bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes and the impact of genomic characteristics on patients with metastatic urothelial carcinoma enrolled in early phase trials.
Authors: Alhalabi Omar , Hahn Andrew W , Meric-Bernstam Funda , Naing Aung , Piha-Paul Sarina Anne , Janku Filip , Pant Shubham , Yap Timothy A , Hong David S. , Fu Siqing , Campbell Erick , Le Hung , Shah Amishi Yogesh , Campbell Matthew T , Tannir Nizar M. , Siefker-Radtke Arlene O. , Gao Jianjun , Roszik Jason , Subbiah Vivek
Published: May 2020

5029

Background: With the recent approvals of checkpoint inhibitors (CPIs), a fibroblast growth factor receptor (FGFR) inhibitor, and an antibody-drug conjugate, patients with platinum-refractory metastatic urothelial carcinoma (mUC) have several treatment options available. However, many patients with platinum-refractory mUC need novel therapies after progressing on current therapies. We assessed the role of early phase trials in treatment of mUC and the impact of genomic alterations on their outcomes. Methods: We retrospectively analyzed medical records of patients with mUC who received an investigational therapy at the phase 1 clinic and had CLIA-certified clinical next generation sequencing. Clinical parameters and mutations were abstracted. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Among the 57 pts enrolled in 41 unique phase 1 trials between 2015 and 2019, 16% (9/57) had variant histology: neuroendocrine carcinoma (n = 3) and urachal carcinoma (n = 6). Median age was 64. Majority were males (72%). 97% received prior platinum therapy and 60% had received prior CPI therapy. Across the pure urothelial carcinoma cohort (n = 48), median PFS was 4.2 months (m), median OS was 9.8 m, and the overall response rate (ORR) was 19%. TP53, FGFR, TERT, and ARID1A alterations (alt) were detected in 54%, 41%, 21% and 17% of UC patients, respectively. Patients harboring a TP53 alt, compared to no alt, had a shorter median PFS of 3.2m vs 9.6 m (HR = 2.738 [1.247 - 6.011], p = 0.0121). On the contrary, median PFS was longer in FGFR alt, compared to no alt, 6.3m vs 3.2m (HR = 0.4662 [0.224 - 0.971], p = 0.0415). Of note, 64% of FGFR alt patients were treated under an early phase FGFR targeting trial. Median OS was numerically longer in FGFR alt and shorter in TP53 alt but did not reach statistical significance (table). Conclusions: Patients with mUC may derive clinical benefit from enrollment in phase I clinical trials. Patients with TP53 alterations had numerically worse outcomes. Patients with mUC should be considered for an FGFR targeting therapy in the setting of an FGFR alteration. [Table: see text]
Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings.
Authors: Lyou Yung , Grivas Petros , Rosenberg Jonathan E. , Hoffman-Censits Jean H. , Quinn David I. , Petrylak Daniel Peter , Galsky Matt D. , Vaishampayan Ulka N. , De Giorgi Ugo , Gupta Sumati , Burris III Howard A. , Rearden Jessica , Andresen Corina , Wang Hao , Daneshmand Siamak , Bajorin Dean F. , Pal Sumanta K.
Published: May 2020

5038

Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), previously reported to be effective and well tolerated in patients with locally advanced/unresectable or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al. Cancer Discovery 2018]. However, this previous study did not examine differences in infigratinib activity based on number of prior lines of treatment (LOT). TKIs studied in other indications (e.g. VEGFRis in renal cell carcinoma) have shown consistent activity in both the first and later LOT. Given the effect seen with other TKIs, we sought to determine if infigratinib showed consistent treatment responses in patients with mUC according to LOT. Methods: Eligible patients had mUC and prior platinum-based chemotherapy unless contraindicated and activating FGFR3 mutations/fusions. Infigratinib was dosed at 125 mg orally daily (3 weeks on/1 week off). The primary endpoint of objective response rate (ORR: partial response [PR] and complete response [CR]) was assessed, as well as disease control rate (DCR: CR + PR + stable disease [SD]). After classification of LOT for each patient, subgroup analysis of response by LOT was performed. Results: 67 patients were enrolled; 81% received ≥1 prior LOT for mUC. 13 patients (19.4%) received infigratinib as 1st LOT for mUC due to ineligibility to receive platinum-based chemotherapy. ORR for the 67 patients was 25% (95% CI 15.5–37.5) and DCR was 64% (95% CI 51.5–75.5). The ORR with 1st-line infigratinib was 31% (95% CI 9.1–61.4) compared with 24% (95% CI 13.5–37.6) for 2nd and later (salvage) LOT. DCR was 46% (95% CI 19.2–74.9) for 1st-line and 69% (95% CI 54.4–80.5) for ≥2 LOT. 13 of the 59 patients with urothelial bladder carcinoma (UBC) received 1st-line treatment with an ORR of 31% (95% CI 9.1–61.4) and 46 patients in ≥2 LOT had an ORR of 20% (95% CI 9.4–33.9). All 8 patients with upper tract urothelial carcinoma (UTUC) received salvage therapy, with an ORR of 50% and a DCR of 100%. An analysis of other outcome measures (e.g. PFS, OS) will be presented. Conclusions: These results indicate that infigratinib has activity in patients with mUC regardless of LOT. Additionally, patients with UTUC showed a trend for better ORR and DCR. Taken together, these results support the ongoing adjuvant PROOF 302 study comparing infigratinib with placebo in patients with resected disease, assessing infigratinib in an even earlier setting in a UTUC-enriched population (NCT04197986). Clinical trial information: NCT01004224 .
Outcomes of patients (pts) with metastatic urothelial carcinoma (mUC) following discontinuation of enfortumab-vedotin (EV): Emergence of a new unmet need.
Authors: Curran Catherine , Pond Gregory Russell , Kazakova Vera , Grivas Petros , Diamantopoulos Leonidas Nikolaos , Alva Ajjai Shivaram , Su Christopher , Jain Rohit K. , Tandon Ankita , Zhang Jingsong , Necchi Andrea , Marandino Laura , Merchan Jaime R. , Plastini Trisha M. , Sonpavde Guru
Published: May 2020

