bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of RB1 mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Necchi Andrea , Spiess Philippe E. , Wise David R , Danziger Natalie , Parimi Vamsi , Sokol Ethan , Tukachinsky Hanna , Levy Mia Alyce , Ross Jeffrey S. 
Published: June 2022

5063 Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC in RB1 mutated vs non-mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, we identified 415 cases (3.1%) with a diagnosis of small cell PC or NEPC as determined by the submitting physician. They were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of pathogenic GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were uncommon in both groups. gLOH was higher in RB1 mut+ than RB1 mut- (P =.005). There were more cases of non-European ancestry in the RB1 mut- group. APC I1307K mut were found in 3/162 (1.9%) RB1 mut- NEPC only. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Further study of RB1 status as a guide in trial designs on therapy selection for men with NEPC appears warranted. [Table: see text]
Overall survival (OS) and biomarker results from combat: A phase 2 study of bipolar androgen therapy (BAT) plus nivolumab for patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Taplin Mary-Ellen , Aggarwal Rahul Raj , Sena Laura , Wang Hao , Lalji Aliya , Meyers Jennifer , Skaist Alyza , Gupta Anuj , Gomes-Alexandre Carolina , Jones Tracy , Hicks Jessica , Kachhap Sushant , Yegnasubramanian Srinivasan , De Marzo Angelo M , Denmeade Samuel R. , Antonarakis Emmanuel S. 
Published: June 2022

5064 Background: During BAT, intramuscular (IM) administration of testosterone (T) results in rapid cycling of serum T from supraphysiologic to near-castrate levels in men with mCRPC. In a retrospective study, clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT were observed. Here, we report the OS and biomarker results of a Phase 2 study in mCRPC pts treated with BAT in combination with nivolumab (COMBAT; NCT03554317). Methods: This was a multi-center, single arm, open label Phase 2 study in mCRPC pts who received T cypionate 400mg IM (BAT) every 28 days plus nivolumab 480mg IV every 28 days. Pts initially received BAT alone for a 12-week period, prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue metastases amenable to biopsy, and who progressed on at least one prior novel AR targeted therapy (and up to one prior chemo for mCRPC). The primary endpoint was confirmed PSA50 response. OS and radiographic progression free survival (rPFS) were key secondary endpoints. All pts underwent baseline metastatic biopsies, and 24 had a second biopsy after 12 weeks of BAT. Semi-quantitative IHC (for AR, Ki67, MYC, PTEN, TP53, RB1) was performed on 24 paired biopsies, of which 15 pairs were also evaluable for RNA (whole transcriptome) sequencing. Results: 45 pts were enrolled. As previously reported, the PSA50 response was 40% (18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis), and median rPFS was 5.6 (95% CI: 4.4–6.0) months. After a median follow-up of 17.8 months, the median OS was 27.8 (95%% CI: 17.6–NR) months. In 24 pts with paired biopsies prior to administration of nivolumab, BAT significantly decreased median MYC (P=0.046) and Ki-67 (P=0.030) expression by IHC. 71% (17/24) of pts had any decrease in MYC following BAT, with 29% (7/24) having a >50% decrease. A >50% MYC protein decline was associated with longer rPFS (HR 0.33, 95%CI 0.14–0.78, P=0.005) and a nonsignificant association towards longer OS (HR 0.78, 95%CI 0.24–2.48, P=0.679). MYC protein and mRNA levels were tightly intercorrelated (r=0.65, P<0.001). Both rPFS and OS were numerically longer in pts with >50% declines in MYC mRNA levels (P>0.1 for both). Conclusions: BAT combined with nivolumab led to a median overall survival of >2 years in heavily pretreated mCRPC pts. BAT attenuated MYC expression, correlating with better outcomes. Clinical trial information: NCT03554317.
Pembrolizumab + chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer: Subgroup analysis of KEYNOTE-826.
Authors: Tewari Krishnansu Sujata , Colombo Nicoletta , Monk Bradley J. , Dubot Coraline , Cáceres M. Valeria , Hasegawa Kosei , Shapira-Frommer Ronnie , Salman Pamela , Yañez Eduardo , Gumus Mahmut , Olivera Hurtado de Mendoza Mivael , Samouëlian Vanessa , Castonguay Vincent , Arkhipov Alexander , Tekin Cumhur , Li Kan , Toker Sarper , Keefe Stephen Michael , Lorusso Domenica 
Published: June 2022

