bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare resource utilization (HCRU) and costs for patients (pts) with metastatic renal cell carcinoma (mRCC) receiving first-line (LOT1) pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N).
Authors: Shah Neil J. , Shinde Reshma , Moore Kristin , Sainski-Nguyen Amy , Le Lisa , Cao Feng , Song Rui , Singhal Puneet , Motzer Robert J.
Published: June 2022

4528

Background: Approval of immuno-oncology (IO) agents have changed treatment paradigm for mRCC pts. While IO-based therapies have demonstrated improved survival, these can be associated with considerable HCRU and costs necessitating their examination in real-world practice. Methods: This retrospective claims analyses utilizing Optum Research Database included adult pts with mRCC diagnosis from July-2017 to Aug-2020 and received P+A or I+N as LOT1 from Jan-2018 to May-2020 (first claim=index date). All eligible pts required continuous enrollment for minimum of 6-months prior and 3-months post the index date unless death occurred. All-cause HCRU counts, and associated costs were examined during the first 90 days (LOT1-90) and entire LOT1 duration and reported as overall and per-pt-per-month (PPPM) estimates. Results: The study identified 507 pts (P+A=126, I+N=381). Average age of the entire cohort was 67 years, 71% were male, mean NCI Charlson score was 2.4, and lung (55%) and bone (33%) were the most common metastatic sites. Mean (SD) distance from mRCC diagnosis to index date was 97 (172) days. Pts with P+A and I+N had similar baseline characteristics. Total % of pts with ambulatory visits was similar for P+A and I+N for LOT1-90 and entire LOT1 (99.2 vs. 100.0%, p=0.082 for both). During LOT1-90, we observed a lower % of pts on P+A with ER visits and inpatient (IP) stay compared to I+N (34 vs. 48, p=0.008; 19 vs. 38, p<0.001, respectively). We also observed a shorter mean (SD) IP stay for P+A vs. I+N during LOT1-90 (1.9 (6.5) vs. 5.6 (13.24) days, p<0.001). Similarly, P+A had lower mean PPPM ambulatory visits, IP stay, and ICU stay during both LOT1-90 and entire LOT1 (Table). In addition, mean PPPM total (medical + pharmacy) and mean PPPM medical costs were lower for P+A compared to I+N, but mean PPPM pharmacy costs were higher for P+A for both LOT1-90 and entire LOT-1 (Table). Conclusions: This study noted significantly higher HCRU with I+N including higher mean PPPM ambulatory visits, IP stays, and ICU stays compared to P+A. Although, P+A had higher mean PPPM pharmacy costs, the total medical plus pharmacy costs were significantly lower compared to I+N. [Table: see text]
Association between tumor burden and response to immunotherapy in patients with metastatic renal cell carcinoma.
Authors: Yasin Hesham Abdallah , Chen Yu-Wei , Tucker Matthew D , Beckermann Katy , Schaffer Kerry , Davis Nancy B. , McAlister Renee , Wallace Deborah , Kaiser Elizabeth , Rini Brian I.
Published: June 2022

4541

Background: Immunotherapy (IO) has become the standard of care in patients with metastatic renal cell carcinoma (mRCC), yet clinical biomarkers of outcome remain elusive. Preclinical and clinical studies have demonstrated that a lower tumor volume burden is associated with better response to IO in melanoma and lung cancer. Methods: Retrospective chart review of mRCC patients treated with Immunotherapy/Immunotherapy or Immunotherapy/Tyrosine kinase inhibitors (TKI) combinations at Vanderbilt Ingram Cancer Center was conducted. Baseline target tumor lesions including primary kidney tumors and treatment response were assessed by RECIST 1.1 criteria. The association between baseline tumor burden and outcomes of interest [progression-free survival (PFS) and overall survival (OS)] were assessed with multivariable Cox regression model. Results: 79 patients with mRCC were included in the cohort. The median age was 64, 80% were male, 82% had clear cell histology, and 73% were IMDC intermediate/poor risk group. 53% received IO/IO and 39% received IO/TKI. 71% had prior nephrectomy and 14% had prior systemic therapy. The median baseline tumor burden was 87 mm (range: 16-363 mm). After adjusting for age, gender, histology, prior nephrectomy/systemic therapy and IMDC risk, baseline tumor burden was not associated with either PFS (p-value: 0.42) or OS (p-value: 0.99). At the initial follow-up scan (median time of 3.1 months from treatment initiation) 22 (28%) patients had an objective response and 41 (52%) patients had stable disease. Among patients with tumor shrinkage, every 10% decrease seen in the sum of the target lesions was associated with improved PFS (AHR: 0.77, 95%CI: 0.63-0.94, p-value:0.009) and OS (AHR: 0.62, 95%CI: 0.42-0.93, p-value:0.02). Conclusions: While baseline tumor burden volume was not associated with clinical outcome to immunotherapy-based therapy in patients with metastatic RCC; however, the degree of early tumor shrinkage was significantly associated with better outcomes. Large tumor burden does not preclude response and good outcome to immunotherapies.
A classification system for urothelial carcinoma (UC) defined by genomic drivers and the tumor microenvironment (TME) is predictive of immunotherapy response.
Authors: Chernyshov Konstantin , Miheecheva Natalia , Love Anna , Nomie Krystle , Fowler Nathan , Frenkel Felix
Published: June 2022

4591

Background: UC is associated with high recurrence rates, progression, and resistance to platinum-based therapy. Checkpoint inhibitors (CPIs) are often used for treating UC, but predictive biomarkers that characterize response are lacking in the majority of patients. Defining the TME is essential to understanding patient response to CPIs. Employing a transcriptome-based classification platform, we sought to identify predictive and prognostic subtypes of UC using malignant cell and TME features. Methods: We collected a metacohort of 2,418 UC samples from 14 publicly available datasets, one of which had atezolizumab response data (IMvigor210). Using the methodology described in Bagaev et al. 2021, we selected 28 signatures composed of specific gene sets reflecting distinct cellular processes. Analysis of signature expression and unsupervised clustering was performed. Results: We identified 7 recurring novel UC subtypes (Table 1) with unique genomic and molecular characteristics. The subtypes and key findings include: an immune desert (D) subtype characterized by genomic instability high HER2 expression; an immune desert, FGFR-altered (D-FGFR) subtype with FGFR alterations; an immune enriched (IE) subtype with an enriched TME and high CPI response; a fibrotic (F) subtype with a mesenchymal TME, and strong TGFβ signaling; an immune enriched, fibrotic (IE-F) subtype with a mixed TME and a high CPI response rate; a fibrotic, basal (F-B) subtype with a mesenchymal TME and minimal genomic targets, and a neuroendocrine-like (NE-L) subtype with a high CPI response rate. Conclusions: UC can be classified into 7 subtypes with distinct prognoses, CPI response rates, and druggable targets using malignant cell and TME profiling. Patients with IE, IE-F, and NE-L UCs may be good candidates for CPIs. D UCs may benefit from HER2-i and PARP-i, while FGFR-i might be more suitable for D-FGFR UCs. TGFβi and PARPi may be effective for F UCs, but F-B UCs have no targetable findings. These findings warrant additional investigation for clinical translation. [Table: see text]
A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vaishampayan Ulka N. , Keessen Marianne , Heath Elisabeth I. , Dreicer Robert , Buchler Tomas , Árkosy Péter Ferenc , Csoszi Tibor , Wiechno Pawel J. , Kholtobin Denis , Kopyltsov Evgeny , Shore Neal D. , Nosov Aleander , Orlov Sergey , Plekhanov Alexey , Smagina Maria , Varlamov Sergey , Vogelzang Nicholas J.
Published: June 2022

5016

Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in patients (pts) with mCRPC. ModraDoc006 is an oral formulation of docetaxel. To enhance bioavailability of ModraDoc006, it is co-administered with ritonavir (/r). The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines The oral combination (ModraDoc006/r) was compared to IV docetaxel in a randomized phase 2b study in pts with mCRPC evaluating two doses of ModraDoc006/r (30-20/200-100 mg and 20-20/200-100 mg). Data on outcomes in the larger cohort, receiving the lower dose, are being presented. Methods: Eligible pts had mCRPC, performance status of 0-1 and no prior chemotherapy for mCRPC. Sixty-two pts were enrolled in open label 1:1 randomized study comparing ModraDoc006/r 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m2 in 21-day cycles. All pts received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Results: 31 pts were enrolled on IV docetaxel 75 mg/m2 and 31 on ModraDoc006/r 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 pts with measurable disease were included in the ORR analysis. Median PSA was 46 (range 1 to 1460 ng/ml). Prior therapy with enzalutamide in 8 pts, abiraterone in 10 pts. ModraDoc006/r was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% G1 only on ModraDoc006/r vs 9.7% G1 and 19.4% G2 on IV docetaxel, whereas alopecia was reduced to 16.1% G1 and 6.5% G2 on ModraDoc006/r vs. 22.6% G1 and 19.4% G2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥G3) vs 29%, nausea 29% vs 13% and stomatitis 3% (G3) vs 13% (3% ≥G3), respectively. Conclusions: ModraDoc006/r demonstrated a favorable safety profile and comparable efficacy to IV docetaxel in pts with mCRPC, thus providing a compelling rationale for conduct of an expanded pivotal program. A key clinical program focus is the comparison of ModraDoc006/r to best available therapy in refractory mCRPC. Studies of ModraDoc006/r in other malignancies are also in active development. Clinical trial information: NCT04028388. [Table: see text]
Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial.
Authors: Huppert Laura Ann , Rugo Hope S. , Pusztai Lajos , Mukhtar Rita A. , Chien Amy Jo , Yau Christina , Wolf Denise M. , Berry Donald A. , van 't Veer Laura , Yee Douglas , DeMichele Angela , Esserman Laura ,   I-SPY2 Consortium
Published: June 2022

504

Background: Hormone receptor positive (HR+), HER2- breast cancer (BC) is a heterogenous disease. We hypothesized that molecular subtypes capturing luminal, basal, and immune biology could predict response for patients (pts) with HR+/HER2- disease in the I-SPY2 trial. Methods: I-SPY2 trial is a phase II, randomized, adaptive study evaluating multiple investigational agents as neoadjuvant BC therapy; the primary endpoint is estimated pCR rate. Investigational agents are given with control weekly paclitaxel x 12, followed by AC x 4. Regimens graduate when the predicted pCR rate in any signature meets the pre-specified threshold of 85% probability of success in a hypothetical 300 pt randomized, phase 3 trial. We analyzed estimated pCR rates for the 1st 7 investigational agents in the HR+/HER- subset, analyzed by clinical/molecular features: BluePrint (BP) Luminal vs. Basal, Mammaprint High1 [MP1] vs. Mammaprint High2 [MP2], MP2 is < -0.57, Responsive Predictive Subtype-5 (RPS-5) (classification based on HR, HER2, immune, DNA-repair, and basal/luminal markers), histology, and stage/nodal status. Results: 38% (379/987) of pts had HR+/HER2- disease. Only pembrolizumab met the pre-specified graduation criteria for HR+/HER2- BC. pCR rates by treatment arm and molecular subtype are described in the Table. 28% were MP2; 72% were MP1. Overall, pCR rates were higher in pts with MP2 vs MP1 disease (30% vs 11%) including with pembrolizumab (55% vs. 21%). 29% were BP Basal, 71% were BP Luminal; BP Basal was more likely to be MP2 than BP Luminal (77% vs 8%). In all arms except MK2206, HR+/HER2- BP Basal pts were more likely to achieve pCR than BP Luminal pts. For MK2206, BP Luminal pts were more likely to achieve pCR. Immune+ by RPS-5 (39% of HR+/HER2-) predicted pCR to pembrolizumab irrespective of BP Basal or Luminal status (11 pCR/16 pts). Results by histology and stage/nodal status will also be reported. Conclusions: Our data suggest that MP2 and BP Basal signatures identify a subset of HR+/HER2- BC more likely to respond to neoadjuvant therapy; and that an immune signature can identify pts more likely to respond to pembrolizumab. These findings will aid in guiding prioritization of targeted agents with the goal to optimize pCR for all pts. Clinical trial information: NCT01042379. [Table: see text]
Survival analysis of the randomized phase II trial to investigate androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Maluf Fernando Cotait , Soares Andrey , Bastos Diogo Assed , Schutz Fabio A. B. , Cronemberger Eduardo , Luz Murilo , Martins Suelen P. S. , Muniz David Queiroz Borges , Carcano Flavio Mavignier , Smaletz Oren , Peixoto Fábio A , Gomes Andrea J , Cruz Felipe Melo , Franke Fabio , Herchenhorn Daniel , Gidekel Rosemarie , Rebelatto Taiane Francieli , Gomes Rafaela , Souza Vinicius Carrera , Fay Andre P.
Published: June 2022

5076

Background: LACOG 0415 is a phase II, open-label, clinical trial evaluating ADT-free alternatives for advanced castration sensitive prostate cancer (CSPC). Methods: Patients with locally advanced, high-risk biochemical recurrence or metastatic CSPC were randomized (1:1:1) to receive ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA), or apalutamide with AAP (APA+AAP). The primary endpoint of the trial was the proportion of patients who achieved PSA≤0.2 ng/mL level at week 25. Patients without disease-progression and with clinical benefit after week 25 were allowed to maintain treatment at the discretion of physicians. Herein, we presented the outcomes of 2 year-overall survival (2y-OS) and time-to-treatment failure (TTF). The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were randomized to the ADT+AAP (n = 42), APA (n = 42), and APA+AAP (n = 44) arms. At week 25, PSA≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in the ADT+AAP, APA, and APA+AAP arms, respectively. 110 patients continued treatment after week 25. At the 2-year visit, 80 (62.5%) patients remained on the study medication. Median TTF was 24.0 months (95%CI 23.3 - 24.0) with ADT+AAP, 24.0 months (95%CI not estimated) with APA, and 24.0 months (95%CI 13.0-24.0) with APA+AAP. The main reasons for treatment discontinuation were disease progression (n = 8, 6.3%), toxicity (n = 10, 7.8%), death (n = 6, 4.7%), withdrawal (n = 4, 3.1%), and other (n = 19, 14.8%). The estimated proportion of patients who were alive at 2 years (2y-OS rate) was 92.5% (95%CI 84.3-100) with ADT+AAP, 87.9% (95%CI 77.9-97.8) with APA, and 92.7% (95%CI 84.8-100) with APA+AAP (p = 0.5926). 2y-OS was 92.9% (95% CI 85.3 - 96.2) in patients with PSA ≤ 0.2 ng/mL at week 25, while 2y-OS was 85.0% (95% CI 72.9-97.1) in patients with PSA > 0.2 ng/mL at week 25 (p = 0.1250). Conclusions: Patients with advanced CSPC treated with ADT+AAP, APA, or APA+AAP had high rates of PSA response and favorable 2y-OS. PSA ≤ 0.2 ng/mL at week 25 seems to be a surrogate prognostic predictor of OS in advanced CSPC. In the overall sample, patients with PSA ≤ 0.2 ng/mL at week 25 had higher 2y-OS rate than those with PSA > 0.2 ng/mL at week 25 (92.9% vs. 85.0%), however without statistical significance. Clinical trial information: NCT02867020.
Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate cancer.
Authors: Reddy Deepika , Dudderidge Tim , Shah Taimur , McCracken Stuart , Arya Manit , Fiorentino Francesca , Day Emily , Prevost Andrew , Emberton Mark , Staffurth John , Sandhu Sarbjinder , Hindley Richard , Arumainayagam Nim , Sydes Matthew R. , Khoo Vincent , Winkler Mathias , Ahmed Hashim Uddin
Published: June 2022

5086

Background: Randomised comparative data is lacking for focal therapy in localised prostate cancer. Imperial Prostate 4 CHRONOS (IP4- CHRONOS) is an RCT designed to reflect patient and physician equipoise to maximise acceptance to randomisation. Methods: Patients and physicians could opt for CHRONOS-A or CHRONOS-B. CHRONOS-A randomised between focal therapy (HIFU/cryotherapy) and radical therapy (radiation/prostatectomy). Using a multi-arm-multistage design, CHRONOS-B randomised between focal and focal combined with neoadjuvant medication (3 months of either finasteride or bicalutamide). We report the pilot phase outcomes on feasibility of randomisation. IP4-CHRONOS had ethics committee approval and was registered (ISRCTN17796995). Results: Due to impact of COVID-19, the target for CHRONOS-A was modified from 60 to 36; 36 patients were randomised over 24 months from 7 sites (Nov/2019-Nov/2021). CHRONOS-B randomised 64 patients over 14 months across 6 sites (Dec/2019-Feb/2021). Median (IQR) age and PSA (ng/ml) for CHRONOS-A were 69 (65-72) years and 6 (5-7) and for 66 (60.5-70) years and 6 (4-7) for CHRONOS-B, respectively. 34/36 (94%) and 60/64 (94%) had ISUP Grade Group > / = 2, respectively. 4/18 (22%) randomised to radical in CHRONOS-A withdrew consent; 1/22 (5%) randomised to focal withdrew. In CHRONOS-B, only 1/21 (5%) randomised to focal alone, and another randomised to focal with neoadjuvant bicalutamide withdrew. A qualitative recruitment intervention partially improved accrual to CHRONOS-A. Conclusions: IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Randomising between focal and radical therapy is not feasible due to strong patient preferences. A multi-arm, multi-stage RCT investigating the role of neoadjuvant agents combined with focal therapy is feasible. Clinical trial information: 17796995.
Exploring homologous recombination deficiency thresholds for predicting response to platinum-based treatment in triple negative breast cancer.
Authors: Timms Kirsten , Lenz Lauren , Cogan Elizabeth S. , Mayer Erica L. , Kaklamani Virginia G. , Stearns Vered , Abramson Vandana G , Falkson Carla Isadora , Jankowitz Rachel Catherine , Marcom P. Kelly Kelly , Tung Nadine M. , Gradishar William John , Ford James M. , Vinayak Shaveta , Boughey Judy Caroline , Goetz Matthew P. , Storniolo Anna Maria , Connolly Roisin M. , Richardson Andrea L. , Telli Melinda L.
Published: June 2022

525

Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC0301, TBCRC0082, NCT013725793, PrECOG 01054, combined cisplatin cohort4) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]
Safety and tolerability of olaparib combined with breast radiotherapy in patients with triple-negative breast cancer: Final results of the RADIOPARP phase 1 trial.
Authors: Loap Pierre , Loirat Delphine , Berger Frederique , Rodrigues Manuel , Bazire Louis , Pierga Jean-Yves , Vincent-Salomon Anne , Laki Fatima , Boudali Latifa , Raizonville Laurence , Mosseri Veronique , Jochem Anne , Diallo Mamadou , Stern Marc-Henri , Fourquet Alain , Kirova Youlia M.
Published: June 2022

534

Background: Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells were sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy may consequently enhance the biological effectiveness of the irradiation, leading to improved locoregional control in TNBC patients. We aimed to establish the appropriate dosing and the safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. Methods: RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or to the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. Results: Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 65% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. Conclusions: Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered. Clinical trial information: NCT03109080.
Cisplatin-induced nephrotoxicity in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitigated by sodium thiosulfate: Clinical and toxicotranscriptomic results of a prospective trial.
Authors: Lugo Santiago Nicole , Han Ernest Soyoung , Raoof Mustafa , Wu Xiwei , Cho Hyejin , Lee Stephen , Lin Wei-Chien , Lin Jeff Feng-Hsu , Stewart Daphne B. , Ruel Nora H. , Wang Edward Wenge , Paz Isaac Benjamin , Wakabayashi Mark Tsuneo , Rodriguez-Rodriguez Lorna , Cristea Mihaela C. , Dellinger Thanh Hue
Published: June 2022

5570

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC). Unfortunately, cisplatin is associated with significant renal toxicities. Sodium thiosulfate (ST) has been suggested as a nephroprotectant for patients undergoing HIPEC with cisplatin. Methods: A feasibility trial ( ClinicalTrials.gov: NCT01970722) evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during optimal cytoreductive surgery (CRS) in patients with EOC and endometrial cancer (n = 40), with or without ST. Twenty-one patients received no sodium-thiosulfate (nST group), and nineteen patients received sodium thiosulfate (ST group). Toxicities were reported according to CTCAE v. 5. Progression-free survival was followed. Normal tissue biopsies were collected intra-operatively immediately following HIPEC and cisplatin exposure in a subset of patients (n = 21), and profiled with transcriptomic sequencing to identify RNAseq signatures correlating with toxicities. Hierarchical cluster analyses identified distinct transcriptomic signatures in post-HIPEC normal samples of patients with renal AEs (rAEs) compared to no renal AEs (nrAEs). KEGG pathway analysis identified up- or downregulated gene sets using GSEA. Results: Forty patients had HIPEC at time of optimal CRS. Renal toxicities were higher in the nST group (no sodium thiosulfate) compared to the ST group. nST patients had 17% any grade, and 9% Grade 3 AEs for acute and chronic kidney injuries. In contrast, ST patients suffered 0% renal AEs. rAE patients demonstrated upregulation of immune signaling pathways (Toll-like receptor, Natural killer cell, Nod-like receptor); and downregulation of metabolic pathways. Top upregulated genes in rAE patients included immune (e.g. neutrophil) related genes, while downregulated genes included metabolism genes. Kaplan-Meier curves demonstrated improved PFS in primary ovarian cancer patients undergoing HIPEC who were treated with ST vs no ST (p = 0.04, NR vs 13.4 mo). Conclusions: HIPEC with cisplatin results in significant renal toxicities. The mechanisms of cisplatin-induced nephrotoxicity in HIPEC are immune-related and reflect reduced metabolism. Sodium thiosulfate abrogated renal toxicities and did not decrease PFS. Clinical trial information: NCT01970722.
Mutational landscape of low-grade serous carcinoma of the ovary.
Authors: Schink Julian C. , Garg Ruchi , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Farley John H. , Markman Maurie
Published: June 2022

5578

Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that are potential therapeutic targets. We present an analysis of comprehensive genomic profiling (CGP) of a large series of low grade serous ovarian carcinoma patients assayed in a nationwide cancer network. Methods: 40 Pts with advanced low grade serous ovarian carcinoma (LGSOC) underwent hybrid-capture based CGP for up to 324 cancer-related genes on archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 thru 06-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 44 years (range, 25-65), 68% were White and 23% were Black. Genomic alterations (GA) were identified in 80% (32/40) of LGSOC, of which 22 (55%) had a clinically relevant genomic alteration (CRGA). There were no apparent racial differences between mutation frequencies. The table below details the frequency of the most common of these clinically relevant mutations. Additionally, 1 patient had an ESR1 activating mutation commonly seen in acquired hormone therapy resistance in breast cancer; and single cases of the following mutations were also noted: TSC1, PTCH1, PTEN, FGFR1, and AKT2. Conclusions: In a large series of Low Grade Serous Ovarian Cancer patients assayed with CGP, 55% of pts had mutations potentially targeted by precision medicine therapy. The most common target is KRAS, seen in 33% of patients, these are potentially treatable with FAK and MEK inhibitors. Another 10% of patients had either a BRCA or ATM mutations making PARP inhibitor therapy an additional targeted treatment option. While mutations in the RAS pathway are most common in LGSOC they are not the only actionable target. Furthermore, this approach might also help identify baseline or acquired resistance to the hormone therapies often used to treat this cancer. The results of this study demonstrate the significant heterogeneity of genomic alterations in this rare cancer and highlight the importance of genomic profiling in this cancer which has a marked propensity for recurrence. [Table: see text]
HER2 in uterine carcinosarcoma: Testing platforms and implications for targeted therapy.
Authors: Maredia Navin , Wu Sharon , Farrell Alex , Oberley Matthew James , Thomaier Lauren , Jones Nathaniel L. , Herzog Thomas J. , Thaker Premal H. , Powell Matthew A. , Klc Tenley , Erickson Britt Kristina
Published: June 2022