5048

Background: Enfortumab vedotin (EV) is an antibody drug conjugate recently approved to treat mUC following prior platinum and PD1/L1 inhibitors. The outcomes and patterns of therapy of pts following discontinuation of EV has yet to be studied. We investigated outcomes of pts who completed EV treatment for mUC at multiple institutions in order to identify benchmarks for evaluation of new agents following EV. Methods: Clinical data were obtained from mUC patients who had completed EV treatment from collaborating academic institutions. Descriptive stats were performed to describe the overall dataset and compare patient characteristics and outcomes of those who went on to receive further treatment post-EV and those who did not. Results: Data were available for 63 patients from 6 collaborating institutions: DFCI, University of Michigan, University of Washington, Moffitt Cancer Center, INT Milan and University of Miami. 17 (27%) were female and 46(73%) were male. The median age was 68 (range 43-83. The primary site of malignancy included bladder, upper tract, and other in 43 (68%), 19 (30%), and 1pt (.02%), respectively. The histologies included pure UC and mixed predominant UC in 49 (78%), and 14 pts (22%), respectively. 32 pts (51%) received further therapy after EV and 31pts (49%) did not. Longer duration of prior EV therapy was associated with receipt of post-EV therapy (p=0.0437). Treatments received post-EV were: trial therapy (n=14), PD1/L1 inhibitor (n=7), pemetrexed (n=4), taxane (n=3), carboplatin (n=2) and unknown in 2 pts. Objective response was observed in 3 of 32 pts (9.4%) who received therapy post-EV. The median duration of time from end of EV to death was 24 weeks. The median overall survival (OS) of those who received post-EV therapy and did not receive post-EV therapy was 37.5 weeks and 12 weeks, respectively. Conclusions: Outcomes of mUC following discontinuation of EV are dismal with only 51% receiving subsequent therapy. This study identifies an unmet need setting and establishes benchmarks for the interpretation of activity of new agents evaluated following EV.
Maintenance oral etoposide (VP-16) after high-dose chemotherapy (HDCT) for patients with relapsed metastatic germ-cell tumors (mGCT).
Authors: Anouti Bilal , Akel Reem , Althouse Sandra K. , Abonour Rafat , Abu Zaid Mohammad Issam , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: May 2020

5051

Background: HDCT and peripheral-blood stem-cell transplant (PBSCT) can cure up to 60% of patients with relapsed mGCT. Maintenance daily oral VP-16 after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the role of maintenance VP-16 post HDCT+PBSCT compared to observation. Methods: The prospectively maintained Indiana University testicular cancer database was interrogated. Patients with relapsed non-seminoma who completed HDCT+PBSCT and achieved serologic remission and hematologic recovery were evaluated. Outcomes of patients who received maintenance VP16 (N = 141) were compared to patients who were observed (N = 252). In this retrospective study, Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariable and multivariable cox regression models were used to determine variables associated with PFS. Results: 2-year PFS in the maintenance VP-16 versus observation group was 55% vs. 44% (p = 0.008). 2-year OS was 61% vs. 52% (p = 0.01). A multivariable analysis was performed including the factors: primary tumor site (testis vs. mediastinum), IGCCCG risk, platinum refractory, HDCT line of therapy (2nd vs. ≥3rd), tumor marker amplitude at HDCT initiation, and receipt of maintenance VP-16 post HDCT vs. observation. Maintenance VP-16 was confirmed as an independent predictor of improved PFS with HR 0.48 [95% CI, 0.35-0.66] (p < 0.001). Conclusions: Maintenance oral VP-16 post HDCT+PBSCT improved PFS and OS. In a multivariable model including known adverse prognostic factors, maintenance VP-16 was an independent predictor of improved PFS. [Table: see text]
SBRT versus nephrectomy in the treatment of renal cell carcinoma.
Authors: Patel Mausam , Kim Thomas , Li Chenghui , Safar Ahmed , Maraboyina Sanjay
Published: May 2020

5059

Background: Stereotactic body radiotherapy (SBRT) is being increasingly used for renal cell carcinoma (RCC) treatment in non-surgical candidates. However, no studies have compared survival between nephrectomy and SBRT. The National Cancer Database (NCDB) database was used to assess overall survival in patients undergoing SBRT vs nephrectomy. Methods: All cases of T1-T4, N0, M0 RCC diagnosed between 2004 and 2016 were extracted from the NCDB. Only patients undergoing either nephrectomy or SBRT, but not both, were included in the final analysis. Primary outcome was overall survival, defined as time in months from diagnosis to death due to any cause. Descriptive statistics were calculated for all variables. Univariate survival analysis was performed using the Kaplan Meier method and log rank test. Multivariate Cox proportional hazards regression models were performed to determine the predictive performance of covariates with respect to overall survival, reported as hazard ratio [HR] with 95% CIs. Nephrectomy patients were propensity score matched to SBRT patients for sub-cohort survival analysis. Comparisons were considered statistically significant at P < 0.05. Results: There were 243,754 patients meeting inclusion criteria with 243,488 undergoing nephrectomy and 266 undergoing SBRT. Five year OS rates were 53% and 80% for SBRT and nephrectomy, respectively (P < 0.001). On multivariate Cox regression, SBRT was associated with an increased risk of death as compared to nephrectomy (HR, 2.05; 95% CI, 1.72 – 2.44; P < 0.001). Sex, race, insurance coverage, comorbidity index, tumor grade, lymphovascular invasion status, T-stage, tumor size, and academic status of treatment facility were also independent predictors of survival. After propensity score matching of 266 SBRT patients to 266 nephrectomy patients, there were no significant differences in baseline characteristics between the groups. However, SBRT continued to demonstrate worse survival and an increased risk of death as compared to nephrectomy (HR, 1.85; 95% CI, 1.41 – 2.44; P < 0.001). Conclusions: Among node-negative, non-metastatic RCC patients, SBRT is associated with inferior survival outcomes as compared to nephrectomy, even after correcting for underlying differences in demographics, tumor characteristics, socioeconomic status, and comorbidities. These results indicate that nephrectomy should remain the standard of care for RCC patients, with SBRT reserved for non-surgical candidates.
Baseline and early change of systemic inflammation index (bSII and ΔSII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with Nivolumab: Final results of the Meet-URO 15 (I-BIO-REC) study.
Authors: Rebuzzi Sara Elena , Atzori Francesco , Di Napoli Marilena , Stellato Marco , Messina Marco , Chiellino Silvia , Vignani Francesca , Cavo Alessia , Soto Parra Hector J. , Roviello Giandomenico , Prati Veronica , Bimbatti Davide , De Giorgi Ugo , Bersanelli Melissa , Paolieri Federico , Zucali Paolo Andrea , Fantinel Emanuela , Procopio Giuseppe , Signori Alessio , Fornarini Giuseppe
Published: May 2020

5072

Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are still needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was collected at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to baseline neutrophil-to-lymphocyte ratio. Secondary analyses included bSII defined as platelet x NLR (cutoff = 1375) and ΔSII defined as the difference between SII at 2ndcycle and bSII (median used as cutoff = 383). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd(67%), 3rd(22%) and > 3rd(11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. SII was available in 404 patients: SII < 1375 (82%) correlated with statistically significant improvement of PFS [10.2 vs 4.1 months, HR 2.06 (1.54-2.76), p< 0.001], OS [46.2 vs 9.5 months, HR 3.16 (2.23-4.49), p< 0.001], ORR (35% vs 21%, p= 0.035) and DCR (67% vs 40%, p< 0.001). ΔSII was available in 360 patients: ΔSII < 383 (75%) correlated with statistically significant improvement of PFS [11.3 vs 4.7 months; HR 1.64 (1.23-2.18), p= 0.001] and OS [NR vs 21.1 months; HR 1.76 (1.21-2.56), p= 0.003], ORR (37% vs 24%, p= 0.023) and DCR (68% vs 53%, p= 0.01). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bSII and ΔSII with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bSII and early ΔSII with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.
Randomized prospective trial assessing Bifidobacterium-containing probiotic supplementation in metastatic renal cell carcinoma (mRCC) patients receiving vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs).
Authors: Dizman Nazli , Hsu Joann , Bergerot Paulo Gustavo , Gillece John D , Folkerts Megan , Reining Lauren J , Trent Jeffrey M. , Highlander Sarah K , Pal Sumanta K.
Published: May 2020

5078

Background: Studies suggest a link between the gut microbiome and mRCC outcomes, including evidence that mRCC patients (pts) possess a lower abundance of Bifidobacterium spp compared to healthy adults (Pal et al Clin Cancer Res 2015). The aim of this study was to assess if Bifidobacterium-containing probiotics could modulate the gut microbiome and impact rates of clinical benefit (CB) from VEGF-TKIs. Methods: Pts initiating VEGF-TKI therapy for mRCC were randomized to probiotic supplemented (PSu) or probiotic restricted (PRe) treatment arms. Pts in the PSu arm consumed two 4 oz servings of Activia daily. Stool samples were collected prior to therapy and at wks 2, 3, 4 and 12. Gut microbiota composition was assessed using whole genome shotgun metagenomic sequencing (Zhu et al Microbiome 2018). The primary endpoint was change in Bifidobacterium spp with therapy. Microbiome composition was compared across pts with CB (complete/partial response or stable disease) versus no CB (NCB). Results: In total, 20 pts were enrolled. The most frequent VEGF-TKIs were cabozantinib (45%), sunitinib (25%) and lenvatinib (25%). Median progression-free survival (PFS) was 6.5 months (95%CI 0.3-12.9) and CB rate was 75%. Bifidobacterium animalis, the active ingredient of Activia, reached detectable levels in all pts in the PSu arm, but was only detectable in one pt in the PRe arm. CB rate was not significantly different in PSu vs PRe arms (70% vs 80%, p > 0.05), and there was no difference in PFS. LDA effect size (LEfSe) analysis of MetaPhIAn2 data captured 25 enriched species demonstrating an LDA score > 3 in either CB or NCB. Of those with high LDA scores, Barnesiella intesitinihominis and Akkermansia municiphila were the most significant members (p = 7.4 x 10−6 and p = 5.6 10−3, respectively). While 92% of B. intestinihominis positive pts obtained a CB, only 50% of B. intestinihominis negative pts obtained CB (p = 0.036). Conclusions: This is the first prospective randomized study demonstrating modulation of the gut microbiome with probiotics in mRCC. While microbiome modulation by probiotics did not increase CB rates as intended, consecutive stool specimens allowed us to identify an association between B. intesitinihominis, A. municiphila and CB with VEGF-TKIs. In addition to the previously documented association between A. municiphila and immunotherapy outcome (Routy et al. Science 2018), this species may predict activity with VEGF-TKIs. Clinical trial information: NCT02944617 .
Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ (DCIS): Comparison of patients with and without index surgery.
Authors: Ryser Marc D , Hendrix Laura , Thomas Samantha M. , Lynch Thomas , McCarthy Anne , Mohammed Zahed , Francescatti Amanda B. , Frank Elizabeth S. , Partridge Ann H. , Thompson Alastair Mark , Hyslop Terry , Hwang Eun-Sil Shelley
Published: May 2020

