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Background: In estrogen receptor-positive metastatic breast cancer, ESR1 mutations (ESR1 m ) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact ESR1 alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific ESR1 allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1 m metastatic breast cancer and associated clinical factors., Methods: ESR1 m were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1 m or non- ESR1 -mutant (non-ESR1 m ) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment., Results: One hundred forty-five patients with ESR1 m and 612 with non-ESR1 m metastatic breast cancer were analyzed. ESR1 m and non-ESR1 m tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of ESR1 status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1 m had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant., Conclusions: These data suggest ESR1 variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1 m metastatic breast cancer.

Purpose: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory., Methods: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL)., Results: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores., Conclusions: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011)., (© 2024. The Author(s).)

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 10 11 , 5.0 × 10 11 , 1.0 × 10 12 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 10 12  vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 10 12  vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling., (© 2023. The Author(s).)

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers., Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity., Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%)., Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients., Competing Interests: SK reports research funding to institutions from AADi, Aivita Biomedical, Inc., Bavarian Nordic, Bayer, Biocept, Blue Earth Diagnostics, Caris MPI, CNS Pharmaceuticals, EpicentRx, Incyte, Lilly, Oblato, Orbus Therapeutics, and Stemedica Cell Technologies; reports stock or other ownership interests in xCures; reports receiving honoraria from Jubilant Biosys and Pyramid Biosciences; and is a consultant/advisory board member for Curtana Pharmaceuticals, Nascent Biotech, Biocept, iCAD, and xCures. JAC reports research funding to institution from Nascent Biotech and Novocure. NW reports research funding to institution from Bavarian Nordic, Bayer, Biocept, Boehringer Ingelheim, Caris MPI, CNS Pharmaceuticals, EpicentRx, Incyte, Novocure, Oblato, Pyramid Biosciences, Stemedica Cell Technologies, xCures, and Xoft. GB is a consultant for Vascular Technologies, Inc. and Cerevasc Inc.; reports payment for expert testimony; is the Data Monitoring Committee Chair for Cerevasc Inc.; and is an executive committee member of the Congress of Neurological Surgeons (CNS) and American Association of Neurological Surgeons (AANS) Tumor Section. DFK reports royalties or licenses from Mizuho, Inc. All other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100 mg palbociclib, 5 mg everolimus, 25 mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n = 6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAF V600E ), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies., (© 2024. The Author(s).)

Purpose: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma., Patients and Methods: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers., Results: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms., Conclusions: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted., (©2023 American Association for Cancer Research.)

Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. We developed a DNA-based signature of radiotherapeutic efficacy among patients with BrM to better characterize recurrence risk., Methods: We identified 570 patients with 1487 BrM managed with whole-brain (WBRT) or stereotactic radiation therapy at Brigham and Women's Hospital/Dana-Farber Cancer Institute (2013-2020) for whom next-generation sequencing panel data (OncoPanel) were available. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with versus without somatic alterations of likely biological significance across 84 genes. Genes with a q-value ≤ 0.10 were utilized to develop a "Brain-Radiation Prediction Score" ("Brain-RPS")., Results: Genomic alterations in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, and MDM4) and 2 genes (FBXW7 and AURKA) were associated with decreased or increased risk of local recurrence, respectively (q-value ≤ 0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray's competing risks regression, RPS [1.66 (1.44-1.91, P < .001)], metastasis-associated edema [1.60 (1.16-2.21), P = .004], baseline size [1.02 (1.01-1.03), P < .001] and receipt of WBRT without local therapy [4.04 (2.49-6.58), P < .001] were independent predictors of local failure., Conclusions: We developed a genomic score to quantify local recurrence risk following brain-directed radiation. To the best of our knowledge, this represents the first study to systematically correlate DNA-based alterations with radiotherapeutic outcomes in BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation in BrM., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome., Competing Interests: Declaration of interests C.K.O. is a consultant/advisory board member for AstraZeneca, GlaxoSmithKline, Pfizer, Puma Biotechnologies, and Tolmar and on the Data Monitoring Committee for Eli Lilly. R.S. has received research support (to institute) from Puma Biotechnology, Gilead Sciences, and AstraZeneca; is a consultant/advisor of MacroGenics; holds patents, royalties, and other intellectual property from Wolters Kluwer/UpToDate; and has a patent pending (via institution; NRF Ref. BAYM.P0312US.P1-1001123973 “A multiparameter classifier to predict response to HER2-targeted therapy without chemotherapy in HER2-positive breast cancer”) with no revenue received. N.W. is a consultant/advisor for Eli Lilly and AstraZeneca, a member of the scientific advisory board and stockholder for Relay Therapeutics, and a member of the scientific advisory board and stockholder for Flare Therapeutics. He has previously received research support from Novartis and Puma Biotechnology, consulted with Novartis, and consulted with Foundation Medicine. R.J. has received research funding from Pfizer. M.F.R. has received research support from Pfizer and consults with Genentech, Novartis, Daiichi, AstraZeneca, Seagen, and MacroGenics. M.G. is a consultant/advisor for Eli Lilly, MSD, Novartis, Pfizer, Roche, and Seagen., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Erb-B2 receptor tyrosine kinase 2 ( ERBB2 )-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2 -positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population., Methods: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2 -positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes., Results: Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53 . Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2 , STIL , PIK3CA , and GATA3 . There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples., Conclusion: ERBB2 -positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

Background: Leptomeningeal disease (LMD) is a relatively uncommon manifestation of advanced cancer. Patients with LMD carry a poor prognosis and often decline rapidly, complicating inclusion in clinical trials. Identification of LMD subsets of greater incidence and more favorable prognosis might facilitate dedicated clinical trials in the future. We hypothesized that patients with breast cancer may represent such a population and sought to assess the relative incidence and prognosis of LMD secondary to breast vs. non-breast primaries., Methods: We identified 2411 patients with intracranial metastases secondary to breast (N = 501) and non-breast (N = 1910) primaries at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 1996 and 2020, of whom 112 presented with and an additional 161 subsequently developed LMD. A log-rank test and Cox modeling were used to compare outcomes in patients with breast vs. non-breast primaries., Results: Among patients with newly diagnosed intracranial disease, the incidence proportion of concurrent LMD was 11.4% vs. 2.9% among patients with breast vs. non-breast primaries (P < .001). Development of LMD among initially LMD-naïve patients was also more common among patients with breast vs. non-breast primaries (HR = 1.49 [1.05-2.11], P = .03). Patients with LMD secondary to breast vs. non-breast primaries displayed lower all-cause mortality (HR 0.70 [0.52-0.93], P = .01; median survival: 5.2 vs. 2.4 months, respectively), with a greater numerical difference observed in patients with LMD at intracranial involvement (7.4 vs. 2.6 months, respectively)., Conclusions: Patients with breast cancer and LMD may represent an ideal population for clinical trials given the higher incidence and potentially more favorable prognosis seen in this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression., Methods: We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[-] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture., Results: In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(-) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 ( P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells., Conclusion: For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(-) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2- MBC.

Despite much vaunted progress in cancer therapeutics and diagnostics, outcomes for many groups of non-White patients with cancer remain worse than those for their White compatriots. One reason for this is the lack of inclusion and representation of non-White patients in clinical trials, preclinical datasets, and among researchers, a shortfall that is gaining wide recognition within the cancer research community and the lay public. Several reviews and editorials have commented on the negative impacts of the status quo on progress in cancer research toward medical breakthroughs that help all communities and not just White patients with cancer. In this perspective, we describe the existence of research silos focused either on the impact of socioeconomic factors proceeding from systemic racism on cancer outcomes, or on genetic ancestry as it affects the molecular biology of cancer developing in specific patient populations. While both these research areas are critical for progress toward precision medicine equity, breaking down these silos will help us gain an integrated understanding of how race and racism impact cancer development, progression, and patient outcomes. Bringing this comprehensive approach to cancer disparities research will undoubtedly improve our overall understanding of how stress and environmental factors affect the molecular biology of cancer, which will lead to the development of new diagnostics and therapeutics that are applicable across cancer patient demographics., (©2023 American Association for Cancer Research.)

Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research., Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities., Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants., Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries., Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis., Methods: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m 2 ) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual., Findings: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011)., Interpretation: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population., Funding: Genentech., Competing Interests: Declaration of interests SMT has received grant support (paid to institution) from AstraZeneca, Merck, Nektar, Novartis, Pfizer, Genentech (Roche), Gilead, Exelixis, BMS, Eisai, NanoString, Cyclacel, Sanofi, Seagen, and Eli Lilly; and has received consulting or advisory board fees (paid to self) from AstraZeneca, Eli Lilly, Merck, Novartis, Pfizer, Genentech (Roche), Gilead, BMS, Eisai, Sanofi, SeaGen, Daiichi-Sankyo, Athenex, OncoPep, Kyowa Kirin Pharma, CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec, Infinity Therapeutics, BeyondSpring Pharma, OncXerna, Zymeworks, Zentalis, ARC Therapeutics, Reveal Genomics, Blueprint Medicines, Myovant, Umoja Biopharma, Stemline (Menarini), and Artios Biopharma. PT has received consulting or advisory board fees from AstraZeneca, Daiichi-Sankyo, and Lilly and has received payment or honoraria for educational events from AstraZeneca and Daiichi-Sankyo. NT has received honoraria for a Clinical Research Workshop at the San Antonio Breast Cancer Symposium. LP is an employee of Reveal Genomics and has a patent (EP 20 382 679.7—in vitro method for the prognosis of patients suffering from HER2-positive breast cancer). GV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, GSK, Pierre Fabre, and Pfizer and has participated on a data safety monitoring board or advisory board for AstraZeneca. CTD has received research funding from Genentech (Roche) and Puma and has received consulting fees from Daiichi-Sankyo, Novartis, Pfizer, Gilead, Seagen, and Genentech (Roche). DAY has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute; grant support (paid to institution) from Ambrx, Amgen, BIOMARIN, Biothera Pharmaceuticals, Clovis Pharma, Dana-Farber Cancer Institute, Lilly, Genentech (Roche), G1 Therapeutics, Gilead Sciences, Incyte, Innocrin Pharmaceuticals, Macrogenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, the National Surgical Adjuvant Breast and Bowel Project, Pfizer, and Polyphor; and has received consulting fees (paid to institution) from AstraZeneca, Athenex, bioTheranostics, G1 Therapeutics, Gilead Sciences, Immunomedics, Merck, Novartis, Pfizer, and Sanofi-Aventis. PKM has received support (paid to institution) for the present manuscript from Genentech; has participated on a data safety monitoring board for Genentech (Roche); has stock or stock options in Veracyte; and was a full-time employee of Veracyte at time of manuscript submission. KSA has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute for data management support. HSR has received grant funding (paid to UC Regents only) from Ambrx, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Genentech (Roche), Gilead Sciences, GSK, Lilly, Merck & Co, Novartis Pharmaceuticals, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Seattle Genetics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru; has received consulting fees from Puma, Napo Pharmaceuticals, and Blueprint; and has received support for attending meetings and travel from Merck, AstraZeneca, and Gilead. MJE has reported a PAM50 Bioinformatics for Prosigna royalty-bearing license to Veracyte; and and has been an