5590

Background: Uterine carcinosarcomas (UCS) are rare, aggressive tumors accounting for 5% of all uterine cancers. Recurrence rates are high and 5-year survival is only 18-39%. HER2 is an emerging prognostic and therapeutic target in uterine cancer including UCS. Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to determine HER2 prevalence in UCS and the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of UCS specific testing guidelines. We also evaluated the rate of downstream mutations and immune biomarkers that may affect response to HER2 directed therapy. Methods: Eight hundred and seventy-five UCS tumor samples (primary 81.4%; metastatic 17.1%; unknown 1.5%) were analyzed using NGS (592, NextSeq; WES, NovaSeq, Caris Life Sciences, Phoenix, AZ). A subset of tumors with HER2 positivity were tested with IHC (4B5, Ventana) and/or CISH (INFORM DUAL HER2 ISH Assay, Ventana) based on 2018 ASCO/CAP HER2 Breast Cancer guidelines. Amplification of ERBB2/HER2 by NGS used a copy number cut-off >6. PD-L1 expression was analyzed by IHC (SP142, positive cut-off ≥1%, Ventana). Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (TMB high cut-off > 10 mutations per Mb). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Results: Rates of HER2 positivity were 3.4% (28/820) by NGS. Among the IHC/CISH-tested cohort, 7.2% was positive (10/139) by IHC, and 19.5% (27/133) by CISH. In the 105 samples tested with both IHC and CISH, the concordance was 100%. Specifically, 9/105 patients (8.6%) were IHC+/CISH+ and 96 patients (91.4%) were IHC-/CISH-. The concordance between CISH and NGS (N = 127) was 90.6% (sensitivity 100% and specificity 89.3%). Common gene alterations in CISH HER2+ UCS tumors that may implicate resistance to HER2 targeted therapy included mutations in TP53 (100%), FBXW7 (22.2%), PIK3CA (33.3%), PIK3R1 (18.5%), PTEN (3.7%) and KRAS (3.7%) and gene amplification of KRAS (11.1%). CISH+ HER2+ UCS tumors had low immunotherapy biomarker prevalence (0% MSI-H, 0% TMB high, 7.7% PD-L1+). Conclusions: Increased HER2 positivity was detected via CISH testing compared to IHC and NGS, which may reflect the heterogeneity of HER2 amplification due to mixed histology between the sarcoma and carcinoma portion of the tumor. High concordance rates were observed between CISH and IHC. These testing platforms need to be validated by response to HER2 targeted therapies in order to develop UCS specific testing guidelines.
Impact of travel burden on overall survival in patients with lung cancer.
Authors: Stoyanov Dragomir Svetozarov , Tonev Ivan , Dimitrova Eleonora , Panayotova Teodorika , Manev Rostislav , Donev Ivan , Conev Nikolay
Published: June 2022

6522

Background: High-volume specialized centers are more efficient at managing patients with lung cancer than low-volume centers. Centralization of cancer treatment has the potential to improve patient outcomes and quality of treatment. However, the growing centralization also increases patient’s travel burden (measured as travel distance or travel time) and may negatively impact access to specialist services. The aim of our study was to evaluate the potential impact of travel burden on clinical outcomes in patients with lung cancer. Methods: A retrospective analysis of a single Bulgarian center was performed. A total of 9240 lung cancer patients treated between 2005-2020 were included in the study. Travel distance between patients’ city of residence and the treating facility was calculated with an online tool to determine the shortest route for travel using the existing road network. The mean of travel time values for every workday of the week was calculated to control for daily changes in typical traffic. The probability of survival was estimated using the Kaplan-Meier method and differences in survival in each subgroup were evaluated with a log-rank test. Results: About one third of all included patients were living in the same city as the treating facility (n = 2746, 29.7%). The medians for travel distance and travel time were used to stratify patients into subgroups. According to travel distance the patients were grouped into three strata – same city, < 50 km and ≥ 50 km. A cut-off of 60 min was used to stratify patients into three groups by travel time – same city, < 60 min and ≥ 60 min. Overall survival in our patient population was significantly lower with increasing travel distance (p < 0.001, Mantel-Cox log rank) and travel time (p < 0.001, Mantel-Cox log rank). The 1-year OS rate according to travel distance was 27.1% in the same city group, 22.4% in < 50 km group and 20.5% in ≥ 50 km group (p < 0.001). The corresponding values for the 5-year OS rate were: 2.9%, 2.6% and 1.4% (p < 0.001). Conclusions: In this retrospective study we discovered significant differences in overall survival of patients with lung cancer depending on travel distance and travel time to the treating oncological facility. Despite having similar clinical and pathological characteristics (age, sex, stage at initial diagnosis, histologic subtype), the median overall survival was significantly lower in those subgroups of patients with a higher travel burden. [Table: see text]
Analysis of demographic characteristics and disparities of enrollment in cancer clinical research at the U.S. National Cancer Institute (NCI): A 15-year experience.
Authors: Choradia Nirmal , Gulley James L. , Floudas Charalampos S.
Published: June 2022