519

Background: Most women diagnosed with ductal carcinoma in situ (DCIS) undergo surgical resection, potentially leading to overtreatment of patients who would not develop clinically significant breast cancer in the absence of locoregional treatment. We compared the risk of ipsilateral invasive breast cancer (iIBC) between DCIS patients who received breast conserving surgery (BCS) for their index diagnosis of DCIS (BCS group) and patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods: A treatment-stratified random sample of patients diagnosed with screen-detected and biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Excluding patients who received a mastectomy ≤6 months, the final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcome was the 8-year absolute difference in iIBC risk between BCS and SV; a subgroup analysis was performed for grade I/II patients. A propensity score (PS) model for treatment was fitted with sampling design (SD) weighting and random effects for patients within facilities. Absolute risk differences were estimated using PS-SD-weighted Kaplan Meier estimators. Results: Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with estrogen receptor-positive (80.6%), and nuclear grade I/II (54.5%) DCIS. The fraction of patients with a Charlson comorbidity score of ≥2 was higher in SV (14.2%) compared to BCS (6.4%, p < 0.001). The 8-year risk of iIBC was 3.0% (95% CI: 2.4%-3.6%) for BCS and 7.7% (95% CI: 4.9%-10.5%) for SV, with an absolute risk difference of 4.7% (95% CI: 4.5%-4.9%; log-rank p < 0.001). Among patients with grade I/II tumors, the 8-year risk of iIBC was 3.1% (95% CI: 2.3%-4.0%) for BCS and 6.1% (95% CI: 2.5%-9.8%) for SV; difference: 3.0% (95% CI: 2.7%-3.2%; p = 0.005). Conclusions: Despite an increased risk of iIBC in SV patients compared to BCS patients, the 8-year risk did not exceed 10% in either group. The risk of recurrence in BCS patients was comparable to previously reported estimates. These data demonstrate a considerable degree of overtreatment among patients with non-high grade DCIS. Prospective clinical trials will help determine the tradeoffs between universally directed as opposed to selectively applied surgery for low risk DCIS.
Statistical machine learning model to predict Oncotype DX risk category in women over age 50.
Authors: Pawloski Kate R. , Gonen Mithat , Wen Hannah Yong , Tadros Audree B. , Abbate Kelly , Thompson Donna , Morrow Monica , El-Tamer Mahmoud
Published: May 2020

524

Background: The 21-gene Oncotype DX Breast Recurrence Score multigene assay (RS) identifies women with ER positive, HER negative, axillary node-negative breast cancer (BC) for whom chemotherapy provides no invasive disease-free survival benefit compared to endocrine therapy alone. International adoption of RS testing is limited by cost and resource availability. We created a supervised statistical machine learning model using standard clinicopathologic data to predict RS risk category in women > 50 years old. Methods: From 2012 to 2018, women with ER positive, HER2 negative, pathologically node-negative BC of all ages were retrospectively identified from a prospective institutional database. Standard clinicopathologic data and RS were collected. Per institutional protocol, RS are ordered for all early-stage, ER positive tumors > 5 mm. Data were randomly split into training (n=3755) and validation sets (n=1609). A random forest model with 500 trees was developed on the training set, then evaluated on the validation set. Model predictors included age, tumor size, histologic subtype, hormone receptor status, lymphovascular invasion, and overall grade. The model was used to predict RS category (low risk: RS ≤ 25, high risk: RS > 25) in women > 50 years old. Results: 5364 unique tumors in 5189 women were identified. 3731 (70%) of tumors were identified in women > 50 years; median age was 63 years (IQR 57-69). In women > 50, median tumor size was 12 mm (IQR 9-17). Most tumors were invasive ductal (79%), low or intermediate grade (79%), and LVI was absent in 82% of tumors. Median ER staining by IHC was 95%; 28% of tumors had negative or weakly positive PR staining (1-20%). The model correctly classified 96.8% of patients as low risk (95% CI: 95.7-97.7). Negative predictive value for identifying low risk category was also high (92.3%, 90.7-93.6). Sensitivity for identifying high-risk women was 44.7% (37.4-52.1) and positive predictive value was 67.2% (58.2-75.3). A classification table on the validation set includes tumors with complete data available, including predictors and RS. Conclusions: Our model was highly specific (96.8%) for identifying women > 50 with RS ≤ 25 who do not benefit from adjuvant chemotherapy. This model may be utilized in lieu of RS testing if cost and availability are prohibitive. True RS > 25 was not as well predicted. The model will be refined following pathologic review of discordant cases to reduce false negatives. [Table: see text]
The predictive potential of the spatial signature of lymphocytes in breast cancer patients.
Authors: Balint-Lahat Nora , Mayer Chen , Ben-Baruch Noa , Yosepovich Ady , Sacks Kira , Ish-Shalom Shahar , Molchanov Yossef , Dadiani Maya , Morzaev-Sulzbach Dana , Gal-Yam Einav Nili , Achtenberg Albert , Gabay Yuval , Gluskin Roman , Griosman Alon , Shachaf Yuval , Luchtenstein Amir , Zelichov Ori , Alexander Kathrina , Lazar Alexander J. , Barshack Iris
Published: May 2020

530

Background: Tumor-infiltrating lymphocytes in breast cancer have emerged as both a prognostic and a potentially predictive immunotherapy biomarker. Advancements in artificial intelligence can extract pathology-based spatial immune fingerprints for use as treatment decision support tools. Methods: We examined 908 primary breast cancer patients with whole slide images (WSI) available from TCGA database. Digital structuring of WSIs included automated detection of lymphocytes, tumor and tumor adjacent stroma, using deep learning-based semantic segmentation. Prognosis was defined as progression free interval (PFI). A Cox Survival analysis was used to detect prognostic spatial features. We used principal component analysis (PCA) to reduce and decorrelate significant features. The resulting PCA features were used to fit the final model. The model was then validated on an independent database of WSI of breast lumpectomies, from two tertiary hospitals in Israel. Results: The analysis included 908 WSI. The average age was 58.4 years old, with a majority of early stage breast cancer (76.7%, stage I and II). The detection performance for tumor area and lymphocytes reached F1 scores of 99% and 97% respectively, in comparison to human annotation. In the Kaplan Meier (KM) analysis of 414 early stage luminal breast cancers, a high number of lymphocyte clusters (LC) and a high ratio between stromal lymphocyte density and tumor lymphocyte density (LD-S/LD-T) were significantly associated with longer PFI (p = 0.005 and p = 0.038, respectively). Based on these features, two continuous PCA features were added to the multivariate model, and remained significantly associated with PFI after adjusting for age (HR = 1.19, 95% CI 1.05-1.35; HR = 1.26 95% CI 1.03-1.55). The validation set was underpowered (n = 79) and data is still being collected. In a preliminary KM analysis of 37 early stage luminal breast cancer cases from the validation set, LD-S/LD-T was significantly associated with longer PFI (p = 0.046). Conclusions: In our study, LC and LD-S/LD-T, presumably surrogate measures of peritumoral lymphocytes, were found significantly associated with longer PFI.
Disparities in receipt of and time to adjuvant therapy after lumpectomy.
Authors: Dankwa-Mullan Irene , Roebuck M. Christopher , Tkacz Joseph , Fayanju Oluwadamilola Motunrayo , Ren Yi , Jackson Gretchen Purcell , Arriaga Yull Edwin
Published: May 2020

534

Background: Adjuvant treatment after breast conserving surgery (BCS) has been shown to improve outcomes, but the degree of uptake varies considerably. We sought to examine factors associated with post-BCS receipt of and time to treatment (TTT) for adjuvant radiation therapy (ART), cytotoxic chemotherapy (ACT) and endocrine therapy (AET) among women with breast cancer. Methods: IBM MarketScan claims data were used to select women diagnosed with non-metastatic invasive breast cancer from 01/01/2012 to 03/31/2018, who received primary BCS without any neoadjuvant therapy, and who had continuous insurance eligibility 60 days post-BCS. Logistic and quantile regressions were used to identify factors associated with receipt of adjuvant therapy (ART, ACT, AET) and median TTT in days for ART (rTTT), ACT (cTTT), and AET (eTTT), respectively, after adjustment for covariates including age, year, region, insurance plan type, comorbidities, and a vector of ZIP3-level measures (e.g., community race/ethnicity-density, education level) from the 2019 Area Health Resource Files. Results: 36,270 patients were identified: 11,996 (33%) received ART only, 4,837 (13%) received ACT only, 3,458 (10 %) received AET only, 5,752 (16%) received both ART and AET, and 9,909 (27%) received no adjuvant therapy within 6 months of BCS. (318) 1% of patients received combinations of either ART, AET or ACT. Relative to having no adjuvant therapy, patients > 80 years were significantly less likely to receive ART only (relative risk ratio [RRR] 0.65), ACT only (RRR 0.05), or combination ART/AET (RRR 0.66) but more likely to receive AET alone (RRR 3.61) (all p < .001). Patients from communities with high proportions of Black (RRR 0.14), Asian (RRR 0.13), or Hispanic (RRR 0.45) residents were significantly less likely to receive combination ART and AET (all p < .001). Having HIV/AIDS (+11 days; p = .01) and residing in highly concentrated Black (+8.5 days; p = .01) and Asian (+12.2 days; p = .04) communities were associated with longer rTTT. Longer cTTT was associated with having comorbidities of cerebrovascular disease (+6.0 days; p < .001), moderate to severe liver disease (+12.3 days; p < .001) and residing in high-density Asian communities (+18.0 days; p < .001). Shorter eTTT (-11.4 days; p = .06) and cTTT (-14.8 days; p < .001) was observed in patients with comorbidities of dementia. Conclusions: Results from this cohort of privately insured patients demonstrate disparities in receipt of post-BCS adjuvant radiation and systemic therapy along multiple demographic dimensions and expose opportunities to promote timely receipt of care.
Association of intraoperative opioids with improved recurrence-free survival in triple-negative breast cancer.
Authors: Montagna Giacomo , Hannum Margaret L , Tan Kay See , Plitas George , McCormick Patrick J. , Fischer Gregory W , Morrow Monica , Mincer Joshua S
Published: May 2020