5506 Background: In KEYNOTE-826 (NCT03635567),pembrolizumab (pembro) + chemotherapy (chemo) ± bevacizumab (bev) provided statistically significant, clinically meaningful PFS and OS improvements in patients with persistent, recurrent, or metastatic cervical cancer. In the present analysis of KEYNOTE-826, we assessed outcomes in several key patient subgroups. Methods: Eligible adult patients had persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix not previously treated with chemo and not amenable to curative treatment; measurable disease per RECIST v1.1; ECOG PS 0–1; and a tumor sample to determine PD-L1 status. Patients were randomized 1:1 to pembro 200 mg Q3W or placebo (pbo) for up to 35 cycles + chemo (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) ± bev 15 mg/kg. Dual primary endpoints are PFS by investigator assessment per RECIST v1.1 and OS in patients with PD-L1 CPS ≥1, all comers, and CPS ≥10. Treatment effects on PFS and OS were examined in patient subgroups defined by bev use (yes or no), histology (squamous or non-squamous [including adenocarcinoma and adenosquamous]), platinum use (carboplatin or cisplatin), and prior chemoradiation therapy (CRT). Hazard ratios (HR) and 95% CIs were based on a stratified Cox regression model. Results: 617 patients were randomized (pembro + chemo ± bev, n=308; pbo + chemo ± bev, n=309). At the May 3, 2021 data cutoff, median follow-up was 22 months. Pembro + chemo prolonged PFS and OS vs pbo + chemo in all subgroups evaluated in the all-comer population (Table). Similar benefits of pembro + chemo on PFS and OS were also seen in the protocol-specified CPS ≥1 and CPS ≥10 populations. Conclusions: Pembro + chemo ± bev prolonged PFS and OS vs pbo + chemo ± bev among the subgroups defined by bev use, histology, platinum use, and prior CRT and provided clinically meaningful benefits similar to the broader population of patients with persistent, recurrent, or metastatic cervical cancer. Clinical trial information: NCT03635567. [Table: see text]
Predominance of BRCA2 mutation and estrogen receptor-positive breast cancer among BRCA1/2 mutation carriers.
Authors: Pujol Pascal , Yauy Kévin , Coffy Amandine , Duforet-Frebourg Nicolas , Gabteni Sana , Daurès Jean-Pierre , Penault-Llorca Frederique Madeleine , Collet Laetitia , Thomas Frédéric , Turnbull Clare , Galibert Virginie , Rideau Chloé , You Benoit , Geneviève David , Hughes Kevin S. , Philippe Nicolas 
Published: June 2022

551 Background: PARP inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer (BC) who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA1/2) in both the metastatic and adjuvant setting. Therefore, we need to redefine the criteria of women and tumor phenotype that should be tested for gBRCA1/2. Methods: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with BC and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected BC patients with gBRCA1/2.We performed a meta-analysis of studies of unselected BC that analyzed the relative contribution of gBRCA1 versus gBRCA2 and ER+ tumors among gBRCA1/2 carriers. We then performed a meta-analysis of gBRCA1/2 carriage in unaffected individuals, from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of BC in unselected patients with gBRCA1/2 (n=108,699) and 59% of unaffected individuals (n=238,973) as compared with 38% of gBRCA1/2 family cohorts (n=29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected BC patients carried a gBRCA1 and gBRCA2, respectively. In unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA1/2. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5-4.1) and 5.7% (95% CI 5.1-6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA1/2 were ER+ (n=86,870). Conclusions: This meta-analysis showed that gBRCA2 carriage is predominant in unselected BC and in unaffected individuals. ER+ tumors among women with gBRCA1/2-related BC is predominant and has been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA1/2 BC in both the adjuvant and metastatic setting, BC should be considered regardless of ER status for BRCA1/2 screening for therapeutic purposes.
Adavosertib in combination with carboplatin in advanced TP53-mutated platinum-resistant ovarian cancer.
Authors: Embaby Alaa , Geenen Jill Jacqueline , Kutzera Joachim , Pluim Dick , Lopez-Yurda Marta I. , Beijnen Jos H. , Huitema Alwin , Witteveen Petronella , Steeghs Neeltje , van Haaften Gijs , van Vugt Marcel A.T.M. , de Ridder Jeroen , Opdam Frans 
Published: June 2022

