bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of provider education on prostate cancer genetic counseling referrals.
Authors: Moody Emily , Larson McCall , Greenberg Samantha , Jump Taylor , Bell Mckenzie , Gygi Jesse , Garcia Lisa , Dougherty Desiree , O Neil Brock , Lynch Steven C , Haslem Derrick S. , Gill David Michael 
Published: February 2022

59 Background: Guidelines recommend germline genetic not only for men with advanced and metastatic prostate cancer but also those with NCCN-high risk disease. Many men harboring germline DNA repair defects would not have met criteria for testing under previous guidelines (Nicolosi et al, JAMA Oncol 2019). Knowledge of germline mutations is pertinent due to recent regulatory approval of PARP inhibitors olaparib and rucaparib and guides screening for first-degree relatives who are at increased risk for other cancers (Pritchard et al, NEJM 2016). Knowledge gaps for germline genetic testing have been previously described (Loeb et al, Cancer Treat Res Commun 2020). Through a series of educational sessions, we sought to increase utilization of appropriate genetic services for men with prostate cancer. Methods: Starting March 2021, virtual educational presentations were held for nurse navigators, urologists, and medical oncologists throughout our large community-based healthcare system. Surveys were distributed following each presentation to measure clinicians’ perception of their knowledge regarding prostate cancer genetics referrals on a five-step scale. Prostate cancer patient referral data was measured from September 2020 to August 2021, six months prior to and after the presentations. Results: Self-reported understanding of prostate cancer genetics referral practices following the educational presentations increased by an average of 1.7/5 steps (2.5 to 4.2/5) for physicians and 1.4/5 steps (2.9 to 4.1/5) for nurse navigators. From March to August 2021, there were 107 genetic referrals for prostate cancer (average 17.8 referrals/month) compared to 49 referrals from September 2020 to February 2021 (8.2 referrals/month). Conclusions: Prostate cancer genetics referrals increased 118% following educational presentations to urologists, medical oncologists, and nurse navigators. This correlates with an improvement in self-reported knowledge gaps. Provider education interventions may improve access to genetic services for men with prostate cancer. The increase in referrals likely does not account for all patients meeting criteria for germline testing. Work is ongoing to calculate the number of referrals as a proportion of the eligible population.[Table: see text]
A phase Ib, open-label study evaluating the safety and efficacy of ipatasertib + rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pook David William , Geynisman Daniel M. , Carles Joan , De Braud Filippo G. , Joshua Anthony M. , Perez-Gracia Jose Luis , Llácer Pérez Casilda , Shin Sang Joon , Fang Bruno , Barve Minal A. , Maruzzo Marco , Bracarda Sergio , Kim Miso , Kerloeguen Yannick , Gallo Jorge Daniel , Maund Sophia , Harris Adam , Huang Kuan-Chieh , Sutaria Dhruvitkumar S. , Gurney Howard 
Published: February 2022

95 Background: mCRPC remains an incurable disease with unmet need for improved therapies. PARP inhibition has demonstrated antitumor activity, and preclinical studies suggest synergy between PARP and AKT inhibition. This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose of PARP inhibitor rucaparib (ruca) with AKT inhibitor ipatasertib (ipat) and explore early safety and efficacy in patients (pts) with mCRPC. Methods: The study had 2 parts: a part 1 dose-escalation phase (cohort [C]1: ipat 300 mg QD + ruca 400 mg BID; C2a: ipat 300 mg QD + ruca 600 mg BID; C2b ipat 400 mg QD + ruca 400 mg BID; C3: ipat 400 mg QD + ruca 600 mg BID) in unselected pts with mCRPC or advanced breast or ovarian cancer, and a Part 2 dose-expansion phase in pts with mCRPC whose previous androgen deprivation therapy failed. The primary safety endpoints were AEs and dose-limiting toxicities, with the goal of identifying a recommended phase II dose (RP2D). The