542

Background: Opioid-induced immunomodulation may be of particular importance in triple negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and outcomes in a large TNBC cohort. Methods: Consecutive patients with stage I-III primary TNBC treated between 03/2010 and 12/2016 were identified from our prospectively maintained database. Total intraoperative opioid dose was extracted from anesthetic records and converted to oral morphine milligram equivalents (MME) (10 MME = 50 mcg fentanyl IV). Univariable and multivariable (MVA) Cox proportional hazards analysis (adjusting for relevant clinicopathological features, (neo)adjuvant therapy, anesthesia technique and morbidity score), were performed to quantify the association between opioid exposure and recurrence-free survival (RFS) and overall survival (OS). Results: 1143 patients were included. Median age was 54 years (IQR 45, 64). 911 (80%) had ductal histology, 359 (31%) had nodal metastases, and 1070 (94%) were poorly differentiated. 781 (68%) received adjuvant chemotherapy and 313 (27%) received neoadjuvant chemotherapy. 525 (46%) received total intravenous anesthesia and 618 (54%) had general anesthesia. Median intraoperative opioid dose was 30 MME (IQR 20, 60). 5-year RFS was 81% (95% CI 79%-84%), 5-year OS was 86% (95% CI 84%-88%). In MVA, higher opioid administration was associated with favorable RFS but did not significantly affect OS (Table). Conclusions: Our study is the first to directly evaluate intraoperative opioid administration in TNBC and suggests a protective effect on RFS. Future work will focus on elucidating the underlying mechanism for this effect, including possible modulation of endogenous opioid signaling pathways and immunologic correlates. [Table: see text]
A novel biosignature to assess residual risk in ductal carcinoma in situ (DCIS) patients after standard treatment.
Authors: Bremer Troy , Shah Chirag , Patel Rakesh , Wadsten Charlotta , Kesslering Christy , Shivers Steven , Whitworth Pat W. , Warnberg Fredrik , Vicini Frank
Published: May 2020

548

Background: There is an unmet need to identify women diagnosed with DCIS with elevated risk after standard treatment for whom enhanced treatment strategies should be considered. A response type (RSt) signature has been assessed in women treated with breast conserving surgery (BCS) with or without radiotherapy (RT), or with mastectomy. Methods: Women diagnosed with pure DCIS and treated with BCS or, BCS with whole breast RT were consecutively collected in Sweden, 1986-2004 and the USA, 1999-2008. A third cohort treated with mastectomy was collected in Sweden from 1986-2004. Patients with FFPE tissue were included unless they had prior or simultaneous invasive breast cancer (IBC). The RSt and DCISionRT biosignatures were calculated using biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2), scored by board certified pathologists. Pathology and clinical data were collected from medical records. Only women at elevated risk by DCISionRT (DS > 3) and negative margins were included in analysis. Total breast event risk included either ipsilateral DCIS or IBC. Multivariate Cox proportional hazards and survival analysis were used to assess cumulative incidence risk differences, hazard ratios, and 10-year risks adjusted for year of diagnosis. Results: Women with a poor RSt were all HER2 positive and remained at particularly elevated risk after BCS and RT (23% 10-yr risk, p < 0.0001, Table), with a risk profile similar to women treated with BCS without RT (RSt not evaluated). The distribution of age and size were not statistically different for good versus poor RSt, but poor RSt were more commonly Grade 3. In a small cohort of women treated with mastectomy, those women with a poor RSt were still at elevated risk after surgery, comparered to women with a good RSt (HR = 5.4, p = 0.014). The 10-year risk profile for women with a good RSt treated with BCS plus RT or mastectomy, was low (table). Conclusions: A novel biosignature identified women with a good and poor RSt, where the good RSt identified women with an apparent substantial benefit from RT, as well as women with a poor RSt who remained at particularly elevated risk after RT, and for whom enhanced treatment strategies should be considered. Additional validation studies are ongoing. [Table: see text]
PROREPAIR-A: Clinical and molecular characterization study of prostate cancer (PC) patients with and without previously known germline BRCA1/2 mutations.
Authors: Lozano Rebeca , Castro Elena , Aragon Isabel , Thorne Heather , López-Campos Fernando , Sanz Alejandro , Alonso Concepción , Anido Urbano , maria Jose Juan , Gutierrez Pecharroman Ana , Ramirez-Backhaus Miguel , Balmana Gelpi Judith , Chirivella Isabel , Llort Gemma , Romero-Laorden Nuria , Arevalo Sara , Rubio Jose , Di Domenico Tomás , Sandhu Shahneen Kaur , Olmos David
Published: May 2020