6529

Background: Racial, gender, and socioeconomic disparities in cancer clinical trials participation have been well documented. The intramural program of the NCI in the National Institutes of Health (NIH) Bethesda campus conducts clinical research where participants are referred by their physician or self-referred, treated without charge and receive aid in travel expenses. We sought to describe the demographics of participants and identify potential disparities. Methods: We used the clinical research data repository of the NIH, Biomedical Translational Research Information System (BTRIS), to extract self-reported demographic data of enrollees in NCI protocols from 2005-2020. Comparisons were made with the U.S. population of patients with cancer as captured in the Surveillance, Epidemiology, and End Results (SEER) Program (2005-2018). The average household income per zip code was derived from the American Community Survey at five-year increments from 2011, 2015, and 2019. Results: We obtained data on 40,007 participants; 38,531 (95%) came from the U.S., of which 18,606 (48%) from DC, Maryland, or Virginia (DMV). Median age at consent was 54 years (range 2 – 89). Proportions of basic demographic attributes and corresponding values from SEER data were presented. Notably, Hispanic male, non-Hispanic female, and white female participants were under-represented in NCI clinical research compared to SEER data. African Americans were under-represented in the non-DMV population (5%) vs. the DMV (19%). Also, for patients from the DMV area, median income was consistently less for African American participants compared to White and Asian participants. Conclusions: The identified disparities may be partially due to the specific research activities available at the NCI, but strategies aiming at increasing the participation and representation of under-represented groups are required. [Table: see text]
Are pivotal clinical trials for lymphomas that led to drug approval representative of the population affected by these diseases?
Authors: Casey Mycal , Odhiambo Lorriane Achieng , Shoukier Mahran , Islam KM , Aggarwal Nidhi , Cortes Jorge E.
Published: June 2022

6531

Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]
Access to definitive treatment and survival for intermediate-risk and high-risk prostate cancer at hospital systems serving health disparity populations.
Authors: Labban Muhieddine , Nguyen David-Dan , Briggs Logan , Cole Alexander P , Lipsitz Stuart R. , Iyer Hari S. , Rebbeck Timothy , Weissman Joel S. , Choueiri Toni K. , Trinh Quoc-Dien
Published: June 2022

6555

Background: Socioeconomic and racial disparities in prostate cancer (PCa) can be attributed to patient-level and physician-level factors. However, there is growing interest in investigating the role of the facility of care in driving cancer disparities. Therefore, we sought to examine receipt of guideline-concordant definitive treatment, time to treatment initiation (TTI), and survival for men with PCa receiving care at hospital systems serving health disparity populations (HSDPs). Methods: We conducted a retrospective analysis of the National Cancer Database (2004-2016) among men with intermediate-risk or high-risk PCa eligible for definitive treatment. The primary outcomes were receipt of definitive treatment and TTI within 90 days of diagnosis. The secondary outcome was survival. We defined HSDPs as minority-serving hospitals – facilities in the highest decile of proportion of Non-Hispanic Black (NHB) or Hispanic cancer patients – and/or high-burden safety-net hospitals – facilities in the highest quartile of proportion of underinsured patients. We used mixed-effect models with facility-level random intercept to compare outcomes between HSDPs and non-HSDPs among the entire cohort and among men who received definitive treatment. We evaluated interactions between HSDP status and race for each of the outcomes. Results: The cohort included 821,931 men with intermediate-risk or high-risk PCa. We included 968 non-HSDPs (72.2%) and 373 HSDPs (27.8%) facilities. Treatment at HSDPs was associated with lower odds of receipt of definitive treatment (aOR 0.64; 95% CI 0.57-0.71; p < 0.001), lower odds of TTI within 90 days of diagnosis (aOR 0.74; 95% CI 0.68-0.79; p < 0.001), and worse survival (aHR 1.05; 95% CI 1.02-1.09; p = 0.003). However, no difference was found in survival among patients who received definitive treatment. NHB men at HSDPs had also worse outcomes than NHB men treated at non-HSDPs as well as NHW men treated at HSDPs (Table). Conclusions: Patients treated at HSDPs were less likely to receive timely definitive treatment and had worse survival. NHB men have worse outcomes than NHW at HSDPs. NHB men with PCa remain largely disadvantaged since they are more likely to be treated at hospitals with worse outcomes and have worse outcomes than other patients at those same institutions. [Table: see text]
Self-reported financial difficulties among patients with multiple myeloma and chronic lymphocytic leukemia: An Alliance for Clinical Trials in Oncology study.
Authors: Conti Rena M. , McCue Shaylene , Dockter Travis , Dusetzina Stacie , Rapkin Bruce D. , Weiss Elisa S. , Behrens Robert J. , Richardson Paul G.
Published: June 2022