primary efficacy endpoint was prostate-specific antigen (PSA) response (PSA reduction of ≥ 50%) in pts with mCRPC. Secondary efficacy endpoints included ORR per RECIST 1.1, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 and OS in pts with mCRPC. We assessed homologous recombination deficiency (HRD), PIK3CA/ AKT1/ PTEN status and other alterations by next-generation sequencing. Results: Part 1 enrolled 21 pts: 17 with mCRPC, 3 with ovarian cancer and 1 with breast cancer (C1 [n=8], C2a [n=6] and C2b [n=7], C3 [not opened]). Ipat 400 mg QD + ruca 400 mg BID was the selected RP2D. 30 pts enrolled in Part 2, so 37 pts with mCRPC (C2b + Part 2) received the RP2D (median follow-up 93 days). All grade AEs occurred in 37 pts (100%), serious AEs in 8 pts (22%) and AEs leading to treatment modification in 26 pts (70%). The most frequent AEs (all grade and grade 3, respectively) were diarrhea (35 [95%] and 2 [5%]); asthenia (24 [65%] and 4 [11%]); and nausea (24 [65%] and 2 [5%]). There was 1 grade 4 AE (anemia) and no grade 5 AEs. See the table for efficacy data. In biomarker subgroups, the PSA response rate was 50% (3/6) in pts with HRD tumors vs 25% (4/16) in pts with HR-proficient tumors, and 14% (1/7) vs 40% (6/15) in pts with PIK3CA/ AKT1/ PTEN–altered or intact tumors, respectively. Conclusions: The combination of ipat and ruca was well tolerated but did not show clinically relevant antitumor activity in pts with mCRPC, including in predefined biomarker subpopulations. Clinical trial information: NCT03840200. [Table: see text]
Survival outcomes and characterization of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) who do not achieve an optimal PSA response (PSA ≤0.2 ng/mL).
Authors: Sayegh Nicolas , Tripathi Nishita , Chigarira Beverly , Jo Yeonjung , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Li Haoran , Tandar Clara , Goel Divyam , Sahu Kamal Kant , Haaland Benjamin , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: February 2022

123 Background: In pts with mCSPC undergoing intensified ADT, achieving a PSA nadir ≤0.2 ng/mL “anytime” after the start of treatment was associated with a significantly improved overall survival (OS) versus those with a PSA >0.2 ng/mL: HR 0.17 (95% CI, 0.13-0.23) (Chi AUA 2021, abstract 1281). Our objective was to validate these findings in a real-world population and characterize the clinical and tumor genomic landscape according to PSA response. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: presence of mCSPC undergoing intensified ADT with either docetaxel or novel hormonal therapy (NHT) started within 3 months of diagnosis, availability of PSA nadir, and availability of tumor comprehensive genomic profiling (CGP) prior to start of ADT. Variants of unknown significance and genomic aberrations present in <5% pts were excluded. Optimal PSA response (OR): PSA≤0.2 ng/mL. Study endpoints: PFS was calculated per PCWG-2 defined PSA progression or radiographic progression or clinical progression whichever occurred first; OS was defined as start of therapy to date of death or censored after last follow-up. The relationship between PSA nadir and both PFS and OS was assessed in the context of Cox proportional hazards. Gene prevalence was compared using a chi square test. Results: 134 pts were eligible and included. Optimal responders (OR) (n=104) and non-OR (n=30): median age at diagnosis 63 vs 65 years; median PSA at ADT start 18.1 vs 74.5 ng/mL; high volume of disease 48% vs 77%. For OR and non-OR: median PFS, 60.6 vs 13.2 (P<0.001); median OS, 94.9 vs 35.2 months (P<0.001) respectively. Multivariate analysis is described in the table. Conclusions: Only a minority of pts with mCSPC do not achieve an optimal PSA response with intensified ADT. Those non-OR have worse outcomes on treatment with intensified ADT. Herein we externally validate that achieving a PSA nadir ≤0.2 ng/mL is correlated with superior OS. Detailed genomic landscape of these pts will be presented in the meeting.[Table: see text]
Immune system and intestinal microbiota determine efficacy of androgen depletion therapy against prostate cancer.