5511

Background: Germline BRCA1/2 (g BRCA1/2) mutations are associated with poor clinical outcomes in PC. Previous studies showed that g BRCA2 carriers present more CNV in several genes associated with more aggressive disease. These aberrations may explain the poor clinical outcomes of these patients, but larger studies are needed to confirm these findings. Methods: PROREPAIR-A is a multicenter case-control study in which g BRCA2 carriers with available diagnostic timor-tissue were matched 1:2 by Gleason and stage at diagnosis (M0 vs M1) with known non-carriers (NC). A minimum of 120 controls-60 cases were required to prove a 5yr Cause Specific Survival (CSS)-rate of 85% vs 60%. The primary endpoint was to confirm the independent prognostic value of g BRCA2 in PC CSS. In addition, we explored the prognostic role of g BRCA1 and somatic events in BRCA2, RB1, MYC, PTEN and TMPRSS2-ERG by FISH. Χ2, Kaplan-Meier, log-rank and cox-regression models were carried out to identify associations with baseline characteristics and outcomes: Metastases Free Survival (MFS), Time to Castration-Resistance (TTCR) and CSS. Results: A total of 80:160 matched cases-controls were initially included, but tumor tissue and clinical data were only available in 73 g BRCA2 and 127 NC. 14 g BRCA1 were also included. At diagnosis, g BRCA2 were younger (median 62.6 vs 64.5, p = 0.02) and had cT3-4 disease more often than NC (31.5% vs 9.4%, p < 0.01), but no other significant differences were found. Somatic BRCA2-RB1 codeletion (40.8% vs 11.8%, p < 0.01) and MYC amplification (51.4% vs 22.8%, p < 0.01) were more frequent in g BRCA2 compared to NC, but no significant differences in PTEN and TMPRSS2-ERG were observed. g BRCA2 mutations as well as somatic BRCA2-RB1 codel and MYC amplif were significantly associated with shorter CSS, MFS and TTCR (Table). MVA model confirmed the independent prognostic value of g BRCA2 (HR 1.94, p = 0.03), BRCA2-RB1 codel (HR 3.16, p < 0.01), MYC amplif (HR 2.36, p < 0.01), Gleason ≥8 (p < 0.01) and M1 at diagnosis (p < 0.01) for CSS. Conclusions: PROREPAIR-A confirmed the independent prognostic value of g BRCA2 for CSS. Somatic BRCA2, RB1 and MYC aberrations were more frequent in g BRCA2 carriers. Those alterations are associated with shorter CSS, MFS and TTCR, and may contribute to poor clinical outcomes in g BRCA2 and NC. [Table: see text]
Population-based prostate cancer screening using a prospective, blinded, paired screen-positive comparison of PSA and fast MRI: The IP1-PROSTAGRAM study.
Authors: Eldred-Evans David , Burak Paula , Connor Martin John , Day Emily , Evans Martin , Fiorentino Francesca , Gammon Martin , Hosking-Jervis Feargus , Klimowska- Nassar Natalia , McGuire William , Padhani Anwar R , Price Derek , Prevost Toby , Sokhi Heminder , Tam Henry , Winkler Mathias , Ahmed Hashim Uddin
Published: May 2020

5513

Background: The prostate-specific antigen (PSA) test can lead to under- and over-diagnosis of prostate cancer and has not been recommended for population screening. A fast MRI scan might overcome the limitations of PSA. IP1-PROSTAGRAM is the first study to evaluate the performance of a 15-minute non-contrast MRI for prostate cancer screening in comparison to PSA. Methods: IP1-PROSTAGRAM was a prospective, population-based, screen-positive paired-cohort study. Men aged 50-69 years in the UK were invited for prostate cancer screening through seven primary care practices or community-based recruitment. Participants underwent a PSA and MRI scan (T2-weighted and diffusion). MRI was scored using PIRADS version 2.0 without knowledge of PSA; screen-positive MRI (defined as either PIRADS score 3-5 or 4-5) were compared against a screen-positive PSA defined as ≥3ng/ml. If any test was screen-positive, a systematic 12-core biopsy was performed with MRI-ultrasound image-fusion targeted biopsy to MRI suspicious areas, as appropriate. Clinically-significant cancer was defined as any Gleason score ≥3+4. The primary outcome was the proportion of screen-positive MRI at different scores; important secondary outcomes were the number of clinically-significant and insignificant cancers detected. Results: 2034 men were invited to participate of whom 408 consented and 406 were screened by both PSA and MRI (10/Oct/2018-15/May/2019). The proportion with a screen-positive MRI (score 3-5) was higher than the proportion with a screen-positive PSA (17.7% [95%CI 14.3-21.8] vs. 9.9% [95%CI 7.3-13.2]; p < 0.001). A screen-positive MRI (score 4-5) was similar to a screen-positive PSA (10.6% [95%CI 7.9-14.0] vs. 9.9% [95%CI 7.3-13.2], p = 0.71). An MRI score 3-5 or 4-5 used to denote a screen-positive MRI, compared to PSA alone, detected 14, 11 and 7 clinically-significant cancers, respectively. There were 7, 5 and 6 clinically-insignificant cancers detected, respectively. No serious adverse events occurred. Conclusions: When screening the general population for prostate cancer, MRI using a score of 4-5 to define a screen-positive test, compared to PSA alone at ≥3ng/ml, could lead to more men diagnosed with clinically-significant cancer without increasing the number of men biopsied or diagnosed with clinically-insignificant cancer. Clinical trial information: NCT03702439 .
Final overall survival (OS) from PROSPER: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Sternberg Cora N. , Fizazi Karim , Saad Fred , Shore Neal D. , De Giorgi Ugo , Penson David F. , Ferreira Ubirajara , Ivashchenko Petro , Efstathiou Eleni , Madziarska Katarzyna , Kolinsky Michael Paul , Cubero Daniel Iracema , Noerby Bettina , Zohren Fabian , Lin Xun , Modelska Katharina , Sugg Jennifer , Steinberg Joyce Leta , Hussain Maha H. A.
Published: May 2020