6602

Background: Treatment advances have greatly improved survival and quality of life among blood cancer patients, yet significant financial costs are a growing concern. Methods: We conducted an observational, prospective survey in 2019-2020 to estimate the self-reported prevalence of financial difficulty among multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients and identify sociodemographic correlates of financial difficulty. Patients with an MM or CLL diagnosis >/= 18 years of age were recruited from NCI NCORP sites of care. Financial difficulty was measured in a previously validated single question from the EORTC QLQ C30 and a composite measure of five questions from the EORTC QLQ C30. Results: 521 MM and CLL patients were registered to the study, 416 patients were administered all or part of the patient survey, for an overall response rate of 79.8%. 16.8% of respondents reported experiencing financial difficulty in response to the single item question and 58.6% reported experiencing financial difficulty in response to the composite measure. Respondents reporting financial difficulty to both measures had reported household incomes of less than $60,000, identified their highest education levels as a high school diploma or GED, had more than one medical comorbidity and used an expensive oral chemotherapeutic agent to treat their blood cancer. Conclusions: Blood cancer patients treated at NCI NCORP sites are experiencing financial difficulties. Results of this study aim to inform physician, site of care and policy efforts to improve access among cancer patients. Clinical trial information: NCT03870633. [Table: see text]
Assessing eligibility for non-intensive chemotherapy (IC) randomized clinical trials (RCT) in patients (pts) with newly diagnosed (ND) AML from the Connect Myeloid Disease Registry.
Authors: Erba Harry Paul , Pollyea Daniel Aaron , Sekeres Mikkael A. , Garcia-Manero Guillermo , Seiter Karen , DeGutis Irene , Kiselev Pavel , McBride Ali , Yu Edward , Roboz Gail J.
Published: June 2022

7029

Background: Pts with AML in RCTs often do not reflect the population seen in clinical practice due to strict eligibility criteria. This study evaluated criteria from a recent RCT of non-IC against a broad cohort of real-world pts with AML from the Connect® Myeloid Disease Registry (NCT01688011). Methods: Pts were stratified into 3 groups based on the non-IC phase 3 VIALE-A trial eligibility criteria: 1) “eligible” pts who would have met all VIALE-A inclusion criteria; 2) “unfit” pts who would have been ineligible for VIALE-A due to ≥ 1 of the following: abnormal liver/kidney function, high ECOG, recent prior malignancy, comorbidities score ≥ 2 by ACE-27, hepatic grade ≥ 1, AIDS grade ≥ 1; 3) “fit” pts who would have been ineligible for VIALE-A because they would have qualified for IC (defined as: ≤ 74 y of age, low ECOG, no apparent cardiovascular/renal comorbidities, and did not meet any criteria in #2). Baseline characteristics were summarized by eligibility group. Overall survival (OS) by group was estimated using the Kaplan–Meier method. Induction regimens were categorized as IC (any regimens containing 7+3, MEC, CLAG, FLAG) or venetoclax (VEN)-based. Hazard ratios (HRs) for induction regimens among each group were estimated using Cox models adjusted for age, ELN risk, ECOG, frailty score, and comorbidity index. Results: Of 734 enrolled pts with AML (Dec 2021), most were male (61%) and white (84%); median age 71 y (range 55–97). Only 26% of pts (n = 192) were eligible for a non-IC RCT, 45% (n = 327) were ineligible due to unfitness, and 29% (n = 215) were ineligible due to overall fitness. The main reason for non-IC RCT ineligibility was high overall comorbidity grade (n = 265 [36%]). Fit pts intended to undergo transplant more often compared with unfit pts. Median OS for eligible, unfit, and fit pts were 14, 10, and 22 months, respectively. Among unfit pts, those receiving IC had significantly longer OS compared with pts receiving a VEN-based regimen (median OS 14 vs 6 months, respectively; HR: 0.51, 95% CI: 0.27–0.98, P = 0.042; Table). Eligible pts who received IC tended to have shorter median OS (13 months) vs pts who received VEN-based therapies (23 months; not sig.). Conclusions: The majority of pts with ND AML in the Registry would have been ineligible for a non-IC RCT due to being too fit or unfit. Pts ineligible for an RCT due to unfitness but who received IC maintained an OS benefit vs those receiving VEN-based therapies. This analysis suggests that non-IC RCTs may be excluding pts who appear unfit but can potentially tolerate IC and experience improved survival outcomes. Clinical trial information: NCT01688011. [Table: see text]