Shrujal S. Baxi

Purpose:There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC.Patients and Methods:Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants.Results:Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2–11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1–6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2–M checkpoint).Conclusions:The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.

Purpose: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. Patients and Methods: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. Results: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2–11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1–6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2–M checkpoint). Conclusions: The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.

Purpose: The objective of this study was to determine whether differences in patients’ race/ethnicity, preferred language, and other factors were associated with patient enrollment in oncology research studies. Patients and Methods: We conducted a retrospective cross-sectional analysis of all adults (>18 and ≤90) seen at a large, metropolitan cancer center from 2005 to 2015, examining if enrollment to a research study, varied by race/ethnicity, preferred language, comorbidities, gender, and age. Results: A total of 233 604 patients were available for initial analysis. Of these, 93 278 (39.9%) were enrolled in a research protocol (therapeutic and non-therapeutic studies). Patients who self-reported their race/ethnicity as Native, Other, Unknown, or Refuse to Answer were less likely to be enrolled on a study. Patients with one or more comorbidities, and those whose preferred language was English, were more likely to be enrolled on a research study. A logistic regression model showed that, although Non-Hispanic Black patients were more likely to have one or more comorbidities and had a higher proportion of their subset selecting English as their preferred language, they were less likely to be enrolled on a study, than our largest population, Non-Hispanic/White patients. Conclusions: We identified differences in research study enrollment based on preferred language, and within race/ethnicity categories including Native-Populations, Other, Unknown or Refuse to Answer compared to Non-Hispanic/White patients. We also highlighted the lower odds of enrollment among Non-Hispanic/Black patients, in the setting of factors such as comorbidities and English language preference, which were otherwise found to be positive predictors of enrollment. Further investigation is needed to design targeted interventions to reduce disparities in oncology research study enrollment, with particular focus on language diversity.

Summary: In this issue, Smyth and colleagues investigate the natural history of AKT1-mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic data. A rare subset of tumors, AKT1-mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as AKT1–wild-type tumors, but a longer duration of therapy on mTOR inhibitors.See related article by Smyth et al., p. 526.

Background and Objective: The Surveillance, Epidemiology, and End Results Program (SEER) program and the National Program of Cancer Registries (NPCR), are authoritative sources for population cancer surveillance and research in the US. An increasing number of recent oncology studies are based on the electronic health record (EHR)-derived de-identified databases created and maintained by Flatiron Health. This report describes the differences in the originating sources and data development processes, and compares baseline demographic characteristics in the cancer-specific databases from Flatiron Health, SEER, and NPCR, to facilitate interpretation of research findings based on these sources. Methods: Patients with documented care from January 1, 2011 through May 31, 2019 in a series of EHR-derived Flatiron Health de-identified databases covering multiple tumor types were included. SEER incidence data (obtained from the SEER 18 database) and NPCR incidence data (obtained from the US Cancer Statistics public use database) for malignant cases diagnosed from January 1, 2011 to December 31, 2016 were included. Comparisons of demographic variables were performed across all disease-specific databases, for all patients and for the subset diagnosed with advanced-stage disease. Results: As of May 2019, a total of 201,570 patients with 19 different cancer types were included in Flatiron Health datasets. In an overall comparison to national cancer registries, patients in the Flatiron Health databases had similar sex, age at initial diagnosis, and geographic distributions but appeared to be diagnosed with later stages of disease compared with patients in other datasets. For variables such as stage and race, Flatiron Health databases had a greater degree of incompleteness. There are variations in these trends by cancer types. Conclusions: These three databases present general similarities in demographic and geographic distribution, but there are overarching differences across the populations they cover. Differences in data sourcing (medical oncology EHRs vs cancer registries), and disparities in sampling approaches and rules of data acquisition may explain some of these divergences. Furthermore, unlike the steady information flow entered into registries, the availability of medical oncology EHR-derived information reflects the extent of involvement of medical oncology clinics at different points in the specialty management of individual diseases, resulting in inter-disease variability. These differences should be considered when interpreting study results obtained with these databases.

Background: We explored if age affects quality of life (QOL) in survivors of locally advanced human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (SCC).Methods: In a cross‐sectional survey of 185 patients, at least 12 months from radiation, we evaluated generic (EuroQOL‐5D questionnaire [EQ‐5D]) and head and neck specific (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Head and Neck 35‐questions [EORTC‐QLQ‐H&N35]) QOL questionnaires and compared differences between younger (P = .53). Patients ≥65 years reported more immobility (P < .01), problems with social eating (P < .0001), and coughing (P < .01). Patients ≥65 years were not more likely to ever require a gastrostomy (P = .24) but were more likely to remain gastrostomy‐dependent at the time of the survey (P = .02).Conclusion: Despite similar generic QOL, older survivors may have more mobility problems and issues with social eating compared with younger survivors deserving of further evaluation.