Authors: Terrisse Safae , Goubet Anne-Gaëlle , Ueda Kosuke , Thomas Andrew M. , Quiniou Valentin , Thelemaque Cassandra , Dunsmore Garett , Clave Emmanuel , Gamat-Huber Melissa , Yonekura Satoru , Derosa Lisa , Culine Stephane , Opolon Paule , Ginhoux Florent , Toubert Antoine , Segata Nicola , McNeel Douglas G. , Fizazi Karim , Kroemer Guido , Zitvogel Laurence 
Published: February 2022

168 Background: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). While it is recognized that ADT has an immunomodulatory effect, little is known about the intestinal microbiome effect on therapeutic outcome of ADT. Methods: We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients to analyze their feces and blood specimen. Results: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice, or oral gavage with Akkermansia improved the efficacy of ADT. This appear to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared to HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy. Conclusions: These findings suggest that reversing the intestinal dysbiosis and repairing acquired immune defects in PC patients have a potential impact on the therapeutic outcome of ADT.
Immuno-oncology (IO) combinations +/- VEGF targeted therapy (VEGF TT) in patients (pts) with advanced mit family translocation renal cell carcinomas (tRCC): Results from an international multicenter study.
Authors: Alhalabi Omar , Thouvenin Jonathan , Negrier Sylvie , Vano Yann-Alexandre , Campedel Luca , Hasanov Elshad , Bakouny Ziad , Hahn Andrew Warren , Bilen Mehmet Asim , Choueiri Toni K. , Viswanathan Srinivas Raghavan , Sircar Kanishka , Albiges Laurence , Malouf Gabriel , Tannir Nizar M. 
Published: February 2022

343 Background: IO combinations are standard of care for first-line therapy of clear-cell RCC; however, non-clear cell histologies including tRCC were not included in the registrational trials. We previously reported a modest efficacy (objective response rate [ORR] <20%) with IO monotherapy (PD-1 blockade) in tRCC (Boilève et al, JITC. 2018). The efficacy of IO combinations +/- VEGF TT has not been reported. Methods: This is a retrospective, international, multicenter study of pts with tRCC treated with IO-IO or IO+VEGF TT at 11 centers in the US, France, and Belgium. Only pts with confirmed TFE3 or TFEB translocation by fluorescent-in-situ hybridization (FISH) were included. ORR and progression-free survival (PFS) were assessed by RECIST. Overall survival (OS) was assessed by Kaplan-Meier methods. OS was measured from initiation of therapy till death or last follow up. We also assessed the association between OS and baseline prognostic variables. Results: 29 patients with metastatic tRCC were included in this analysis. Median age at starting therapy was 38 (IQR 27, 53) years. Female:Male ratio was 0.9:1. FISH revealed a translocation involving TFE3 and TFEB in 22 and 7 patients, respectively. Most frequent metastatic sites at diagnosis were lungs (76%), liver (52%), retroperitoneal adenopathy (48%), and bone (38%). IMDC risk at diagnosis was favorable (31%), intermediate (45%) and poor (24%). Combinations of IO+VEGF TT and anti-PD1 (L1) + anti-CTLA-4 (IO+IO) were used in 11 and 18 pts, respectively. 17 (59%) pts received IO combinations as 1L, 7 (24%) pts as 2L and 5 (17%) pts as ≥3L. ORR in the IO+IO group was 1/18 (5.5%), while in IO+VEGF TT group was 4/11 (36%). For 20 (69%) pts, progressive disease was the best overall response. At a median follow-up of 12.9 months (mo), median PFS was 3.2 mo and median OS was 13.5 mo for all 29 pts (Table). Median PFS in the IO+IO group was 2.8 mo, and 5.4 mo in IO+VEGF TT group (HR=0.81, 95% CI: 0.35-1.84). Conclusions: In this small retrospective study of tRCC, IO+IO therapy produced modest activity based on low ORR and short PFS while IO+VEGF TT produced numerically higher ORR and longer PFS. Insights into the biological basis of tRCC are necessary to develop more effective therapies for this rare and aggressive RCC variant.[Table: see text]
BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC).
Authors: Rosenberg Jonathan E. , Park Se Hoon , Dao Tu V. , Castellano Daniel E. , Li Jian-Ri , Mukherjee Som , Howells Kathryn , Dry Hannah , Lanasa Mark C. , Stewart Ross , Bajorin Dean F. 
