from 1973-2010 have been used to show that minority women have disproportionately higher percentages of breast cancers diagnosed at younger ages in comparison with White women. METHODS: The authors analyzed SEER 21 invasive breast cancer incidence data for 2014-2017 and National Center for Health Statistics mortality data for 2014-2018 and compared invasive incidence and mortality by age in non-Hispanic Black (NH-Black), Asian American/Pacific Islander (AAPI), Native American, and Hispanic women with those in non-Hispanic White (NH-White) women. They evaluated incidence rates and percentages of invasive breast cancer cases and breast cancer deaths occurring before the age of 50 years along with advanced-stage incidence rates and percentages in minority women versus NH-White women. RESULTS: Recent SEER data showed that invasive breast cancers were diagnosed at significantly younger ages in minority women versus NH-White women. Among women diagnosed with invasive breast cancer, compared with NH-White women, minority women were 72% more likely to be diagnosed under the age of 50 years (relative risk [RR], 1.72; 95% confidence interval [CI], 1.70-1.75), 58% more likely to be diagnosed with advanced-stage breast cancer under the age of 50 years (RR, 1.58; 95% CI, 1.55-1.61), and 24% more likely to be diagnosed with advanced-stage (regional or distant) breast cancer at all ages (RR, 1.24; 95% CI, 1.23-1.25). Among women dying of breast cancer, minority women were 127% more likely to die under the age of 50 years than NH-White women. CONCLUSIONS: NH-Black, AAPI, Native American, and Hispanic women have higher proportions of invasive breast cancers at younger ages and at advanced stages and breast cancer deaths at younger ages than NH-White women. LAY SUMMARY: This study analyzes the most recently available data on invasive breast cancers and breast cancer deaths in US women by age and race/ethnicity. Its findings show that non-Hispanic Black, Asian American/Pacific Islander, Native American, and Hispanic women have a higher percentage of invasive breast cancers at younger ages and at more advanced stages and a higher percentage of breast cancer deaths at younger ages than non-Hispanic White women.

Ehrmann, S., J. Li, M. Ibarra-Estrada, Y. Perez, I. Pavlov, B. McNicholas, O. Roca, S. Mirza, D. Vines, R. Garcia-Salcido, G. Aguirre-Avalos, M. W. Trump, M. A. Nay, J. Dellamonica, S. Nseir, I. Mogri, D. Cosgrave, D. Jayaraman, J. R. Masclans, J. G. Laffey and E. Tavernier (2021). “Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial.” Lancet Respir Med Aug 20;S2213-2600(21)00356-8. [Epub ahead of print].

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BACKGROUND: Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. METHODS: In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov, NCT04325906, NCT04347941, NCT04358939, NCT04395144, NCT04391140, and NCT04477655. FINDINGS: Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75-0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62-0·91), and the HR for mortality was 0·87 (0·68-1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. INTERPRETATION: Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula.