bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter randomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF trial): Analysis of overall survival.
Authors: Kudo Masatoshi , Hasegawa Kiyoshi , Kawaguchi Yoshikuni , Takayama Tadatoshi , Izumi Namiki , Yamanaka Naoki , Shimada Mitsuo , Inomata Masahumi , Kaneko Shuichi , Baba Hideo , Koike Kazuhiko , Omata Masao , Makuuchi Masatoshi , Matsuyama Yutaka , Kokudo Norihiro
Published: June 2021

4093

Background: The initial report of the multicenter SURF trial (surgery vs. radiofrequency ablation [RFA] for small hepatocellular carcinoma [HCC]) showed that recurrence-free survival (RFS) did not differ significantly between patients undergoing surgery and RFA. The focus of the present report was to assess the effect on overall survival (OS). Methods: The SURF trial was a multicenter, open-label, randomized, controlled, phase 3 trial conducted in 49 institutions in Japan. Patients (aged between 29 and 79 years) with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. Before enrollment, both liver surgeons and hepatologists who perform RFA confirm that all the patients can be treated using both surgery and RFA. Patients were then randomly assigned in a 1:1 ratio to undergo surgery or RFA, stratified by age, hepatitis-C virus infection, numbers of HCC, largest HCC diameter, and institution. The co-primary endpoints were RFS and OS. As per the protocol, RFS was reported previously at 3 years after the last accrual of patients. OS was planned at 5 years after the last accrual. This trial is registered in UMIN000001795. Results: During 2009–2015, 308 patients were enrolled. After excluding ineligible patients, the surgery and RFA groups included 150 and 152 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range, 1.5–2.2 cm) in the surgery group and 1.8 cm (interquartile range, 1.5–2.3 cm) in the RFA group. The median (range) follow-up period was 6.4 (0.4–10.8) years in the surgery group and 6.6 (0–10.7) years in the RFA group. OS did not differ significantly between the surgery and RFA groups as the 5-year OS (95% confidence interval [CI]) was 74.6% (66.5%–81.0%) in the surgery group and 70.4% (62.2%–77.3%) in the RFA group (hazard ratio (HR), 0.96; 95% CI, 0.64–1.43; P= 0.828). The analysis after long-term follow-up in the current report showed that RFS was not significantly different between the surgery and RFA groups: the 5-year RFS (95% CI), 54.7% (46.0%–62.5%) vs. 50.5% (42.1%–58.3%); HR 0.90; 95% CI 0.67–1.22; P= 0.498. Conclusions: SURF trial revealed that OS and RFS were not significantly different between patients undergoing surgery and RFA for small HCC (≤ 3 cm and 3 nodules). Clinical trial information: 000001795.
Prognostic impact of pSTAT3 on overall survival (OS) in gastrointestinal (GI) cancers: Data from 3 phase 3, randomized controlled trials (RCTs).
Authors: Brooks Emily , Lebedinsky Claudia , Bekaii-Saab Tanios S. , Shah Manish A. , Jonker Derek J. , Kuchimanchi Kamesh , Wybieralska Ewa , Fontaine Marilyn , Oh Cindy , Sari Suha , Foos Emma , Xu Bo , Hitron Matthew
Published: June 2021

4147

Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]
Large cell neuroendocrine carcinoma of the urothelial tract (LNEC): The MSKCC experience.
Authors: Guercio Brendan John , Gandhi Jatin , Teo Min Yuen , Lattanzi Michael , Funt Samuel Aaron , Aggen David Henry , Chen Ying-Bei , Fine Samson , Pietzak Eugene J. , Bochner Bernard H. , Dalbagni Guido , Berger Michael F. , Solit David B. , Tickoo Satish , Reuter Victor E. , Bajorin Dean F. , Rosenberg Jonathan E. , Al-Ahmadie Hikmat A. , Iyer Gopa
Published: June 2021

4526

Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (<ypT2N0) after NAC was 25% for LNEC and 50% for SNEC-only (p =.13); the ypT0N0 rate was 25% for LNEC and 40% for SNEC-only (p =.52). Perioperative chemo did not improve OS compared to surgery alone in LNEC, adjusting for age and concurrent SNEC (HR 1.46, 95% CI 0.12-17.5, p =.76), but was associated with longer OS among SNEC-only pts (n = 98; HR 0.39, 95% CI 0.22-0.69, p =.001). Two M1 LNEC pts received immunotherapy (IO) in the first-line: 1 atezolizumab, 1 atezolizumab + chemo. Both remained free of progression on IO at a follow-up of 20 and 12 mos, respectively. Of 18 sequenced LNEC tumors, 89% had TERT promoter alterations (alts), similar to 85% seen in 52 SNEC tumors. All LNEC tumors had alts of TP53 or RB1, and 10 (56%) had both. Median tumor mutational burden (TMB) was 14 (IQR 8-38) in LNEC and 30 (IQR 15-55) in SNEC. Epigenetic modifiers were altered in 78% LNEC and 79% SNEC. Two LNEC pts had ERCC2 alts and received platinum chemo; both were alive at last follow-up from NEC diagnosis of 30.7-39.1 mos. Conclusions: LNEC pts experienced longer OS compared to pts with SNEC-only in this cohort, but did not appear more chemo-sensitive. Genomic profiles of LNEC and SNEC-only tumors were similar; TERT promoter mutations suggest a potential urothelial precursor. Further investigation of IO for LNEC is warranted.[Table: see text]
Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.
Authors: Pal Sumanta K. , McDermott David F. , Escudier Bernard , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Atkins Michael B. , Needle Michael N. , Rini Brian I.
Published: June 2021

4567

Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. [Table: see text]
Immune checkpoint inhibitors (ICI) in advanced sarcomatoid renal cell carcinoma (sRCC): A multicenter study.
Authors: Gopalakrishnan Dharmesh , Collier Katharine , Park Joseph J , Zaemes Jacob P , Lam Elaine Tat , Alaklabi Sabah , Jaeger Ellen , Parikh Rahul Atul , Barata Pedro C. , Kauffman Eric , Atkins Michael B. , Alva Ajjai Shivaram , Yang Yuanquan , George Saby
Published: June 2021

4568

Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI+ and ICI- groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. Association between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P < 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI+ gp and 48 in ICI- gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI+ had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI+ gp (Table). OS benefit, compared to ICI-, was maintained in pts who received ICI in ≥ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P <.001). TIF was comparable between pts treated with ICI upfront vs in ≥ second line (6.0 vs 5.3 mos, HR 1.27, 95% CI 0.87-1.85, P =.21). On multivariate analysis, ICI- (HR 2.50, 95% CI 1.61-3.88, P <.001), non-CC histology (HR 3.14, 95% CI 1.98-5.00, P <.001) and sarcomatoid component ≥20% (HR 1.92, 95% CI 1.28-2.90, P =.002) were predictive of all-cause mortality. Among pts with non-CC or mixed histology (n=45), ICI+ had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P <.001) and ORR (44% vs 12%, P =.03), compared to ICI-. Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC.[Table: see text]
Characterization of the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC): Prognostic value and therapeutic implications of an M0-macrophage enriched subtype.
Authors: Farha Mark , Vince Randy , Nallandhighal Srinivas , Stangl-Kremser Judith , Goldenthal Steven , Triner Daniel , Morgan Todd Matthew , Palapattu Ganesh S. , Udager Aaron M. , Salami Simpa Samuel
Published: June 2021

4572

Background: Metastatic clear cell renal cell carcinoma (ccRCC) has a 5-year survival of 12%, but the number of approved immune checkpoint blockade (ICB) agents is growing, necessitating the need to better identify responders. The composition and role of the tumor immune microenvironment (TIME) has yet to be comprehensively characterized in ccRCC. Here, we leveraged a genomic data driven approach to characterize TIME subtypes in ccRCC. Methods: Whole transcriptome data from patients with local and metastatic disease in the Cancer Genome Atlas KIRC (TCGA-KIRC) project was utilized (n = 537). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free (PFS) and overall (OS) survival of each cluster was analyzed, and Gene Set Enrichment analysis was performed among clusters. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB in the TCGA-KIRC clusters. Results: There was a distinct M0hi cluster identified which demonstrated a higher proportion of patients with stage III/IV disease, decreased PFS and OS (Table). Additionally, the M0hi cluster was characterized by lower PD-L1 expression (ANOVA, p = 0.0045) and an enrichment of epithelial to mesenchymal transition (EMT) hallmark genes [Enrichment Score = 0.64, p = 0.001]. The M0hi cluster also showed a higher degree of T-Cell Exclusion (ANOVA, p = 2.2x10-16), predominance of Cancer Associated Fibroblasts (CAFs; ANOVA, p = 2.2x10-16) and Myeloid Derived Suppressor Cells (MDSCs; ANOVA, p = 4.1x10-10). The M0hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (Table). Conclusions: Comprehensive characterization of the TCGA-KIRC cohort led to identification of a distinct cluster of ccRCC defined molecularly by decreased PD-L1 and increased EMT gene expression and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and an exclusion of T Cells. Patients within this cluster exhibited aggressive disease and poor predicted response to ICB. These findings warrant further validation to identify appropriate therapeutic approaches for this ccRCC subgroup.[Table: see text]
TROP-2 co-expression with androgen receptor splice variants as a new therapeutic target in prostate cancer.
Authors: Stahlfeld Charlotte , Sperger Jamie , Slovin Susan F. , Tagawa Scott T. , Kyriakopoulos Christos , Kohli Manish , Wang Liguo , Wang Liewei , Dehm Scott , Lang Joshua Michael
Published: June 2021