employee of AstraZeneca since March 7, 2022 (AstraZeneca had no role in this study and the author's involvement in this study preceded his employment with AstraZeneca). LAC has received research funding (paid to institution) from Syndax, Novartis, NanoString Technologies, Seattle Genetics, Veracyte, and AstraZeneca and declares participation in uncompensated consulting activities for Eisai (to self), Sanofi (to self), Lilly (to self), Seagen (to self), Novartis (to institution), G1 Therapeutics (to institution), Genentech (Roche; to institution), GSK (to institution), AstraZeneca (to institution), and Daiichi-Sankyo (to institution). RBS has received consulting fees from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or education events from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received support for attending meetings and travel from Daiichi-Sankyo, Eli Lilly, MSD, and Roche; has participated on a data safety monitoring board or advisory board for AstraZeneca, Daiichi-Sankyo, and Roche; and is a member of the Clinical Research Committee of the Brazilian Society of Clinical Oncology. JGTZ has stock or stock options in Loncar Cancer Immunotherapy ETF, iShares Genomics Immunology and Healthcare ETF, iShares Biotechnology ETF, SPDR S&P Biotech ETF, Adaptive Biotechnologies, 2seventy bio, and bluebird bio. NW has received grant support from AstraZeneca; has received consulting fees from Relay Therapeutics, Flare Therapeutics, Eli Lilly, and Section 32; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Genentech; and has stock or stock options in Relay Therapeutics and Flare Therapeutics. AHP has received royalties from UpToDate. AGW has received grant support (paid to institution) from Macrogenics, Genentech, and Merck and has received consulting fees (paid to self) from AstraZeneca. CAH is Chief Executive Officer at the American Society of Clinical Oncology, which pays 100% of the author's personal annual earned income. IEK has received support for the present manuscript from Genentech (Roche); has received grant support from Macrogenics and Pfizer; has received consulting fees from Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca; and has participated on a data safety monitoring board or advisory board for Novartis, Merck, Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca. AP has received funding for the present manuscript from Reveal Genomics; has received grants (paid to institution) from Roche, Daiichi-Sankyo, and Reveal Genomics; has received royalties or licenses from Reveal Genomics (paid to institution); has received consulting fees (paid to self) from Roche, Novartis, Daiicki-Sankyo, and AstraZeneca; has patents licensed to Reveal Genomics: HER2DX, ERBB2, and DNADX genomic tools; and has stock or stock options in Reveal Genomics and Oncolytics Biotech. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant AR amplifications. This study illustrates the power of a growing, longitudinal partnership with patients to generate a more representative understanding of MPC., Competing Interests: DECLARATION OF INTERESTS M.X.H. has been a consultant to Amplify Medicines and Ikena Oncology and is a current employee of Genentech/Roche. E.S.L. is currently in the process of divesting any relevant holdings. N.W. reports advisory relationships and consulting with Eli Lilly and Co.; advising and stockholding interest in Relay Therapeutics; and grant support from Puma Biotechnology. E.M.V.A. reports advisory relationships and consulting with Tango Therapeutics, Genome Medical, Invitae, Illumina, Enara Bio, Mani-fold Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Mani-fold Bio, and Enara Bio; and travel reimbursement from Roche and Genentech, outside the submitted work.

Background: Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment for glioblastoma (GBM). However, so far there is no evidence that intranasal delivery of NEO100 indeed results in POH reaching intracranial malignancies in a patient., Observations: After surgical removal of her recurrent GBM tumor, a patient received daily intranasal NEO100 therapy for more than 3 years before a second recurrence emerged. At that time, a final dose of NEO100 was given shortly before the tumor tissue was surgically removed, and the tissue was processed for high-performance liquid chromatography analysis of POH and its primary metabolite, perillic acid (PA). Both molecules could readily be detected in the tumor tissue., Lessons: This is the first demonstration of POH and PA in brain tumor tissue from any patient. It reveals that intranasal administration of NEO100 is a valid approach to achieve delivery of this agent to a brain tumor. In view of the noninvasive and safe nature of this method, along with tentative indications of activity, our findings add confidence to the notion that intranasal administration of NEO100 holds potential as a new treatment option for brain-localized malignancies.

Background: Nystagmus identification and interpretation is challenging for non-experts who lack specific training in neuro-ophthalmology or neuro-otology. This challenge is magnified when the task is performed via telemedicine. Deep learning models have not been heavily studied in video-based eye movement detection., Methods: We developed, trained, and validated a deep-learning system (aEYE) to classify video recordings as normal or bearing at least two consecutive beats of nystagmus. The videos were retrospectively collected from a subset of the monocular (right eye) video-oculography (VOG) recording used in the Acute Video-oculography for Vertigo in Emergency Rooms for Rapid Triage (AVERT) clinical trial (#NCT02483429). Our model was derived from a preliminary dataset representing about 10% of the total AVERT videos ( n = 435). The videos were trimmed into 10-sec clips sampled at 60 Hz with a resolution of 240 × 320 pixels. We then created 8 variations of the videos by altering the sampling rates (i.e., 30 Hz and 15 Hz) and image resolution (i.e., 60 × 80 pixels and 15 × 20 pixels). The dataset was labeled as "nystagmus" or "no nystagmus" by one expert provider. We then used a filtered image-based motion classification approach to develop aEYE. The model's performance at detecting nystagmus was calculated by using the area under the receiver-operating characteristic curve (AUROC), sensitivity, specificity, and accuracy., Results: An ensemble between the ResNet-soft voting and the VGG-hard voting models had the best performing metrics. The AUROC, sensitivity, specificity, and accuracy were 0.86, 88.4, 74.2, and 82.7%, respectively. Our validated folds had an average AUROC, sensitivity, specificity, and accuracy of 0.86, 80.3, 80.9, and 80.4%, respectively. Models created from the compressed videos decreased in accuracy as image sampling rate decreased from 60 Hz to 15 Hz. There was only minimal change in the accuracy of nystagmus detection when decreasing image resolution and keeping sampling rate constant., Conclusion: Deep learning is useful in detecting nystagmus in 60 Hz video recordings as well as videos with lower image resolutions and sampling rates, making it a potentially useful tool to aid future automated eye-movement enabled neurologic diagnosis., Competing Interests: Author DN-T conducts research related to diagnosis of dizziness and stroke, as well as diagnostic error. He serves as the principal investigator for multiple grants and contracts on these topics, including the NIH-sponsored AVERT clinical trial (NIDCD U01 DC013778, ClinicalTrials.gov #NCT02483429). Johns Hopkins has been loaned research equipment [video-oculography (VOG) systems] by two companies for use in DN-T's research; one of these companies has also provided funding for research on diagnostic algorithm development related to dizziness, inner ear diseases, and stroke. DN-T has no other financial interest in these or any other companies. DN-T is an inventor on a provisional patent (US No. 62/883,373) for smartphone-based stroke diagnosis in patients with dizziness. He gives frequent academic lectures on these topics and occasionally serves as a medico-legal consultant for both plaintiff and defense in cases related to dizziness, stroke, and diagnostic error. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wagle, Morkos, Liu, Reith, Greenstein, Gong, Gangan, Pakhomov, Hira, Komogortsev, Newman-Toker, Winslow, Zee, Otero-Millan and Green.)

Purpose: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs., Methods: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed., Results: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression., Conclusion: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.

Purpose: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients., Experimental Design: We identified 100 patients ≤35 years old at nonmetastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole-exome sequencing of tumor and germline samples was performed. Genomic alterations were compared with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype., Results: Ninety-three tumors from 92 patients were successfully sequenced. Median age was 32.5 years; 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N = 28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2., Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young patients with breast cancer. See related commentary by Yehia and Eng, p. 2209., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Metastatic breast cancer (MBC) and the circulating tumor cells (CTCs) leading to macrometastases are inherently different than primary breast cancer. We evaluated whether whole transcriptome RNA-Seq of CTCs isolated via an epitope-independent approach may serve as a surrogate for biopsies of macrometastases., Methods: We performed RNA-Seq on fresh metastatic tumor biopsies, CTCs, and peripheral blood (PB) from 19 newly diagnosed MBC patients. CTCs were harvested using the ANGLE Parsortix microfluidics system to isolate cells based on size and deformability, independent of a priori knowledge of cell surface marker expression., Results: Gene expression separated CTCs, metastatic biopsies, and PB into distinct groups despite heterogeneity between patients and sample types. CTCs showed higher expression of immune oncology targets compared with corresponding metastases and PB. Predictive biomarker (n = 64) expression was highly concordant for CTCs and metastases. Repeat observation data post-treatment demonstrated changes in the activation of different biological pathways. Somatic single nucleotide variant analysis showed increasing mutational complexity over time., Conclusion: We demonstrate that RNA-Seq of CTCs could serve as a surrogate biomarker for breast cancer macrometastasis and yield clinically relevant insights into disease biology and clinically actionable targets., (© 2022. The Author(s).)

Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities., (© 2022. The Author(s).)

Importance: Research into the genetic and genomic ("genomics") foundations of disease is central to our understanding of disease prevention, early detection, diagnostic accuracy, and therapeutic intervention. Inequitable participation in genomics research by historically excluded populations limits the ability to translate genomic knowledge to achieve health equity and ensure that findings are generalizable to diverse populations., Observations: We propose a novel framework for promoting diversity, equity, and inclusion in genomics research. Building on principles of community-based participatory research and collective impact frameworks, the framework can guide our understanding of the social, cultural, health system, policy, community, and individual contexts in which engagement and genomics research are being done. Our framework highlights the involvement of a multistakeholder team, including the participants and communities to be engaged, to ensure robust methods for recruitment, retention, return of genomic results, quality of engagement, follow-up, and monitoring of participants., Conclusions and Relevance: The proposed engagement framework will guide investigators in optimizing equitable representation in research and enhancing the rigor of genomics investigation.

Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell-cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation-modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer., Significance: Context- and allele-dependent transcriptome and cistrome reprogramming in mutant ESR1 cell models elicit diverse metastatic phenotypes related to cell adhesion and migration, which can be pharmacologically targeted in metastatic breast cancer., (©2022 American Association for Cancer Research.)

Background: Exogenous cDNA introduced into an experimental system, either intentionally or accidentally, can appear as added read coverage over that gene in next-generation sequencing libraries derived from this system. If not properly recognized and managed, this cross-contamination with exogenous signal can lead to incorrect interpretation of research results. Yet, this problem is not routinely addressed in current sequence processing pipelines., Results: We present cDNA-detector, a computational tool to identify and remove exogenous cDNA contamination in DNA sequencing experiments. We demonstrate that cDNA-detector can identify cDNAs quickly and accurately from alignment files. A source inference step attempts to separate endogenous cDNAs (retrocopied genes) from potential cloned, exogenous cDNAs. cDNA-detector provides a mechanism to decontaminate the alignment from detected cDNAs. Simulation studies show that cDNA-detector is highly sensitive and specific, outperforming existing tools. We apply cDNA-detector to several highly-cited public databases (TCGA, ENCODE, NCBI SRA) and show that contaminant genes appear in sequencing experiments where they lead to incorrect coverage peak calls., Conclusions: cDNA-detector is a user-friendly and accurate tool to detect and remove cDNA detection in NGS libraries. This two-step design reduces the risk of true variant removal since it allows for manual review of candidates. We find that contamination with intentionally and accidentally introduced cDNAs is an underappreciated problem even in widely-used consortium datasets, where it can lead to spurious results. Our findings highlight the importance of sensitive detection and removal of contaminant cDNA from NGS libraries before downstream analysis., (© 2021. The Author(s).)

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Kα inhibitor alpelisib in estrogen receptor positive (ER + ) PIK3CA -mutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, for example, MCL1 inhibitors, was experimentally validated in ER + breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line-specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL2 family members were highly expressed. On the basis of these results, newly developed cell line-specific network models were able to recapitulate the observed differential response to alpelisib and BH3 mimetics. This approach illustrates how network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance. SIGNIFICANCE: Network-based mathematical models of oncogenic signaling and experimental validation of its predictions can identify resistance mechanisms for targeted therapies, as this study demonstrates for PI3Kα-specific inhibitors in breast cancer., (©2021 American Association for Cancer Research.)

Purpose: There are limited data on trastuzumab-pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response., Methods: After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m 2 on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients., Results: The six-patient run-in established a dose of eribulin 1.4 mg/m 2 with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2-51.2%) in Cohort A and 0% in Cohort B (95% CI 0-41.0%). WES revealed more frequent alterations in TP53 (p < 0.05, q > 0.05) in patients without clinical benefit (disease control for < 24 weeks) which was not significant after multiple hypothesis correction., Conclusion: Eribulin-HP had manageable toxicity and modest clinical activity in patients without prior pertuzumab exposure. This study provides a preliminary landscape of somatic alterations in this patient cohort. Our data add to the literature on how genomic alterations may predict for therapy response/resistance, as we work to individualize choices in a quickly evolving HER2+ MBC treatment landscape., Trial Registration: www.clinicaltrials.gov , NCT01912963. Registered 24 July 2013., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The enteric nervous system (ENS) consists of an interconnected meshwork of neurons and glia residing within the wall of the gastrointestinal (GI) tract. While healthy GI function is associated with healthy ENS structure, defined by the normal distribution of neurons within ganglia of the ENS, a comprehensive understanding of normal neuronal distribution and ganglionic organization in the ENS is lacking. Current methodologies for manual enumeration of neurons parse only limited tissue regions and are prone to error, subjective bias, and peer-to-peer discordance. There is accordingly a need for robust, and objective tools that can capture and quantify enteric neurons within multiple ganglia over large areas of tissue. Here, we report on the development of an AI-driven tool, COUNTEN (COUNTing Enteric Neurons), which is capable of accurately identifying and enumerating immunolabeled enteric neurons, and objectively clustering them into ganglia. We tested and found that COUNTEN matches trained humans in its accuracy while taking a fraction of the time to complete the analyses. Finally, we use COUNTEN's accuracy and speed to identify and cluster thousands of ileal myenteric neurons into hundreds of ganglia to compute metrics that help define the normal structure of the ileal myenteric plexus. To facilitate reproducible, robust, and objective measures of ENS structure across mouse models, experiments, and institutions, COUNTEN is freely and openly available to all researchers., (Copyright © 2021 Kobayashi et al.)

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i., Patients and Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers., Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib., Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

Purpose: In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS)., Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC., Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2 , and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR + /HER2 - tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC ( P = 0.041)., Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments., (©2020 American Association for Cancer Research.)

Background: Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States., Methods: A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response via Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12])., Results: Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months., Conclusion: Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

