bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of men with HIV-associated germ cell cancer: Results from an international collaborative study.
Authors: Hentrich Marcus , Bower Mark , Daugaard Gedske , Dieing Annette , Bickel Markus , Berretta Massimiliano , Lesmeister Florian , Jurinovic Vindi , Stöhr Albrecht , Heinzelbecker Julia , Krznaric Ivanka , Dieckmann Klaus-Peter , Necchi Andrea , Maroto José , Rockstroh Jürgen , Goncalves Margarida Brito , Otremba Burkhard Joerg , Hoffmann Christian
Published: May 2020

5053

Background: Previous studies showed that men with HIV-associated germ cell cancer (HIV-GCC) have a similar cancer-free outcome compared with their HIV-negative counterparts. However, the overall survival (OS) was inferior and little data is available on treatment and outcome of HIV-GCC in the era of combined antiretroviral therapy (cART). Methods: Men living with HIV aged ≥ 18 years (yrs) with a diagnosis of histologically proven GCC made from 01/1996 to 07/2018 were included. Primary outcomes were OS and progression-free survival (PFS). Secondary outcomes included characteristics of GCC and HIV-infection, treatment and causes of death. Results: Data of 89 men from 23 institutions and 6 countries with a total of 92 HIV-GCC (2 synchronous and 1 metachronous bilateral GCC) were analysed, among them 64 (70%) seminomas and 28 (30%) nonseminomas. 10/89 (11%) cases were primary extragonadal GCC. Median age was 36 yrs (range, 22-52) and median time from HIV to GCC diagnosis was 5 yrs (range, 0-29). Median CD4 count at GCC diagnosis was 420 cells/µl (range, 3-1503) and 83% of pts were on cART. Stage I disease was found in 44/80 (55%) gonadal GCC (metachronous bilateral case included). Of 46 cases with stage II/III/extragonadal GCC 78%, 17% and 4% were assigned to the IGCCCG good, intermediate and poor prognosis group, respectively. Of the 44 stage I cases, 22 (50%) were followed by active surveillance, and 11 (25%) received adjuvant chemotherapy (CT) or radiotherapy. Relapses occurred in 14 pts (6 from stage I, 8 in pts primary disseminated GCC) and CT was applied to 13/14 pts, of which 3 received high-dose CT. Overall, 12/89 (13%) pts have died. Causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3) and other (n = 4). After a median follow-up of 6.5 yrs (range, 0.3-20.9), the 5- and 10-year PFS rate was 81% and 73%, and the 5- and 10-year OS rate was 91% and 85%, respectively. There were no significant differences between the good and intermediate prognosis group or between pts with CD4 counts < 200/µl or ≥ 200/µl. Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC are similar to those reported for HIV-negative GCC. Pts with HIV-GCC should remain on cART and be managed in an identical fashion to HIV-negative pts.
INMUNOSUN-SOGUG trial: A prospective phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront.
Authors: Grande Enrique , Alonso Gordoa Teresa , Reig Torras Oscar , Esteban Emilio , Castellano Daniel , Garcia del Muro Xavier , Mendez Vidal María José , García-Donas Jesús , Arranz Jose Angel , Suarez Rodriguez Cristina
Published: May 2020

5060

Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng's scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427 .
Clinically advanced renal cell carcinoma (RCC) and renal sarcoma (RSC) in young patients: A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Shapiro Oleg , Jacob Joseph M , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Schrock Alexa Betzig , McGregor Kimberly , Reddy Venkataprasanth P. , Alexander Brian Michael , Danziger Natalie , Mollapour Mehdi , Shuch Brian M. , Ross Jeffrey S.
Published: May 2020

5066

Background: We queried whether the landscape of genomic alterations (GA) would differ in patients with metastatic RCC under 40 years of age (under40) and patients 40 years of age or older (over40). Methods: FFPE tissues from 2,128 clinically advanced RCC and 25 RSC underwent hybrid-capture based CGP to evaluate all classes of GA. Samples were classified at time of sequencing as the following RCC subtypes: clear cell (ccRCC), papillary (papRCC), chromophobe (chrRCC), medullary (medRCC), collecting duct (cdRC), sarcomatoid (sarcRCC) and NOS (nosRCC). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: The male preponderance increased in the over40 patients. The GA/tumor increased in the over40 cohorts except for medRCC. Similarly, TMB was consistently higher in over40 groups. MSI high status was virtually absent. PD-L1 expression, available only in small subsets, was generally absent although 44% high positive staining in sarcRCC was noteworthy. Differences in GA in under40 vs over40 RCC were seen and included increased PBRM1 and SETD2 GA in over40 vs under40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in over40 vs under40 papRCC; increased TP53 and decreased VHL, BAP1, SETD2 and PTEN in over40 vs under40 chrRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in over40 vs under 40 sarcRCC; and increased TP53, VHL and TERT in over40 vs under40 nosRCC. Changes in GA in under40 vs over40 medRCC, cdRCC and RSC were noted but insufficient cases prevented further evaluation. Conclusions: When separately evaluated by under/over 40 years of age, CGP of clinically advanced RCC demonstrates differences in genomic landscapes with over40 cases featuring increasing male preponderance, higher GA/tumor, higher TMB and increases in a variety of GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of metastatic RCC. [Table: see text]
A phase II study of the selective MET kinase inhibitor INC280 in advanced papillary renal cell cancer.
Authors: Leger Paul Denis , Girardi Daniel da Motta , Al Harthy Munjid , Friend Julia C. , Mac Lisa , Purcell Erin , Vocke Cathy , Gurram Sandeep , Merino Maria J. , Choyke Peter , Linehan W. Marston , Srinivasan Ramaprasad
Published: May 2020

5075

Background: There are currently no approved systemic agents for patients with advanced type 1 papillary renal cell carcinoma (pRCC). Type 1 pRCC can occur in a hereditary form with germline alterations of MET (hereditary papillary RCC: HPRC) or in a sporadic form. Both hereditary and sporadic forms have similar histologic features and somatic MET alterations have been found in 15-20% of patients with sporadic pRCC. Furthermore, gain of chromosome 7, where MET and the gene for its ligand HGF are located, has been reported in a majority of patients with type 1 pRCC and may represent an alternative means of activating the MET pathway. This is a phase II study evaluating the activity of INC280, a highly selective and potent MET inhibitor, in patients with pRCC. Methods: Patients with advanced type 1 pRCC were treated with INC280 at a starting dose of 600mg PO twice daily (capsules). Later in the study course, the capsules were replaced with exposure-equivalent tablets (400mg PO twice daily). Eligible patients had an ECOG PS 0-2, no active brain metastases, and less than 4 prior lines of therapy. The primary endpoint was overall response rate (ORR) assessed by RECIST 1.1. Secondary endpoints included progression-free survival, disease control rate, and tolerability. Exploratory endpoints included the correlation between MET alteration/copy number gain and response to INC280. Results: Twenty subjects were enrolled from January 2014 to October 2019. Median age was 62 years, 60% of patients were classified as IMDC good risk and 40% as IMDC intermediate risk. Three patients (15%) achieved a confirmed partial response and seven (35%) had stable disease, including 4 (20%) who maintained stable disease for over 6 months. The most common treatment-related adverse events (AEs) were of grade 1-2 including nausea (85%), increased creatinine(70%) diarrhea(60%), fatigue(55%), limb edema(40%), increase in amylase(20%), triglycerides(20%), LFTs(20%), lipase(10%) and leukopenia(10%). INC280-related Grade 3-4 AEs included asymptomatic increased lipase (20%), increased LFTs (10%), increased amylase(5%), leukopenia (5%), lymphopenia (5%) and syncope (5%). Conclusions: INC280 demonstrated clinical activity in patients with advanced type 1 pRCC with an acceptable toxicity profile. The correlation between the presence of MET alteration and/or copy number gain and response to INC280 is under evaluation.
Prediction of watchful waiting in newly diagnosed metastatic clear cell renal cell carcinoma patients with a good or intermediate prognosis.
Authors: Verhoeff Sarah , van Es Suzanne C , Elias Sjoerd G. , Gerritse Sophie , Angus Lindsay , Oosting Sjoukje , Heskamp Sandra , Brouwers Adrienne H. , Arens Anne I.J. , Menke Catharina Wilhelmina , Hoekstra Otto S. , Zwezerijnen Gerben J.C. , Van Der Veldt Astrid Aplonia Maria , Mulders Peter , Van Der Graaf Winette T.A. , De Vries Elisabeth , Oyen Wim J.G. , Aarntzen Erik H.J.G. , Van Herpen Carla M.L.-
Published: May 2020

5079

Background: In metastatic clear cell renal cell carcinoma (mccRCC), the number of International Metastatic Database Consortium (IMDC) risk factors plus metastatic sites may identify patients with rapid or slow disease progression in a period of watchful waiting (WW) (median WW of 8.4 vs 22.2 months; Rini et al. Lancet Oncol. 2016). We aimed to validate this and prospectively assess the added value of baseline PET with [18F]FDG and [89Zr]Zr-DFO-girentuximab to predict the WW-period in the multicenter IMaging PAtients for Cancer drug selecTion (IMPACT)-RCC cohort study. (NCT02228954). Methods: Between February 2015 and March 2018, 40 treatment-naïve mccRCC patients with a good (n=13) or intermediate prognosis (n=25) according to IMDC, were enrolled. Following baseline CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET, CT scans (RECIST1.1) were acquired at 2, 4, 6, 9, 12 months and thereafter every 4 months. Primary endpoint was time to radiological and/or clinical disease progression, requiring systemic treatment. Patients were assigned to a favorable (<2 IMDC risk factors and <3 metastatic sites) or unfavorable for WW-group (all others; Rini et al). Maximum standardized uptake values (SUVmax) were measured in PET-positive lesions measuring ≥10mm, or 15mm in lymph nodes. High and low-uptake groups were defined based on median geometric mean (gm) SUVmax across patients. A one-sided test was used to validate observations by Rini et al; other tests were two-sided. Results: The median WW-period was 9.3 months in the unfavorable WW-group (n=19) vs 20.4 months in the favorable WW-group (n=21) (HR 1.89 95%CI 0.94-3.89; p=0.037), confirming observations of Rini et al. Patients with high [18F]FDG uptake had a median WW-period of 8.5 months compared to 25.2 months in the low-uptake group (HR 4.08 95%CI 1.89-9.28; p=0.0002). Patients with high [89Zr]Zr-DFO-girentuximab uptake had a median WW-period of 10.7 versus 16.4 months in the low-uptake group (HR 1.37; 95%CI 0.69-2.76; p=0.37). [18F]FDG uptake groups improved a Cox-model for WW based on the prognostic groups of Rini et al (p=0.0015); [89Zr]Zr-DFO-girentuximab did not (p=0.98). Conclusions: The IMPACT-RCC study validated the observations by Rini et al. and shows that adding baseline [18F]FDG PET further improves the prediction of the duration of the WW-period in mccRCC patients. Clinical trial information: NCT02228954 .
FDA pooled analysis of time to treatment discontinuation (TTD) in frontline advanced renal cell carcinoma trials.
Authors: Chang Elaine , Gong Yutao , Weinstock Chana , Fernandes Laura L , Hawley Jessica , Gwise Thomas , Regan Meredith M. , Choueiri Toni K. , Rini Brian I. , McDermott David F. , Atkins Michael B. , Suzman Daniel L. , Ibrahim Amna , Tang Shenghui , Theoret Marc Robert , Kluetz Paul Gustav , Pazdur Richard , Beaver Julia A.
Published: May 2020

5081

Background: Time to treatment discontinuation (TTD) has been proposed as a potential pragmatic real-world data (RWD) endpoint, and was closely correlated with progression-free survival (PFS) in pooled analyses of non-small cell lung cancer (NSCLC) and breast cancer trials across therapeutic classes (Blumenthal, Ann Onc 2019; Gao, SABCS Abstract P5-14-02). Methods: We analyzed data from all randomized patients (pts) in the phase 3 trials submitted to FDA 2016-18 evaluating a combination therapy (Rx) of an immuno-oncology agent and another systemic Rx (IO-X) versus sunitinib (SUN) for treatment-naïve advanced renal cell carcinoma (RCC). Protocols specified treatment until progression, but treatment beyond progression was allowed. TTD was defined as the time from the start of Rx to time of treatment discontinuation of both drugs in combination Rx or SUN. We measured TTD in treatment-defined subgroups (IO-X and SUN) and across all pts, and pt-level correlation (Pearson’s r) between TTD and PFS and between TTD and overall survival (OS). We also determined rates of disparity between TTD and PFS greater than 3 months. Results: Of 3758 pts (IO-X, n=1878; SUN, n=1880), 3190 pts (85%) had a TTD event, and 1899 pts (51%) had a PFS event. Median TTD was longer among pts receiving IO-X than SUN (12.3 versus 8.0 months). Regardless of drug class, more pts had early (TTD shorter than PFS by ≥ 3 months) TTD events than late TTD (13.4% versus 6.4%, overall). We found higher correlation between TTD and PFS in pts receiving SUN ( r = 0.89) than pts receiving IO-X ( r = 0.72). Overall, TTD was more closely associated with PFS ( r = 0.80) than with OS (0.61). Conclusions: Observed correlations of TTD to PFS were stronger compared to the correlation of TTD to OS. This may be expected because OS is farther removed in time from TTD than is PFS. In contrast to TTD in NSCLC, more than twice as many pts in RCC trials had early TTD than late TTD, regardless of Rx group, which may indicate earlier discontinuation with combination Rx due to additive toxicity. Limitations include the censoring of PFS and OS and the post-hoc nature of this analysis. [Table: see text]
Patient-reported use of marijuana and cannabinoid (CBD) oil in patients with renal cell carcinoma undergoing systemic therapy.
Authors: Battle Dena , Bergerot Cristiane Decat , Msaouel Pavlos , Zhang Tian , George Daniel J. , Staehler Michael D.
Published: May 2020

5084

Background: The use of cannabis and cannabinoid related products has become increasingly common among cancer patients. We sought to gather independent data from online kidney cancer patient communities to assess frequency of use of marijuana and CBD-oil and estimate influence on treatment duration and side-effects. Methods: The KCCure online survey was performed between August 1, and September 30, 2019. Descriptive statistics were used to characterize patients who self-report using marijuana, their systemic treatments, and interactions with their oncologists. Results: Out of 1,136 patients responding, 411 patients were on systemic therapy with a median age of 57 years (28-86). Of the 441 patients with systemic therapy, 223 patients (54%) were male. There was no difference in gender distribution or race among patients who reported using or not using marijuana and or CBD oil. 93 patients (21%) reported using marijuana or CBD oil and 35 patients (8.5%) reported using both. Patients using marijuana and/or CBD oil had a median age of 55.7 +/- 1.1 years compared with patients not using (65.1 +/- 6.9 years). The median treatment duration was 23.9+/-2.4 months for patients using marijuana and/or CBD oil versus 26.4+/- 1.9 months for patients not using these supplements (p=0.437). Patients using marijuana and/or CBD oil were more likely to have bothersome side effects from therapy (p=0.001) and were less likely to talk to their doctor about their situation (p=0.044). The median NCCN distress score in patients using marijuana and/or CBD oil was 49.5+/-25.7 versus 51.4+/-24.0 (p n.s.). No correlation was seen with the use of steroids, anti-diarrhea drugs, anti-nausea-drugs, hormone substitution or other drugs used to manage side effects. Conclusions: Marijuana and/or CBD oil are used by a significant number of patients. No benefit/harm on treatment duration and use of concomitant drugs to control side effects and severity was seen. Patients using marijuana and/or CBD oil were more likely to report bothersome treatment related side effects and were more willing to report their side effects to their provider. As cannabinoids become more mainstream and legal in a number of states, more research is needed to better understand the impact these supplements may have on patients.
Defining the mutational landscape of 3,217 primary breast cancer transcriptomes through large-scale RNA-seq within the Sweden Cancerome Analysis Network: Breast Project (SCAN-B; NCT03430492).
Authors: Brueffer Christian , Gladchuk Sergii , Winter Christof , Vallon-Christersson Johan , Hegardt Cecilia , Häkkinen Jari , George Anthony M , Chen Yilun , Ehinger Anna , Larsson Christer , Loman Niklas , Malmberg Martin , Rydén Lisa , Borg Åke , Saal Lao H.
Published: May 2020

518

Background: Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. The Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096) is a multi-center population-based ongoing prospective observational study elucidating the global transcriptomic profiles for thousands of patients and tumors using RNA sequencing. Since September 2010, over 15,000 patients with breast cancer have been enrolled at 9 hospitals across a wide geography of Sweden, comprising greater than 90% of all eligible patients in the catchment area. Methods: Within SCAN-B, we developed an optimized bioinformatics pipeline for detection of single nucleotide variants and small insertions and deletions from RNA-seq data. From this, we describe the mutational landscape of 3,217 primary breast cancer transcriptomes, and relate it to patient overall survival in a real-world setting (median follow-up 75 months, range 2-105 months). Results: We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, ESR1, and ERBB2, as well as mutation status of key molecular pathways and tumor mutational burden, identify mutations in one or more potentially druggable genes in 85.3% percent of cases, and reveal significant relationships to patient outcome within specific treatment groups. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source interactive web application, SCAN-B MutationExplorer, publicly accessible at http://oncogenomics.bmc.lu.se/MutationExplorer . Conclusions: These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based signatures and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
Does chemotherapy affect survival of breast cancer (BC) patients with recurrence score 26-30?
Authors: Goranta Sowmya , Drizik Eduard , Omaduvie UyoyoTonte , Haykal Tarek , Bala Areeg , Gorle Swathi , Sidahmed Shima , Pandit Trailokya Nath , Kanugula Ashok Kumar , Bachuwa Ghassan , Katato Khalil
Published: May 2020

523

Background: The Oncotype-DX recurrence score (RS) allows providers to identify hormone receptor positive and HER2-negative breast cancer (BC) patients that may benefit from adjuvant chemotherapy (AC). The TAILORx Trial showed no benefit of AC among patients with RS of 11-25, except for patients younger than 50 years. There are, however, limited studies examining any benefit of AC among those with RS of 26-30. We sought to examine the effect of AC on BC-specific survival among these patients utilizing a national database. Methods: We queried the Surveillance, Epidemiology, and End Results database for newly diagnosed female BC patients between 2010-2015. We included patients with T1-T3, hormone receptor positive, HER2-negative, and lymph node-negative BC with RS of 26-30. Patients with tumors 5 mm or less and with incomplete records were excluded. Cox Proportional-Hazards Model was done to examine the effect of AC on BC-specific survival. A sub-group analysis was performed for patients younger than 50 years to examine the effect of AC on BC-specific survival. Results: We included 2,982 patients, of whom 1,686 (56.5%) received AC. Administration of AC was associated with lower age (56.5 [9.2] vs 61.8 [9.7], p < 0.001), Grade III&IV (39.7% vs 30.2%, p < 0.001), married or patients with partners (66.5% vs 61.5%, p < 0.001), and T stage > 1 (31.3% vs 26.8%, p = 0.03). AC was not associated with insurance status, race, and histology. Overall 5-year BC-specific survival was 97.3% (96.2-98.3%). After adjustment through cox regression, AC was found to not have an effect on survival (HR: 0.54 [0.27-1.10], p = 0.09). There were 579 (19.4%) patients that were younger than 50 years, and AC did not have an effect on survival among these patients (HR: 0.44 [0.08-2.44], p = 0.35). Similarly, among the 2,403 (80.6%) patients aged 50 or older, AC did not have an effect on survival (HR: 0.49 [0.22-1.11], p = 0.09). Conclusions: In this retrospective analysis, administration of AC was associated with lower age, higher grade, marital status, and T stage. AC did not affect BC-specific survival among patients with a RS of 26-30. Subgroup analysis did not show any benefit of AC among patients younger than 50 years or among those 50 or older. Further prospective randomized trials are warranted to identify sub-groups that may potentially benefit from AC.
CX-2009, a CD166-directed probody drug conjugate (PDC): Results from the first-in-human study in patients (Pts) with advanced cancer including breast cancer (BC).
Authors: Boni Valentina , Burris III Howard A. , Liu Joyce F. , Spira Alexander I. , Arkenau Hendrik-Tobias , Fidler Mary J. , Rosen Lee S. , Sweis Randy F. , Uboha Nataliya Volodymyrivna , Sanborn Rachel E. , O'Neil Bert , Harding James J. , LoRusso Patricia , Weise Amy M. , Garcia-Corbacho Javier , Victoria Iván , Frye John W. , Li Rachel , Stroh Mark , Meric-Bernstam Funda
Published: May 2020