Published: February 2022

437 Background: The prognosis for patients (pts) with advanced UC remains poor, particularly for those unable to tolerate platinum-based chemotherapy. Defects in DNA damage repair (e.g., mutations in homologous recombination repair [HRR] genes) are common in UC and render tumor cells sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. HRR gene mutations (HRRm) and PARP inhibition may enhance the antitumor response of immune checkpoint inhibitors. We conducted a randomized phase II study to evaluate D (anti–PD-L1) in combination with O (a PARP inhibitor) or placebo (P) as a first-line treatment for platinum-ineligible pts with unresectable, stage IV UC (BAYOU; NCT03459846). Methods: Eligible pts were an age of ³18 years with an ECOG performance status (PS) of 0, 1, or 2, histologically or cytologically confirmed transitional cell carcinoma, and who had not received prior systemic therapy for unresectable, stage IV disease. Pts were randomized 1:1 to receive D (1500 mg IV q4w) plus O (orally at 300 mg BID) vs D (1500 mg IV q4w) plus O-matching placebo (P). Pts were stratified according to centrally-determined HRR status (mutant vs wild-type) and Bajorin risk index (a composite of visceral metastases and ECOG PS [0, 1 vs 2]). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 (investigator assessed) in the intention-to-treat (ITT) population. Secondary endpoints included overall survival (OS) in the ITT population and PFS in the subset of pts with HRRm. The data cutoff occurred on October 15, 2020. Results: A total of 154 pts were randomized to receive D+O (n = 78) or D+P (n = 76). Among all randomized pts at baseline, 17%, 42%, and 40% had an ECOG PS of 0, 1, or 2, respectively, and 20% had an HRRm. Median PFS was not significantly different between D+O and D+P in the ITT population (Table). In the subset of pts with HRRm, median PFS was 5.6 months in the D+O group and 1.8 months in the D+P group (Table). In the ITT population, median OS (95% CI) was 10.2 months (7.0–13.9) in the D+O group and 10.7 months (7.2–17.3) in the D+P group (HR 1.07, 95% CI 0.72–1.61). Among all treated pts, grade 3 or 4 treatment-related adverse events occurred in 18% and 9% in the D+O and D+P groups, respectively, with one death due to anemia in the D+P group. Conclusions: The BAYOU study did not meet its primary endpoint. However, the results of pre-planned secondary analyses suggest a potential role for PARP inhibition in UC pts harboring HRRm. No new safety signals were observed. Clinical trial information: NCT03459846. [Table: see text]
First-line pembrolizumab in advanced urothelial carcinoma: Clinical parameters associated with efficacy in the phase 2 KEYNOTE-052 and phase 3 KEYNOTE-361 trials.
Authors: Csoszi Tibor , Powles Thomas , Alva Ajjai Shivaram , Castellano Daniel E. , Ozguroglu Mustafa , O'Donnell Peter H. , Loriot Yohann , Hahn Noah M. , Flechon Aude , Rodriguez-Vida Alejo , De Wit Ronald , Cheng Susanna Y. , Oudard Stephane , Vulsteke Christof , Yu Evan Y. , Lin Jianxin , Imai Kentaro , Homet Moreno Blanca , Balar Arjun Vasant , Grivas Petros 
Published: February 2022

521 Background: First-line treatment with pembrolizumab (pembro) monotherapy has shown durable clinical activity in selected patients (pts) with advanced/unresectable or metastatic urothelial carcinoma (UC). In a pooled population of pts with advanced UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) studies, this exploratory analysis evaluated the relationship between baseline characteristics and clinical outcomes of first-line pembro monotherapy. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and chemotherapy-naive pts with advanced UC were enrolled in KEYNOTE-361. For analysis of predictive factors for ORR and OS in pembro-treated pts, the purposeful selection method was used to build the multivariable logistic regression model (ORR) and multivariable Cox model (OS), beginning with a univariable analysis of each independent variable. Any variable in the univariate model with P < 0.10 was a candidate for the multivariate model. The stepwise selection method was used to select the variables in the final model. Significance of the final model was set at P < 0.05. Data cutoff dates were September 26, 2020 (KEYNOTE-052) and April 29, 2020 (KEYNOTE-361). Results: This pooled analysis included 681 pts treated with pembro monotherapy (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307 [170 were cisplatin ineligible]). Median follow-up was 51.9 mo (range, 22.0-65.3). ORR was 29.4% (95% CI, 26.0-32.9; 69 CRs, 131 PRs), and median DOR was 33.2 mo (range, 1.4+ to 60.7+). Median OS was 12.5 mo (95% CI, 11.0-14.6). By multivariate analysis, independent factors significantly associated with higher ORR were PD-L1 status (combined positive score [CPS] ≥10 vs CPS < 10; odds ratio [OR], 1.90 [95% CI, 1.33-2.71]; P = 0.0004), site of metastasis (lymph node only vs visceral disease; OR, 1.66 [95% CI, 1.06-2.59]; P = 0.0265), liver involvement (absent vs present; OR, 1.75 [95% CI, 1.06-2.89]; P = 0.0294), and baseline hemoglobin level ≥10 vs < 10 g/dL; OR, 2.17 [95% CI, 1.09-4.31]; P = 0.0276). Multivariate analysis of OS is displayed in the Table. Conclusions: This exploratory multivariate analysis identified numerous factors, including PD-L1–positive status (CPS ≥10), lymph node only metastasis, and lower ECOG PS score, associated with improved clinical outcomes in pts with advanced UC treated with first-line pembro monotherapy. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]
Incidence and clinical outcomes of HER2-altered bladder cancer (BC) patients (pts).