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Background: PROSPER previously demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) (hazard ratio [HR] 0.29; 95% CI 0.24-0.35; P < .001) in men with nmCRPC and rapidly rising prostate-specific antigen (PSA) who received ENZA. When first reported, OS was immature with only 165 of 596 (28%) prespecified deaths. Here we report results from the final OS analysis. Methods: Men with nmCRPC, PSA doubling time ≤ 10 mo, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. OS treatment effect was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function ( P ≤ .021 required for statistical significance). Medians were estimated using the Kaplan-Meier method; 95% CIs using a stratified Cox regression model. Results: As of Oct 15, 2019 (median follow-up ≈ 48 mo), there were 466 deaths (288 [30.9%] and 178 [38.0%] in the ENZA and PBO arms, respectively). ENZA significantly prolonged OS compared with PBO (HR 0.73; 95% CI 0.61-0.89; P = .0011). Median OS was 67.0 mo (95% CI 64.0-not reached) in the ENZA arm and 56.3 mo (95% CI 54.4-63.0) in the PBO arm. Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the ENZA arm vs 303 (65%) in the PBO arm. Median duration of treatment was 33.9 mo vs 14.2 mo with ENZA vs PBO, respectively. Grade ≥ 3 adverse events (AEs) were reported by 48% of men in the ENZA arm vs 27% in the PBO arm (16% vs 6% were drug related, respectively). AEs with event rates per 100 patient-yr that were ≥ 2 points higher with ENZA vs PBO were falls (9 vs 4), fatigue (14 vs 12), and hypertension (7 vs 5). Conclusions: ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA + ADT before the onset of detectable metastasis improves OS in men with CRPC and rapidly rising PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with previous clinical trials. This final OS analysis from PROSPER provides prospective validation of MFS as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA + ADT as a standard of care in men with nmCRPC and rapidly rising PSA. Clinical trial information: NCT02003924 .
Bone metabolism biomarkers (BMB) and progression-free survival (PFS) in men with metastatic hormone-sensitive prostate cancer (HSPC): SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) with or without orteronel.
Authors: Lara Primo , Mayerson Edward , Gertz Erik , Tangen Catherine , Goldkorn Amir , Van Loan Marta , Hussain Maha H. A. , Gupta Shilpa , Zhang Jingsong , Twardowski Przemyslaw , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie , Agarwal Neeraj
Published: May 2020

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Background: We previously reported that baseline BMB are independently prognostic for overall survival (OS) in men with castration resistant prostate cancer. We correlated BMB with outcomes in mHSPC as part of S1216, a phase III trial of ADT +/- the novel CYP17 inhibitor orteronel. Methods: Blood was obtained at study entry for bone resorption [C-telopeptide(CTx) & Pyridinoline(PYD)] & formation markers [C-terminal collagen propeptide(CICP) & bone alkaline phosphatase(BAP)]. With prior DSMC approval, patients were sampled to mask potential treatment effect. Logistic regression was used to assess if BMB elevation above median was prognostic for a PFS event w/in 2 years across pooled study treatment arms, adjusting for baseline variables (including disease extent, PSA, age, pre-randomization ADT, & presence of bone mets). An additional interaction term between BMB elevation & presence of bone mets was included; if significant, separate models were developed for men +/- bone mets. Results: Of 1,313 men, 656 were included in this analysis. All 4 BMB levels were higher in men with a PFS event w/in 2 years vs. those with no PFS event. The odds ratio (OR) for a PFS event was significantly higher in men w/ elevated baseline BMB (see table). For BAP, a significant interaction between marker elevation and bone mets was seen (p = 0.003); men w/ bone mets and BAP elevation had an OR of 1.83 for a PFS event in 2 years. Conclusions: In men with newly diagnosed HSPC, elevated baseline levels of BMB were significantly associated with PFS, with about a two-fold increased risk of a progression event w/in 2 years. For CICP, CTx, & PYD, this association was independent of the presence of bone metastases. Baseline BMB levels have strong prognostic value in the mHSPC context. Correlative analysis of BMB & OS is planned. Clinical trial information: NCT01809691 . [Table: see text]
Health-related quality of life (HRQoL) for olaparib versus enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations: PROfound.
Authors: Thiery-Vuillemin Antoine , De Bono Johann S. , Saad Fred , Procopio Giuseppe , Shore Neal D. , Fizazi Karim , Roubaud Guilhem , Anjos Gabriel dos , Gravis Gwenaelle , Joung Jae Young , Matsubara Nobuaki , Castellano Daniel , Degboe Arnold , Gresty Christopher , Kang Jinyu , Allen Allison , Burgents Joseph E , Hussain Maha H. A.
Published: May 2020

5539

Background: In the randomized Phase III PROfound trial (NCT02987543), olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (pcNHA, enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior NHA. Olaparib significantly improved time to pain progression in Cohort A. We report additional patient reported outcome measures of HRQoL in the overall study population (Cohorts A+B). Methods: HRQoL was assessed in the overall study population using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing, social wellbeing, and prostate cancer subscale (PCS). The Trial Outcome Index (TOI; PWB+FWB+PCS) and FACT Advanced Prostate Symptom Index (FAPSI-6: derived from 6 FACT-P items) were also calculated. Adjusted mean change and time to deterioration in scores were statistically analyzed. Results: Baseline FACT-P total score was similar for both treatment arms. FACT-P total and subscale scores during treatment were all higher for olaparib vs pcNHA, with clinically meaningful differences between treatment arms in the adjusted least square (LS) mean changes from baseline in all but FWB and FAPSI-6 (Table). The time to deterioration in FACT-P total and TOI, FAPSI-6, PWB and PCS scores favored olaparib but were not statistically significant, with hazard ratios ranging from 0.68 to 0.94. Further HRQoL results for cohort A will also be presented. Conclusions: Olaparib delayed deterioration in HRQoL scores vs pcNHA and was associated with better HRQoL functioning over time compared with pcNHA in men with mCRPC and HRR gene alterations. Clinical trial information: NCT02987543 . [Table: see text]