Methods for highly multiplexed RNA imaging are limited in spatial resolution and thus in their ability to localize transcripts to nanoscale and subcellular compartments. We adapt expansion microscopy, which physically expands biological specimens, for long-read untargeted and targeted in situ RNA sequencing. We applied untargeted expansion sequencing (ExSeq) to the mouse brain, which yielded the readout of thousands of genes, including splice variants. Targeted ExSeq yielded nanoscale-resolution maps of RNAs throughout dendrites and spines in the neurons of the mouse hippocampus, revealing patterns across multiple cell types, layer-specific cell types across the mouse visual cortex, and the organization and position-dependent states of tumor and immune cells in a human metastatic breast cancer biopsy. Thus, ExSeq enables highly multiplexed mapping of RNAs from nanoscale to system scale., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g) BRCA1 / 2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s) BRCA1 / 2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/ 2., Methods: Eligible patients had MBC with measurable disease and germline mutations in non- BRCA1 / 2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1 / 2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS)., Results: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, s BRCA1 / 2 , ATM, or CHEK2 . In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g PALB2 (ORR, 82%) and s BRCA1 / 2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g PALB2 and 6.3 months (90% CI, 4.4 months to NA) for s BRCA1 / 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone., Conclusion: PARP inhibition is an effective treatment for patients with MBC and g PALB2 or s BRCA1 / 2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g BRCA1 / 2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Glioblastoma remains the most common malignant brain neoplasm in adults. The available therapies for treatment have only modestly extended survival. Traditional chemotherapy agents have shown only slight effectiveness in controlling this disease. The use of molecular profiling has allowed personalized medicine options to be explored for the care of these individuals. Targeted therapies have shown significant benefit in numerous other cancer types with survival being extended significantly. In glioblastoma, several promising markers have been identified including vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). These targets have been shown to play a critical role in glioblastoma formation and proliferation. The pathways of these receptors have been elucidated in detail. This level of understanding has led to the a more robust understanding of possible mechanism of pathway modification. The targeting of these specific markers has led to the development of several selective therapies with additional therapies being evaluated. The clinical trials validating these markers have been promising but have yet to show a clear benefit in brain tumors. This identification of alternative methods to address these markers or identify additional targets may be the key to the fight against this disease. The molecular targeting of glioblastoma pathways may have significant impact on disease control and patient survival.

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER + breast cancer., Experimental Design: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ER + metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance., Results: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via FGFR1, FGFR2 , or FGF3 amplifications or FGFR2 mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER + breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor., Conclusions: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors., (©2020 American Association for Cancer Research.)

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR + ) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2 , and FGFR2 , and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA , or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS , and AURKA -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR + metastatic breast cancer. This article is highlighted in the In This Issue feature, p. 1079 ., (©2020 American Association for Cancer Research.)

Purpose: We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets., Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9., Results: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A-RASGRF1 , with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib., Conclusions: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1., (©2020 American Association for Cancer Research.)

Background: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM., Methods: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS)., Results: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms., Conclusion: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental., (© 2020 American Cancer Society.)

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC., Experimental Design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features., Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy ( n = 90) and non-ICI regimens ( n = 169)., Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets., (©2020 American Association for Cancer Research.)

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing., Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples., Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( n = 13/16) in newly diagnosed MBC, 23% ( n = 7/30) at postoperative and 19% ( n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months)., Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track., (©2020 American Association for Cancer Research.)

Background: Patients of lower socioeconomic status (SES) may experience barriers to their oncologic care, but current data conflict over whether SES affects the prognosis of patients with glioblastoma (GB)., Objective: We sought to determine whether SES disparities impaired delivery of neuro-oncologic care and affected the prognosis of GB patients., Methods: The records of GB patients treated from 2010 to 2014 at a safety-net hospital (SNH) or private hospital (PH), both served by 1 academic medical institution, were retrospectively reviewed and compared. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method., Results: A total of 55 SNH and 39 PH GB patients were analyzed with median 11-month follow-up. SNH patients were predominantly Hispanic, low income, enrolled in Medicaid, were less likely to receive radiation (89% vs. 100%), took longer to start radiation (41 vs. 29 days), and were less likely to complete radiation treatment (80% vs. 95%). Concurrent and adjuvant temozolomide use were also lower (85% vs. 94% and 60% vs. 71%, respectively). OS and PFS were not significantly different (15 vs. 16 months and 8 vs. 11 months, respectively). On multivariate analysis, adjuvant chemotherapy and RT completion predicted for better OS, whereas hospital type, income, and insurance did not., Conclusion: Although GB patients at our SNH received less adjuvant treatment compared with PH, outcomes were similar. Access to multidisciplinary care staffed by academic physicians may play an important role in overcoming socioeconomic barriers to treatment availability and quality at SNHs., (Copyright © 2020 Elsevier Inc. All rights reserved.)