Authors: Lattanzi Michael , Niederhausern Andrew , Zheng Junting , Bahadur Nadia , Nichols Chelsea , Barton Laura , Gandhi Fenil , Chan Kimberly , Insinga Alysha , Philip John , Bakker Theodora , Regazzi Ashley Marie , Guercio Brendan John , Teo Min Yuen , Aggen David Henry , Pietzak Eugene J. , Solit David B. , Ostrovnaya Irina , Shah Neil J. , Iyer Gopa 
Published: February 2022

556 Background: Bladder cancer has one of the highest rates of human epidermal growth factor receptor 2 (HER2) alteration. Novel HER2-directed agents are being investigated in metastatic BC. We sought to define the incidence and clinical characteristics of HER2-altered BC across disease states. Methods: We retrospectively analyzed our single-institution, clinically annotated cohort of urothelial BC pts with available genomic profiling data (MSK-IMPACT). We quantified the prevalence of HER2 alterations, defined as driver mutation (based on OncoKB), and/or amplification, across BC disease states. We examined the association between HER2 alteration and disease progression and survival. The Kaplan-Meier method was used for time-to-event analyses. Results: A total of 1073 BC pts underwent MSK IMPACT profiling of tumor tissue derived from the following disease states: 36% (n = 380) non-muscle invasive (NMI)BC, 41% (n = 443) muscle invasive (MI)BC, and 23% (n = 250) (met)BC. At initial diagnosis, the median age was 67 years, 77% (n = 822) were male, 86% (n = 928) were white, and 66% (n = 710) were smokers. Overall, 16% (n = 177) of pts had any oncogenic HER2 alteration (Table), including 11% with a HER2 driver mutation and 7% with HER2 amplification The most frequent mutations were S310F (40%, n = 53) and S310Y (14%, n = 19). The rate of HER2 amplification was different among the three groups (p = 0.002), 9% in MIBC and metBC compared to 3% in NMIBC. Among 514 pts with NMIBC, the median time to progression (TTP) to MIBC or metBC was 111.6 months (95% Cl: 85.7-NR). Among NMIBC pts, TTP was significantly shorter for HER2-amplified (n = 17) vs. non-amplified (n = 497) (HR = 1.99, 95%CI: 1.05-3.76, p = 0.034, median 26 vs. 114 months). Among pts with metBC receiving frontline platinum-based chemotherapy (n = 143), the median overall survival (OS) was 25.3 months (95%CI: 18.5-33.9). OS was numerically higher in pts with any oncogenic HER2 alteration (n = 26) compared to wild-type (n = 117) (HR = 0.59, 95% Cl: 0.33-1.07, p = 0.082), though this difference was not statistically significant. The median OS for platinum-refractory metBC pts receiving 2nd line immunotherapy (n = 63) was 10.3 months (95%CI: 7.2-31.6), and the association between OS and HER2 alteration was not significant (HR = 0.57, 95%CI: 0.24-1.37, p = 0.2). Conclusions: HER2 amplification is more frequent in MIBC and metBC than in NMIBC. In NMIBC, HER2 amplification is associated with shorter TTP to MIBC or metBC. HER2 alteration in metBC is associated with a non-significant trend towards improved OS in frontline platinum-treated pts, though this analysis is limited by small sample size.[Table: see text]