5060

Background: Tumor-associated calcium signal transducer 2 (TROP-2, TACSTD2) is a transmembrane glycoprotein that is highly expressed in many epithelial cancers. Overexpression of TROP-2 is postulated to mediate cancer cell growth, invasion, and is associated with more aggressive disease. TROP-2 has emerged as a therapeutic target for antibody-drug conjugates in clinical trials including sacituzumab govitecan and DS-1062. Here, we evaluated the expression of TROP-2 in tumor biopsies and circulating tumor cells (CTCs) in men with metastatic castration resistant prostate cancer (mCRPC) to evaluate TROP-2 as a clinically relevant target. Methods: RNA-seq data from the SU2C-PCF database and PROMOTE clinical trial (NCT#01953640) was assessed for TACSTD2 and androgen receptor (AR) splice variant ( AR_V7/AR_V9) expression. Prostate cancer ChIP-seq data was analyzed to identify binding of the AR to the TROP-2 promoter. EpCAM and TROP-2 captured CTCs were isolated from patients with mCRPC using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform and assessed for splice variant, neuroendocrine (NE), and AR-regulated gene signatures, in addition to CTC enumeration and TROP-2 protein expression. Results: TROP-2 expression was detectable in 90% of patients, in both bone and visceral metastatic biopsies (SUC2-PCF). Although TROP-2 low biopsies were infrequent (10%), 58% of these samples showed high levels of NE markers, as compared with 5% in all other patients. In the PROMOTE study, elevated TROP-2 gene expression was significantly higher in biopsies with high AR_V7 expression than in those with low (p = 0.04) or negative (p <.01) AR_V7 expression. ChIP-seq data demonstrated binding of AR at the TROP-2 promoter as well as at a potential enhancer site upstream, suggesting that TROP-2 expression can be regulated by AR activity. Splice variants and NE gene signatures were expressed in CTCs captured with both EpCAM and TROP-2, although markedly different gene expression profiles between EpCAM and TROP-2 CTCs were observed in a subset of patients with neuroendocrine prostate cancer. Detection of AR_V7 from TROP-2 CTCs corresponded to shorter overall survival in 20 patients with mCRPC. TROP-2 protein expression was identified on EpCAM captured CTCs, although patients exhibited a wide degree of both intra- and inter-patient heterogeneity. Conclusions: Our findings demonstrate that TROP-2 is highly expressed in mCRPC, and is reduced in a subset of patient tumors expressing neuroendocrine markers. In the PROMOTE clinical trial with abiraterone acetate, TROP-2 AR variant expression correlated with increased TROP-2 expression. Binding of the AR to the TROP-2 promoter and potential enhancer was observed in prostate cancer cell lines and biopsies. These results indicate TROP-2 is a high value a biomarker and therapeutic target mCRPC.
Interim PSMA PET/CT for response evaluation during LuPSMA treatment in mCRPC (INTERIM PET): An explorative, multicenter study.
Authors: Gafita Andrei , Rauscher Isabel , Weber Manuel , Hadaschik Boris A. , Wang Hui , Armstrong Wesley R , Tauber Robert , Czernin Johannes , Rettig Matthew , Herrmann Ken , Calais Jeremie , Weber Wolfgang A , Benz Matthias R. , Fendler Wolfgang Peter , Eiber Matthias
Published: June 2021

5066

Background: The aim of this analysis was to evaluate the prognostic value of interim PSMA PET/CT in men with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA and to develop a novel framework for Response Evaluation Criteria In PSMA-imaging (RECIP). Methods: This was an explorative, multicenter, retrospective study; 124 men with mCRPC who underwent 177Lu-PSMA treatment and received PSMA-PET/CT at baseline (bPET) and at interim after two cycles of treatment (iPET) met the eligibility criteria and were included in this analysis. The primary endpoint was overall survival (OS). Pairs of bPET and iPET were interpreted by three independent readers for appearance of new lesions. Whole-body tumor lesions were segmented using qPSMA software and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Changes in PSMA-VOL on iPET relative to bPET were calculated. After being tested separately for associations with OS, appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP. Results: The median OS was 13.5 months (95%CI, 11.6-15.4). Appearance of at least one new lesion on iPET was observed in 73 (59%) patients and was associated with poor OS (hazard ratio [HR] 2.23; 95%CI, 1.51-3.28; P <.001). Based on the current data, RECIP were defined as: partial response (PSMA-PR) as a decline ≥20% in PSMA-VOL and no appearance of new lesions; progressive disease (PSMA-PD) as an increase ≥20% in PSMA-VOL and appearance of new lesions; stable disease (PSMA-SD) was defined as any condition but not PSMA-PR or PSMA-PD. The OS of men with PSMA-PD (n = 41) was significantly worse compared to men with PSMA-SD (n = 47; HR 2.52; 95%CI, 1.61–3.93; P <.001) and PSMA-PR (n = 36; HR 4.16; 95%CI, 2.54–6.78; P <.001). PSMA-SD was associated with significantly worse OS compared to PSMA-PR (HR 1.65; 95%CI, 1.02–2.65; P =.039). The time dependent C-index of associations with OS for response according to RECIP was 0.68 (95%CI, 0.63-0.72). Conclusions: Interim staging using PSMA-PET/CT and response classification by RECIP is prognostic for survival of men with mCRPC treated with 177Lu-PSMA. Validation of these findings in clinical trials is warranted.
A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793).
Authors: Roque Dana M , Bellone Stefania , Siegel Eric R. , Buza Natalia , Bonazzoli Elena , Guglielmi Adele , Zammataro Luca , Nagarkatti Nupur , Zaidi Samir , Lee Jungsoo , Schwartz Peter E. , Ratner Elena , Alexandrov Ludmil B. , Iwasaki Akiko , Kong Yong , Song Eric , Dong Weilai , Elvin Julia Andrea , Choi Jungmin , Santin Alessandro
Published: June 2021

5523

Background: Microsatellite instability (MSI-H) is a biomarker for response to immune-checkpoint inhibitors (ICIs); however, these neoplasms are heterogenous including Lynch (germline), Lynch-like (somatic) and sporadic ( MLH1-methylated) tumors. Whether mechanisms underlying MSI alter responses to ICIs is unclear. We report data from a phase II pilot study (NCT02899793) of pembrolizumab in recurrent MSI-H endometrial cancer (EC) patients and potential mechanisms of primary/secondary ICI resistance. Methods: Patients with measurable, MSI-H EC confirmed by immunohistochemistry and polymerase chain reaction were evaluated by next-generation sequencing and received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Twenty-five patients (24 evaluable) were treated. Six (25%) patients harbored Lynch/Lynch-like tumors while 18 (75%) had sporadic EC. Tumor mutational burden (TMB) was higher in Lynch-like (median 2939, IQR:867-5108) versus sporadic tumors (median 604, IQR:411-798) ( P= 0.0076). Median follow-up was 25.8 months with an ORR of 58% (95% CI, 36.6-77.9%). ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients ( P= 0.024). The 3-year progression-free (PFS) and overall survival (OS) proportions were 100% versus 30% ( P= 0.017) and 100% versus 43% ( P= 0.043), respectively. Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients. Defective antigen processing/presentation and deranged induction in interferon responses served as mechanisms of resistance in sporadic MSI-H EC. Conclusions: Our study demonstrated prognostic significance of Lynch-like versus sporadic MSI-H EC on ORR, PFS and OS when treated with pembrolizumab. Clinical studies evaluating separate subtypes of MSI-H EC treated with ICIs are warranted. Clinical trial information: NCT02899793.
Parametrial evaluation in cervical cancer by magnetic resonance imaging and clinical examination: Analysis of data from the prospective Leipzig School MMR study.
Authors: Wolf Benjamin , Sodeikat Paulina , Lia Massimiliano , Martin Mireille , Horn Lars-Christian , Höckel Michael , Aktas Bahriye
Published: June 2021

5525

Parametrial evaluation in cervical cancer by magnetic resonance imaging and clinical examination Background: In cervical cancer patients, assessment of parametrial tumor extension is important for staging and treatment planning. The 2019 cervical cancer guideline published by the Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) for the first time includes recommendations for usage of magnetic resonance imaging (MRI) in this setting. However, valid data regarding the accuracy of this method, especially in patients with advanced disease, are sparce. The objective of this investigation was to compare the accuracy of parametrial assessment in cervical cancer patients using MRI and clinical examination under general anesthesia. Methods: A retrospective cohort study based on data from the prospective monocentric observational Leipzig School Mesometrial Resection study was conducted. Cervical cancer patients staged FIGO IB1 to FIGO IVA who underwent primary surgery between 1999 and 2017 were included. Data from pathological specimen of these patients was compared to the MRI findings and the results from clinical examination under general anesthesia. The gynecological oncologist had access to the MR images during clinical assessment. We calculated sensitivities, specificities, and predictive values for both examination methods. We performed logistic regression modelling to determine factors influencing the accuracy of either method. Results: 400 women were included. Pathologically proven parametrial tumor invasion was present in 165 (41%) patients. Examination under anesthesia augmented by intraoperative display of MR images exhibited a higher accuracy (83%) as compared to MRI alone (76%; McNemar’s odds ratio = 2.0, 95%CI 1.25 – 3.27, p = 0.003). While accuracy was not affected by tumor size in clinical examination, MRI was associated with a significant drop in accuracy in tumors ≥ 2.5 cm (univariable logistic regression, OR for a correct diagnosis compared to smaller tumors 0.22, p < 0.001). This association remained significant in a multivariable model. There was also a significant decrease in specificity when evaluating parametrial invasion by MRI in tumors ≥ 2.5 cm in diameter (p < 0.0001). Body mass index had no influence on performance of either method. Accuracy was significantly higher when test results were concordant (OR 7.5 and 6.0 on univariable and multivariable regression modelling, respectively, p < 0.0001 in both cases). Conclusions: Clinical evaluation of the parametrium by pelvic examination under anesthesia in conjunction with intraoperative presentation of MR images leads to more accurate staging in cervical cancer patients as compared to magnetic resonance imaging alone. Clinical examination should therefore remain an integral part of parametrial assessment in cervical cancer patients.
An international, multicenter, real-world analysis of epithelial ovarian cancer treatment and outcomes.
Authors: Hall Geoff , Cheeseman Sue , Levick Bethany , Nam Eun Ji , Lim Subin , Classe Jean-Marc , Martin Elodie , Kubelac Paul , Achimaș-Cadariu Patriciu , Savva-Bordalo Joana , Borges Marina , Becker Sven , Shaid Shabnam , Niklas Nicolas , Guergova-Kuras Mariana
Published: June 2021

5531

Background: Few major studies have examined and compared the management and outcomes of patients from diagnosis to death between countries. We have established an international collaboration across Europe and South Korea to compare treatment and outcomes in Epithelial Ovarian Cancer (EOC). Methods: Patients diagnosed with EOC between January 2012 and December 2018 (age ≥18), were included for analysis. Data from medical records from five European and a single South Korean treatment centre were extracted, standardised to a common data model and analysed at each centre using a common script developed in R. Time to each progression/recurrence event (defined as time to next treatment) and overall survival have been estimated using Kaplan Meier methodology and outcomes stratified by categories of interest. Changes in the use of anti-cancer therapies over time and the incidence of BRCA mutations and incidence/timing of second breast cancers have also been examined. Results: A total cohort of 2925 patients was identified with a median age at each centre of 53 to 67 years. Advanced disease (FIGO stage III - IV) (range 57% to 84%) and high-grade serous morphology (38% to 70%) were most common at each centre. The timing of surgery (primary, interval debulking or delayed) and the proportion of patients undergoing surgery varied with stage. Patients with stage I disease where most likely to undergo surgery (range 73% to 100%) and stage IV the least (range 39% to 84%). Median overall survival for high grade serous cancers ranged from 1.9 to 4.9 years, and for the whole cohort from 2.1 to 5.5 years. Median time to next treatment at first relapse for the whole cohort ranged from 14 to 22 months. Second breast cancers were noted in 6 to 17% of patients and the majority of these occurred before the diagnosis of EOC at a median time of 96 to 118 months prior to diagnosis of EOC. Additional data on treatment pathways, BRCA status and outcomes by line of therapy for each centre will be presented. Conclusions: Preliminary analysis of results across this network suggests a variation in patient populations between sites and substantial differences in both treatments and outcomes. The establishment of a common data model and the use of a common analytic script between sites across six different countries allows for detailed exploration of the factors influencing differences in patient management and treatment outcomes in ovarian cancer patients.
Clinicopathologic features of breast cancers diagnosed in females treated with prior radiation therapy for Hodgkin lymphoma: Results from a population-based cohort.
Authors: Wong Stephanie M , Ajjamada Lissa , Weiss Anna , Prakash Ipshita , Skamene Sonia , Boileau Jean-Francois , Pollak Michael N. , Basik Mark
Published: June 2021

567

Background: Childhood and young adult survivors of Hodgkin Lymphoma are at an increased risk of developing breast cancer, although little data exist on the characteristics and biologic subtype of breast cancers that develop in this high-risk population. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all histologically confirmed breast cancers diagnosed between 1990-2016 in women treated with prior radiation therapy for Hodgkin Lymphoma ≤ 30 years of age. Clinicopathologic features of subsequent breast cancers (BC-HL) were examined and compared to breast cancers diagnosed in women with no prior malignancy (BC-NPM). The association between prior chemotherapy use and biologic subtype of BC-HL was evaluated. Results: We identified 321 breast cancers diagnosed in 257 women with a history of radiation therapy for Hodgkin Lymphoma. The median age at Hodgkin Lymphoma diagnosis was 22 years (range, 12-30 years), and nearly all BC-HL (97.9%) were diagnosed 8 or more years after radiation therapy. Overall, 56 (21.8%) BC-HL patients developed bilateral breast cancer, of which 28 (50%) were synchronous. When compared to women with BC-NPM, women with BC-HL were significantly younger at time of diagnosis (median age, 43 years vs. 60 years, p<0.001) and less likely to present with ductal carcinoma in situ (8.4% vs. 14.9%, p=0.001). Patients with invasive BC-HL were more likely to have high grade (43.8% vs. 32.9%, p<0.001), estrogen receptor (ER) negative breast cancer (27.7% vs. 18.2%, p<0.001), although pathologic tumor size, nodal status, and stage were not significantly different from those with BC-NPM. Compared to women with BC-NPM, the majority of operable BC-HL patients underwent surgical management with mastectomy (86.5% vs. 42.5%, p<0.001). In subset analysis of 102 women for which HER2 status was available, BC-HL were HER2+ in 18.7% of patients. Distribution of biologic subtype between BC-HL and BC-NPM are shown in the table below. In BC-HL patients, prior chemotherapy exposure was not associated with substantial differences in the proportion of ER+HER2- breast cancers (65.8% vs. 63.5%, p=0.82). Conclusions: Breast cancers in women treated with radiation therapy for Hodgkin Lymphoma are characterized by earlier onset and more aggressive biologic features, although the majority remain estrogen sensitive and early stage at presentation. Further studies are warranted to evaluate the use of preventive strategies in this high-risk patient population.[Table: see text]
Independent validation of simbiosys tumorscope to predict response to neoadjuvant chemotherapy (NACT) in early breast cancer (EBC).
Authors: He Gong , Howard Frederick , Pandey Tushar , Abe Hiroyuki , Nanda Rita
Published: June 2021

582

Background: Despite substantial advances in the understanding of breast cancer biology, the decision to use NACT for EBC is based on tumor size, lymph node status, and subtype. Even with aggressive therapy, the majority of women will not achieve a pathologic complete response (pCR). Investigational treatment regimens, including immunotherapy, can increase pCR rates, but are associated with irreversible immune-related toxicities. Being able to accurately predict pCR could identify candidates for intensification or de-escalation of NACT, allowing for personalized medicine. SimBioSys TumorScope (TS) is a biophysical model that utilizes baseline MRI, receptor status, and planned treatment regimen to simulate response to NACT over time. TS has demonstrated accurate prediction of pCR in prior studies. Here, we describe an independent external validation of TS. Methods: We conducted a retrospective study of University of Chicago patients (pts) who received NACT for EBC from Jan 2010 - March 2020. Pts must have had a pretreatment breast MRI. Tumors were analyzed using TS by investigators who were blinded to response data. TS predicted pCR was predefined as a residual tumor volume < 0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. Results: 144 tumors from 141 pts were analyzed. Average age was 52 yrs; 65% had stage II and 19% had stage III disease. Sensitivity and specificity of TS for predicting pCR were 90.4% and 92.4%, respectively. Of the 7 patients who were predicted to achieve a pCR but did not, 5 had a tumor cellularity < 5%. With a median follow-up of 4.7 yrs, the 4-yr distant disease free survival (DDFS) was 100% for patients predicted to achieve pCR, versus 81.5% for those predicted to have residual disease. Results were generally robust for all subgroups analyzed (Table). Conclusions: TS accurately predicts pCR and DDFS from baseline MRI and clinicopathologic data. Given the high sensitivity and specificity of this assay across breast cancer subtypes, TS can be used to aid in escalation/de-escalation strategies for EBC.[Table: see text]
Impact of comprehensive geriatric assesment (CGA) in the treatment decision and outcome of older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Llop Serna Sandra , Ejarque Martinez Clara , Brenes Castro Jesús , Honorato Macarena , Vilajosana Altamis M. Esther , Melero Mireia , Bermejo Oriol , Gomez Garcia Victoria , Fulla Marta , Goma Montse , Linares Isabel , Lozano Alicia , Taberna Miren , Mesia Ricard , Plana Maria , Rebollo Maite Antonio , Oliva Bernal Marc
Published: June 2021