526

Background: CX-2009 is a PROBODY drug conjugate (PDC) directed against CD166 (ALCAM) and conjugated to DM4, a potent microtubule inhibitor (MTI). CD166 is overexpressed in carcinomas but is also ubiquitously expressed in normal epithelium and thus has not been previously considered a viable target for a traditional antibody drug conjugate. PDCs have a peptide mask that blocks normal tissue binding and can be removed by tumor-associated proteases, thereby limiting off-tumor/on-target binding. CX-2009 demonstrated preclinical activity in multiple solid tumor models. Here we report results of the first in human study in patients with advanced cancer. Methods: In this phase I multi-part dose-escalation study, pts with advanced solid tumors received CX-2009 0.25–10 mpk IV every 14 or 21 days (Q2W or Q3W). Tumor types were selected based on expected high CD166 expression and MTI sensitivity. Results: The dose-escalation phase of the trial enrolled 43 pts; 49 additional pts were subsequently enrolled between 4–10 mpk to collect biomarker data and define the recommended phase II dose (RP2D), for a total of 92 pts as of 30 Nov 2019 (39 pts with breast cancer [BC], 22 ovarian [OC], 12 non-small cell lung [NSCLC], 9 head/neck squamous cell [HNSCC], 10 other) with a median of 6 (range 1–19) prior therapies. Median number of CX-2009 doses was 2 (range, 1–15). For Q3W dosing, one dose limiting toxicity (DLT; grade 3 vomiting) was observed at 8 mpk; MTD was not reached up to 10 mpk. The RP2D for Q3W schedule was 7 mpk based on safety, dose-response, and population pharmacokinetic simulations. Q2W dosing continues; DLTs were observed at 6 mpk. Common treatment-related adverse events (TRAEs) at 7 mpk (n=9) were nausea (44%), fatigue, infusion-related reactions (both 33%), vomiting and arthralgias (both 22%). Grade 3 TRAEs occurred in 2 pts (nausea/vomiting; peripheral neuropathy). No pts discontinued at 7 mpk due to TRAEs. Ocular toxicity was dose dependent; mild to moderate reversible keratitis/blurred vision was seen in 3 pts at 7 mpk and mitigated by ocular prophylaxis. Partial responses were seen in 8 pts (2 confirmed, both HR+/HER2- BC) treated between 4–10 mpk, including BC (n=5), OC (n=2), and HNSCC (n=1). SD (≥1 on-study scan) was observed in 21 pts, 5 had SD ≥3 mos. Conclusions: CX-2009 at 7 mpk is the RP2D on Q3W schedule. Phase II expansion has begun in pts with HR+/HER2- BC. The Q2W schedule will continue to enroll pts to define the RP2D. CX-2009 will also be studied in combination with CX-072, a PD-L1 PROBODY therapeutic ( NCT03149549 ) Clinical trial information: NCT03149549 .
Adherence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor (HR)-positive breast cancers.
Authors: Foldi Julia , Schnabel Catherine A. , Salganik Max , Pusztai Lajos , Sanft Tara B.
Published: May 2020

527

Background: Evidence suggests continuing endocrine therapy (ET) beyond 5 years (yr) may reduce breast cancer recurrence in early stage HR+ breast cancers. Given the modest benefit and potentially serious adverse effects of extended ET (EET), improved approaches to identify patients who are at increased risk of late distant recurrence and who derive benefit from EET are critical. Guidelines recommend shared decision-making between oncologists and patients. The adherence rate to EET by 5 yr is only 50-60%. BCI is a gene-expression assay used to predict late distant recurrence and is predictive of benefit from EET. We assessed adherence to EET in women who had BCI testing. Methods: Women with stage I-III HR+ breast cancer s/p 3.5 yr of adjuvant ET and had BCI testing at our institution (8/2013-7/2015) were included. Pts who had < 4 yr of follow-up since BCI testing were excluded. Information including demographics, tumor characteristics, treatment history, number DXA scans, history of osteopenia/osteoporosis were collected. Data on medication adherence was based on prescriptions in the electronic health record. Results: 102 pts were included in our analysis. The median age was 61yr (46-89 yr). The majority of pts had stage I (63%), N0 (77%) and HER2- (90%) disease. 50 pts (46%) received chemotherapy. 44 (43%) received tamoxifen and 79 (77%) had an aromatase inhibitor. BCI categorized 61 (60%) pts as low risk, 26 (25%) as intermediate, and 15 (15%) as high risk for late distant recurrence. 61 (60%) and 41 (40%) pts were predicted to have low and high likelihood of benefit from EET, respectively. All 15 (100%) pts categorized as high risk for late recurrence were predicted to have a high likelihood to benefit from EET; all were recommended to continue EET by their oncologist and all 15 elected EET. 11 (73%) completed 10 yr or were on EET at last follow-up. Of the 4 (27%) pts who stopped before 10 yr, 1 pt had metastatic recurrence and 3 had intolerable side effects. Pts on EET underwent an avg of 1.91 DXA scans, compared with 1.23 for those who stopped ET at 5 yr (p = 0.003). At a median follow-up of 10 yr from diagnosis, there were 2 metastatic (1/15 in the high risk and 1/26 in the intermediate risk group) and 1 local recurrence (1/61 in the low risk group). Conclusions: In pts who continued ET beyond 5 years based on BCI testing and discussion with their oncologist, the rates of adherence and persistence to EET were higher than those previously published. EET may increase the number of DXA scans performed.
Factors associated with adjuvant endocrine therapy adherence in non-metastatic breast cancer.
Authors: Neuner Joan Marie , Winn Aaron N , Pezzin Liliana E , Laud Purushottam W. , Nattinger Ann B , Fergestrom Nicole
Published: May 2020

533

Background: Over 50% of breast cancer patients prescribed adjuvant endocrine therapy (ET) are nonadherent during the recommended 5-year course of therapy. We investigated the role of cancer medication delivery on adherence, including mail order pharmacy use, number of pharmacies and copays. Methods: We conducted a retrospective cohort study of 15,769 commercially insured breast cancer patients age 18-64 with newly diagnosed breast cancer in 2007-2015 that initiated ET. Incident breast cancer was identified by a validated algorithm which identifies mainly non-metastatic breast cancer. We examined the association between 12-month AET adherence (proportion of days covered by fills ≥0.80) and mail order pharmacy use, number of pharmacies, and AET copays. We used Poisson regression to estimate nonadherence risk ratios and adjusted for demographics (age, income, race, urbanicity), comorbidities, total medications, primary cancer treatments (surgery, radiation, chemo, and ET initiated), and generic AI availability. Sensitivity analyses were conducted using alternate specifications for independent variables. To test whether any observed differences were due to self-selection, we also conducted a negative control analysis. Results: Most patients were white (74.4%) and age 55-64 (43.3%). Only 16% of patients used a mail order pharmacy for ET fills, most patients only used one pharmacy (58.8%) and 25.2% had a co-pay of $20 or more. In the primary analysis, mail order patients were more likely to be adherent to their ET (aRR 1.21; 95% CI 1.18-1.24), patients using one pharmacy were more likely to be adherent (1 vs 3+: aRR 1.09; 95% CI 1.06-1.13), and patients with lower copays were more likely to be adherent (quartile 1 vs 4: aRR 1.04; 95% CI 1.01-1.08). Results were consistent across sensitivity analyses, and there was no association between mail order and copays and the negative control outcome of any pneumonia diagnoses. Conclusions: Medication delivery factors are associated with adherence to breast cancer AET. Future work should investigate whether interventions to streamline medication delivery could improve adherence for this population.
Real-world patterns of treatment and recurrence by frailty status among older women with HR-positive, HER2-negative early breast cancer.
Authors: Calip Gregory Sampang , Hubbard Colin , Nabulsi Nadia Azmi , Asfaw Alemseged Ayele , Lee Inyoung , Zhou Jifang , Cueto Jenilee , Mitra Debanjali , Law Ernest H
Published: May 2020

535

Background: Frail health status impacts clinical decision making for older cancer patients and their families, and frailty is independently associated with increased risks of mortality. Our objective was to describe differences in treatment and rates of recurrence by frailty status among older women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Methods: We performed a large, population-based retrospective cohort study of women aged 65 years and older diagnosed with first primary stage I-III HR+/HER2-breast cancer using the Surveillance, Epidemiology, and End Results Medicare-linked database between 2007 and 2015. Using administrative health claims, we ascertained information on breast cancer treatment and utilized validated claims-based algorithms to determine frailty status (robust, pre-frail, and frail) and identify subsequent invasive breast cancer recurrences. Relative hazards of recurrence were determined using Fine and Gray competing risks regression models with estimated subdistribution hazard ratios (SHR) and robust 95% confidence intervals (CI). Results: From an overall cohort of 46,027 women, most women (56%) were classified as robust at breast cancer diagnosis, whereas 37% and 7% were identified as pre-frail and frail, respectively. Compared to robust patients, frail patients were more likely to have stage III disease (10% vs. 7%) and receive mastectomy (27% vs. 18%), and less likely to receive radiation (35% vs. 57%) or chemotherapy (5% vs. 9%). Five-year cumulative incidences of recurrence were 15%, 18% and 22% among robust, pre-frail, and frail women, respectively. In multivariable competing risks models adjusted for age, race, stage, and treatment, frail (SHR 1.28, 95%CI 1.17-1.41) and pre-frail (SHR 1.15, 95%CI 1.09-1.21) women had a significantly increased risk of breast cancer recurrence. Conclusions: Independent of differences in treatment, frailty was associated with increased breast cancer recurrence risk in this population-based cohort of older women. However, the vast majority of older women living with HR+/HER2- early breast cancer were not identified as frail. These study results suggest that age alone is not an adequate indicator of physical resilience and underscores the need to consider additional factors when assessing the benefits and risks of treatments for the prevention of recurrence among HR+/HER2- early breast cancer patients.
Trends in utilization of hypofractionated whole breast radiation in breast cancer: An analysis of the National Cancer Database.
Authors: Woodward Steven Gerard , George Brandon , Varshney Karan , Willis Alliric Isaac
Published: May 2020

536

Background: Utilization of hypofractionated radiation (HR) as a component of breast conserving treatment (BCT) in breast cancer is lacking in the U.S. despite studies demonstrating its efficacy and guidelines supporting its use from the American Society for Radiation Oncology (ASTRO) in 2011 and 2018. Little is known regarding national trends in uptake and factors associated with uptake of HR in the U.S. since the 2011 ASTRO guidelines. Methods: We performed a retrospective review of the National Cancer Data Base (2012-2016) on patients undergoing BCT. Logistic regression modeling was used to identify relationships between patient, hospital, and tumor factors with the use of HR or traditional radiation (TR). Results: A total of 360,834 cases of BCT were identified with 65% (n=235,783) undergoing TR and 35% (n=125,051) undergoing HR. The odds of utilization of HR increased with year of diagnosis, patient age, higher median income, private insurance, treatment at an academic center, travel distance to treatment >20 miles, smaller tumors, lymph node negative disease, and without use of chemotherapy (p-values <0.0001, Table). Conclusions: Despite studies demonstrating the efficacy of its use and the support of ASTRO, HR utilization in the U.S. is still lacking. By understanding which patient populations are still not receiving the benefit of this therapy we can improve our utilization of HR in the U.S. leading to reduced healthcare costs and patient satisfaction. [Table: see text]
Expanding criteria for prognostic stage IA disease in HR+ breast cancer.
Authors: Kantor Olga , King Tari A. , Shak Steven , Russell Christy Ann , Giuliano Armando E. , Hortobagyi Gabriel N. , Burstein Harold J. , Winer Eric P. , Sparano Joseph A. , Mittendorf Elizabeth A.
Published: May 2020