6057

Background: Up to 24% of patients (pts) newly-diagnosed with LA-HNSCC are 70 years old (yo). NCCN guidelines recommend a geriatric assessment to guide treatment decisions in this pts population. Comprehensive geriatric assessment (CGA) of older HNSCC pts was implemented at our institution in 2018. We evaluated the impact of CGA in treatment decision and outcome and compare it to a control cohort with no CGA treated within the same institution. Methods: Retrospective single-institution analysis of two consecutively-treated cohorts of newly-diagnosed elderly LA-HNSCC pts treated at the Catalan Institute of Oncology: a cohort treated based on CGA between 2018-2020; and a control cohort with no CGA treated based on physician criteria following tumor board decision between 2016-2018. Pts demographics and disease characteristics were obtained from our in-site prospective database. Treatment received (standard, adjusted, palliative-intent, best supportive care [BSC]), treatment completion rate (TCR) an overall response rate (ORR) after conservative treatment were collected and compared for both cohorts using chi-square. Results: A total of 197 pts were included: CGA cohort =81; Control cohort=96. Baseline characteristics were similar between cohorts (Table). Pts in CGA cohort were classified as fit (F) 35 (34.7%), medium-fit (MF) 51 (50.5%) and unfit (UF) 15 (14.9%) according to CGA results. CGA changed final treatment decision following tumor board in 31 % of the cases. Pts were more likely to receive standard treatment in the CGA cohort when compared control (36 vs 21%; p = 0.048), with no differences observed in TCR (84% vs 86%; p = 0.805). In pts who underwent conservative treatment, ORR was similar between CGA and control cohort (73.9% vs 66.7 %; p = 0.082), respectively. Tumor progression was the major cause of death in both groups. Conclusions: Older pts with LA-HNSCC who underwent CGA were more likely to receive standard treatment than those who did not, supporting the relevance of CGA for clinical decision-making in this pt population. No differences were observed in CRR, TCR or death cause. In-deep survival analysis are on-going.[Table: see text]
The association of sexual orientation with cancer screening and diagnosis.
Authors: Herriges Michael Joseph , Pinkhasov Ruben , Lehavot Keren , Shapiro Oleg , Jacob Joseph M , Sanford Thomas , Liu Nick , Bratslavsky Gennady , Goldberg Hanan
Published: June 2021

6506

Background: Data on heterogeneity in cancer screening and diagnosis rates among sexual minorities (SMs) is lacking. Recent studies have shown SMs are more likely to engage in risky health behavior and have decreased healthcare utilization compared to heterosexual counterparts. However, few studies have examined how sexual orientation (SO) impacts cancer screening and prevalence. We therefore investigated whether SO affects prevalent gender-specific cancer screening and prevalence, including prostate (PCa), breast (BC), and cervical cancer (CC). Methods: This was a cross-sectional survey-based US study, including men and women aged 18+ from the Health Information National Trends Survey (HINTS) database (part of the National Cancer Institute’s division of cancer control and population sciences) between 2017-2019. The primary endpoint was individual-reported PCa, BC, and CC screening and prevalence rates among heterosexual and SM men and women. Multivariable logistic regression analyses assessed association of various covariates with undergoing screening and diagnosis of these cancers. Results: Overall, 4,441 (95.18%) men and 6,333 (96.75%) women reported a SO of heterosexual whereas 167 (3.6%) and 58 (1.2%) men and 105 (1.6%) and 108 (1.6%) women reported a SO of gay and bisexual, respectively. Mean age was higher in the heterosexual group compared to the gay and bisexual groups in both men (57.7 [±16.0] vs. 52.4 [±14.5] and 51.9 [±18.0] years, p = < 0.001) and women (56.2 [±16.7] vs. 49.0 [±17.1] and 40.0 [±14.8] years, p = < 0.001). Homosexuals and bisexuals were less likely to be screened for PCa (30.53% and 27.58% vs 41.27%, p = < 0.001), BC (63.81% and 45.37% vs 80.74%, p = < 0.001), and CC (90.48% and 86.11% vs 95.36%, p = < 0.001) than their heterosexual counterparts. While rates of PCa and BC diagnoses were similar across SO, more homosexual and bisexual women were diagnosed with CC compared to their heterosexual counterparts (4.76% and 3.70% vs 1.85%, p = 0.039). Multivariable logistic regression models showed that SMs were less likely to be screened for cancer with ORs of 0.61 (95% CI 0.39-0.95, p = 0.030) for PCa, 0.52 (95% CI 0.30-0.92, p = 0.025) for BC, and 0.21 (95% CI 0.09-0.46, p = < 0.001) for CC. Although multivariable models did not show that SMs were more likely to be diagnosed with PC, BC, or CC, SMs were more likely to be diagnosed with any cancer with ORs of 1.64 (95% CI 1.06-2.54, p = 0.026) in women only and 1.50 (95% CI 1.11-2.03, p = 0.009) in men and women combined. Conclusions: These data suggest that in addition to other established and known specific socio-economic risk factors, SMs may be less likely to undergo screening of prevalent malignancies such as PCa, BC, and CC. This provides more evidence of ongoing healthcare inequality, urging our healthcare system to invest more in cancer screening of this vulnerable population.
Health outcomes and resource utilization associated with postsurgical opioid use among cancer patients undergoing curative-intent surgery.
Authors: Lin Na , Xu Yuan , Cheung Winson Y. , Quan May Lynn
Published: June 2021