550

Background: The 8th ed AJCC staging system incorporated grade, receptor status and the Oncotype DX Recurrence Score (RS) result into staging. Based on TAILORx trial data and evidence of utility for RS results in node positive disease, this study was undertaken to determine if staging should incorporate expanded RS criteria. Methods: Patients (pts) with T1-3N0-3 HR+HER2- disease undergoing surgery 2010-15 were identified in the SEER database. 5yr DSS was estimated based on T and N category, grade and RS result; differences were compared between pts with path prognostic stage IA disease and all other groups. Results: 154,054 pts were identified; median follow up was 49 mo (range 0-83). RS results were obtained in 60,886 (39.5%); RS <11 in 13,570 (22.3%) and RS 11-25 in 39,240 (64.5%). The table details 5yr DSS rates. 5yr DSS for path prognostic stage IA pts (n=114,675, 73.4%) was 98.2%. Among all pts with RS <11, 5yr DSS was excellent and not significantly different than for path prognostic stage IA pts. For those with RS 11-25 not receiving chemo, 5yr DSS was inferior to path prognostic stage IA disease for T1-2N1 pts and for those with T2-3N0 disease although among N0 pts the differences were numerically small (1.4%-2.5% vs overall path prognostic stage IA). Conclusions: Pts with Recurrence Score <11 have excellent 5yr DSS regardless of T and N category or grade suggesting further modification of the AJCC staging system using this cutoff. Additional study is required to optimize staging for patients with Recurrence Score 11-25. [Table: see text]
Baseline circulating tumor cell (CTC) count as a prognostic marker of PSA response and progression in metastatic castrate sensitive prostate cancer (mCSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.
Authors: Goldkorn Amir , Tangen Catherine , Plets Melissa , Morrison Gareth , Cunha Alexander , Xu Tong , Pinski Jacek K. , Ingles Sue A. , Triche Timothy , MacVicar Gary R. , Vaena Daniel A. , Crispino Anthony W. , McConkey David James , Lara Primo , Hussain Maha H. A. , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie , Agarwal Neeraj ,   SWOG GU Committee
Published: May 2020

5506

Background: In mCSPC, androgen deprivation therapy (ADT) combined with chemotherapy or androgen receptor signaling inhibition (ARSI) is the new standard of care. Biomarkers that predict clinical outcomes with these therapies are needed. We hypothesized that CellSearch CTC count, an FDA-cleared biomarker in metastatic castrate resistant PC (mCRPC), may be a valuable biomarker in mCSPC. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline), and CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini) per standard manufacturer protocol. CTC counts were analyzed centrally for associations with 2 pre-specified trial intermediate endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. > 4.0, (intermediate endpoint for overall survival, OS); and progression-free survival (PFS) < vs. > 2 years. Because OS data have not matured, analysis was pooled and equal numbers of samples were analyzed from each treatment arm and outcome measure (7mPSA and PFS) as stipulated by the Data Safety Monitoring Committee. Results: From 2014 to 2017, 523 baseline samples were collected. In the 7mPSA analysis (n = 264), CTCs were detected in 38% of men, with a median of 4 CTCs in those with detectable CTCs. In the PFS analysis (n = 336), CTCs were detected in 37% of men, with a median of 3 CTCs in those with detectable CTCs. Adjusting for disease burden (minimal vs. extensive) and ADT status (already initiated or not) at the time of CTC measurement, men with undetectable CTCs were 6.1-fold more likely to attain 7mPSA ≤ 0.2 (OR 6.1, 95% CI 2.1-17.2, p < 0.001) and 3.7-fold more likely to achieve > 2 years PFS (OR 3.7, 95% CI 1.7-8.1, p < 0.001) compared to men with baseline CTCs ≥ 5. Other cutpoints previously validated in mCRPC studies (CTC < 5 vs. ≥5 and CTCs 0 vs. ≥1) also strongly discriminated 7mPSA and PFS with statistical significance in this mCSPC cohort. Conclusions: CTC count at the start of treatment for mCSPC was highly prognostic of 7-month PSA response (intermediate endpoint for OS) and of PFS at 2 years. To our knowledge, this is the first such strong evidence from a prospective phase 3 trial of this magnitude. Additional analyses are planned when the trial is fully reported. Baseline CTC count may serve as a valuable prognostic marker to discriminate men likely to respond favorably to hormonal therapies from those who may benefit from early alternate interventions.
Assessment and management of cardiovascular risk factors among U.S. Veterans with newly diagnosed prostate cancer.
Authors: Sun Lova , Parikh Ravi Bharat , Robinson Kyle William , Takvorian Samuel U , Vaughn David J. , Narayan Vivek , Ky Bonnie
Published: May 2020

5510

Background: Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer (PC). Androgen deprivation therapy (ADT) is associated with increased CVD risk, and American Heart Association guidelines recommend CVD risk factor assessment and management in PC patients starting ADT. We characterized rates of guideline-concordant assessment and management of CVD risk factors for US Veterans with newly diagnosed PC, according to ADT use and prior atherosclerotic CVD diagnosis. Methods: We used cross-sectional data from VA Corporate Data Warehouse to identify Veterans with an incident diagnosis of PC from 2001-2017. Primary outcomes were guideline-concordant baseline CVD risk factor assessment (defined as ≥1 blood pressure, cholesterol, and HbA1c or fasting glucose measurement within 1 year prior to 6 months after ADT start or PC diagnosis), CVD risk factor control, and CVD risk-reducing medication use. Risk difference multivariable regression analyses adjusting for age, race, poverty, PC risk category, and year were used to evaluate the effect of ADT on study outcomes. Results: Of 191,829 Veterans with newly diagnosed PC, 27% (n = 51,419) were treated with ADT within 1 year of diagnosis, and 18% (n = 34,110) had a pre-existing diagnosis of atherosclerotic CVD. From 2001-2017, annual rates of guideline-concordant CVD risk factor assessment increased from 26% to 77%. In adjusted analyses, pre-existing atherosclerotic CVD diagnosis was associated with higher CVD risk factor assessment rate (64% vs 53%), better control of baseline LDL (94 vs 108 mg/dL), and higher rates of anti-hypertensive (90% vs 66%), lipid-lowering (83% vs 49%), and glucose-lowering (32% vs 20%) medication use. Treatment with ADT was associated with similar to minimally higher rates of CVD risk factor assessment (58% vs 54%), LDL control (104 vs 105 mg/dL), and anti-hypertensive (73% vs 69%), lipid-lowering (55% vs 55%), and glucose-lowering (25% vs 21%) medication use. Sixty percent of men starting ADT had at least one sub-optimally controlled CVD risk factor, and 1 in 4 of these men were not receiving a corresponding risk-reducing medication. One third of men starting ADT had BMI > 30 kg/m2. Conclusions: CVD risk factor assessment in Veterans with PC has increased over time. However, ADT does not appear to meaningfully impact CVD assessment or management, despite its known association with CVD risk. Over half of patients initiating ADT had elevated CVD risk factor(s). Multi-disciplinary efforts to improve CVD risk mitigation are needed among men initiating ADT.
Late toxicities and recurrences in patients with clinical stage I nonseminomatous germ cell tumor after one cycle of adjuvant BEP versus primary retroperitoneal lymph node dissection: A 13-years follow-up analysis of a phase III trial cohort.
Authors: Hiester Andreas , Fingerhut Anna , Niegisch Guenter , Siener Roswitha , Krege Susanne , Schmelz Hans U. , Dieckmann Klaus-Peter , Heidenreich Axel , Kwasny Peter , Pechoel Maik , Lehmann Jan , Kliesch Sabine , Koehrmann Kai Uwe , Fimmers Rolf , Loy Volker Volker , Wittekind Christian , Hartmann Michael , Albers Peter
Published: May 2020

5512

Background: One cycle of adjuvant BEP has shown superiority in recurrence free survival over RPLND in patients (pts) with clinical stage (CS) I nonseminomatous germ cell tumor of the testis (NSGCT) (JCO 2008). We report recurrences and late toxicities of this randomized trial after 13 yrs of follow-up (FU). Methods: Questionnaires of 382 unselected pts with CS I NSGCT treated within a phase III trial comparing recurrence rate after 1 cycle of adjuvant BEP (arm A) vs. RPLND (arm B) were evaluated regarding recurrences and late toxicity. Overall (OS) and progression free survival (PFS) was calculated by Kaplan-Meier and arms were compared using logrank test. Categorial data were analyzed by chi-square test (PRISM v8). Results: In each arm 191 pts were analyzed as intention-to-treat with a median FU of 13.75 yrs (0-22.9 yrs); 3/191 pts (1.6 %) in arm A and 16/191 pts (8.4 %) in arm B had a recurrence. 20-yrs PFS in arm A / B was 97 % (CI 96-99 %) / 92 % (CI 90-95 %), ( p = .0049). 20-yrs OS in arm A / B was 90 % (CI 86-94 %) / 88 % (CI 86-94 %), ( p = .83). 23/382 (6 %) pts have died, 22/23 not related to testis cancer, 1/23 died of a recurrence in arm B. 8/191 pts (4.2 %) in arm A and 4/191 pts (2.1 %) in arm B showed metachronous secondary testis cancer ( p = .26). 5/191 pts (2.6 %) in arm A and 4/191 pts (2.1 %) in arm B developed other malignancies. 170/382 questionnaires were evaluable (arm A: 95; arm B: 75). 45 pts were lost to FU. There were no significant differences comparing both treatment arms regarding potentially treatment-related late toxicities. However, excluding pre-existing complaints, ototoxicity (9/95 (9 %) vs. 4/75 (5 %) pts, p = .31) was reported more frequently in arm A. Excluding pre-existing neurological conditions, peripheral neuropathy of all grades was more frequently reported in arm A (15/95 pts; 16 % vs. 9/75 pts; 12 % pts; p = .48). Retrograde ejaculation occurred more frequently after RPLND (9/95 pts; 9% vs. 18/75 pts; 24 %, p = .01). Conclusions: After more than 13 yrs of FU, recurrences in non-risk factor selected pts with CS I NSGCT remain to be significantly more frequent with RPLND. No excess mortality due to secondary malignancies was observed. Late toxicities did not differ between 1 cycle of BEP and RPLND. Only retrograde ejaculation was observed significantly more frequent after RPLND. With long-term observation, 1 cycle of BEP has not only a high efficacy to prevent recurrence but also seems to be tolerated without clinically relevant long-term toxicity.