6515

Background: To date, it remains unclear whether new persistent post-surgical opioid use is associated with subsequent opioid overdose, higher mortality and greater consumption of healthcare resources among cancer patients. To fill this gap, a population-based cohort study by applying real-world data has been performed to compare the long-term outcomes and healthcare resource use between new persistent and non-persistent opioid users among cancer patients after curative-intent surgery. Methods: This retrospective cohort study included all adult cancer patients with solid tumours who received curative-intent surgery in Alberta between 2011 and 2015, with a follow-up period until December 31, 2019. Patients who had multiple tumors, or had a follow-up < 6 months, or > 30 days of hospitalization were excluded. A new persistent post-surgical opioid user was defined as a patient who was opioid-naïve before surgery (no opioid prescription filled prior to the surgery) and subsequently filled at least one opioid prescription between 60 and 180 days after surgery. The outcomes (opioid overdose and mortality within 3 years) and health resource use (emergency department visits and hospitalization within the first year) after surgery were evaluated by applying multivariable logistic and Cox regressions. Results: A total of 19,219 patients received curative-intent surgery with a median follow-up of 47 months, of which 1,530 (8.0%) were identified as postoperative new persistent opioid users. Compared with the non-persistent group, a higher rate of opioid overdose (OR = 1.81, 95% CI: 1.49-2.2) within 3 years of surgery has been observed for new persistent opioid users, who were also associated with a greater likelihood of being hospitalized (OR = 2.52, 95% CI: 2.21-2.87) and visiting an emergency room (OR = 2.0, 95% CI: 1.78-2.24) within the first year after surgery. A higher overall (HR = 1.37, 95% CI: 1.2-1.57) and non-cancer caused mortality (HR = 1.39, 95% CI: 1.18-1.65) has also been detected for new persistent opioid users during the study follow-up period. Conclusions: For cancer patients undergoing curative-intent surgery, reducing new persistent opioid use is imperative to improve subsequent outcomes and health resource utilization.
Significant decline in cancer diagnostic testing in U.S. CMS population during the COVID-19 pandemic.
Authors: Smart Dave , Riccelli Peter , Kerr Keith , Clark Jordan , Fosvig Susanne Munksted , Lawler Mark
Published: June 2021

6536

Background: The COVID-19 pandemic has caused >400,000 infection related deaths in the US to January 2021. Actions taken to limit COVID-19 infection and mortality could potentially lead to unintended consequences, precipitating excess mortality due to other causes. One such cause is delayed cancer diagnosis. Significant decreases in presentation for cancer diagnosis at the primary care level have been noted in the UK. This study aimed to look for evidence of a similar effect in the US. Methods: CMS claims data from JAN18-JUN20 associated with primary diagnosis across 11 cancers (bladder, breast, cervical, colorectal, endometrial, lung, ovarian, pancreatic, prostate, sarcoma and thyroid) were analyzed for use of surgical pathology (SP), a procedure associated with initial diagnosis, and immunohistochemistry (IHC). Test volumes varied widely by test and cancer so were normalized to enable comparison across indications. This was done by dividing the month-on-month difference for the period JAN19-JUN19 vs JAN20-JUN20 by the median monthly test volume for the period JAN18-DEC19 (“pre-COVID period”). Extent and duration of declines in test rates and number of missing patients as the sum of these declines were then determined. The ratio of IHC to SP testing was taken to determine any decline in likely post-initial diagnosis testing. Results: There were significant (>10%) declines in test volumes for SP for all 11 cancers at some time in Q1-Q2 2020. Table. Extent, duration and return to pre-COVID levels for SP testing across 11 cancers Median extent and duration of the decline was 56% (range 41.1%-80.4%) and 2 months (range 1- >4). This equates to 32,192 missing diagnoses across all cancers. SP test volumes for all cancers except lung and breast had returned to around pre-COVID levels by JUN20. There was no significant (>10%) increase in normalized SP test volume after the COVID dip for any cancer. While SP showed decreased test volumes across all cancers at some point during the first half of 2020, test volume ratios of IHC to SP showed increases for most cancers in the same time period. Conclusions: These data highlight that the decline in patients presenting to their primary care physicians with suspicion of cancer for diagnostic investigation was linked to COVID-19 prevention strategies. No evidence for increased, “catch up” testing to address presentational/diagnostic backlog was observed. Thus, it is predicted that these patients may subsequently present with a more advanced cancer. Potential excess morbidity, mortality and cost associated with absent or delayed diagnosis should be factored into cancer control programs going forward.[Table: see text]