5516 Background: Ovarian cancer is globally the second most common cause of death among women with gynecologic malignancies. Despite high initial response rates, the overall prognosis of this patient population remains poor. The majority of advanced ovarian cancers will become platinum resistant defined by recurrence within six months after completion of platinum therapy. In the first part of the current phase II study, the combination of carboplatin and the Wee1 inhibitor adavosertib (AZD1775), showed to be safe and effective in patients with TP53 mutated platinum resistant ovarian cancer. The aim of this additional cohort is to gain more information about the safety and efficacy of the combination and to explore predictive biomarkers for resistance and response to adavosertib. Methods: In this additional cohort 29 evaluable were treated with carboplatin AUC 5 mg/ ml·min and adavosertib 225 mg BID for 2.5 days in a 21-day cycle. The anti-tumor activity was assessed according to RECIST 1.1. Pre-, on- and post-treatment biopsies were obtained to explore genetic determinants of drug resistance and response to adavosertib. Results: A total of 32 patients with a median age of 62 years (39-77 years) were enrolled in this cohort. All patients had carboplatin/paclitaxel as first line therapy. Six patients received a second-line non-platinum containing regimen. Median platinum free interval was 5.8 months (range 1.7 – 11.9). Twenty-nine patients were evaluable for efficacy. Grade 1-2 bone marrow toxicity, nausea, vomiting and fatigue were the most common adverse events. Dose reductions of carboplatin and/or adavosertib were made in 15/29 evaluable patients (52%). Dose delays occurred in the majority of patients (76%), mostly due to neutropenia and thrombocytopenia. Twelve patients showed PR as best response, resulting in an ORR of 38% in the intention-to-treat population (95% CI 21%-56%). The median PFS was 5.6 months (range 1.1-32 months, 95% CI 4.2-7.0) and median duration of response was 5.3 months (95% CI 0.13-10.5). Conclusions: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 in a 21-day cycle could be safely combined and shows promising anti-tumor efficacy in patients with platinum resistant ovarian cancer. Bone marrow toxicity remains the most common reason for dose reductions and dose delays. Translational biomarker results (CCNE1 analysis as potential predictive marker for response and resistance and WGS) to better understand the anti-tumor activity of the combination are pending. Clinical trial information: NCT01164995.
Role of cytoreductive surgery for the second ovarian cancer relapse in patients previously treated with chemotherapy alone at first relapse: A subanalysis of the DESKTOP III trial.
Authors: Sehouli Jalid , Fotopoulou Christina , Vergote Ignace , Reuss Alexander , Ferron Gwenael , Meier Werner , Greggi Stefano , Mosgaard Berit J. , Selle Frederic , Guyon Frederic , Pomel Christophe , Lecuru Fabrice , Zang Rongyu , Hellmann Kristina , Kim Jae-Weon , Romeo Margarita , Raspagliesi Francesco , Eyjólfsdóttir Brynhildur , Du Bois Andreas , Harter Philipp 
Published: June 2022

5520 Background: The DESKTOP III trial has demonstrated a significant survival benefit in AGO-score positive patients who underwent complete cytoreduction at 1st relapse compared to those treated with chemotherapy alone. The question whether eligible patients who missed the opportunity of potentially life prolonging surgery at 1st relapse would benefit from surgery at the time of their second relapse, remains open. Methods: Patients randomized in the standard, non-surgical arm of the DESKTOP III trial who underwent cytoreductive surgery at a subsequent relapse at investigator’s discretion were separately analyzed. Results: The median progression-free survival (PFS) counted from randomization of 201 patients in the control arm of DESKTOP III was 14.0 months. 171 (85%) had progressive or relapsing disease and 32 of 171 (19%) underwent cytoreductive surgery. Patients’ median age at this subsequent surgery was 63 years (range: 46 – 78). Complete tumor resection was achieved in 19 patients (60%), while 5 (16%) had postoperative residual disease (n = 8 missing data). Sixteen patients (50%) commenced systemic treatment within 90 days from surgery, as documented. Thirty- and 90-day surgical mortality rates were 1 (3%) and 2 (6%), respectively. Within a postoperative median follow-up time of 43.8 months, 12 (38%) deaths were reported. Median overall survival after surgery (OS) was 54.0 months. One- and 2-year OS rates were 91% and 84%, respectively. Conclusions: Cytoreductive surgery for subsequent ovarian cancer relapse appears feasible and with low mortality in selected patients who received non-surgical treatment at 1st relapse despite a positive AGO-score. Surgery should be considered as an option in carefully selected patients also later in their journey within a specialized gynecological cancer setting. Clinical trial information: NCT01166737.
Phase 1 trial of first-line bintrafusp alfa in combination with other anticancer therapies in patients (pts) with locally advanced or advanced cervical cancer.
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Diver Elisabeth J. , Jehl Genevieve , Gleicher Stephan A. , Chaudhary Surendra , Vugmeyster Yulia , Hasegawa Kosei 
Published: June 2022

5528 Background: Until the recent FDA approval of pembrolizumab in combination with chemotherapy ± bevacizumab, there have been limited treatment options that address the underlying biology for pts with persistent, recurrent, or metastatic (P/R/M) or locally advanced (LA) cervical cancer. Persistent HPV infection is associated with 99% of cervical cancers and is linked to upregulation of TGF-β. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, has shown promising clinical activity and manageable safety in pts with recurrent or metastatic cervical cancer. We report data from a phase 1 trial evaluating safety of first-line bintrafusp alfa plus chemotherapy ± bevacizumab for pts with P/R/M cervical cancer or bintrafusp alfa plus chemoradiotherapy for pts with LA cervical cancer (INTR@PID 046; NCT04551950). Methods: Pts with P/R/M cervical cancer who had not received prior systemic therapy received bintrafusp alfa 2400 mg Q3W plus cisplatin/carboplatin and paclitaxel with (cohort 1A) or without (cohort 1B) bevacizumab. Pts with LA cervical cancer received bintrafusp alfa 2400 mg Q3W plus concurrent weekly cisplatin and radiotherapy followed by maintenance therapy with bintrafusp alfa (cohort 2). Pts were treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints were safety and tolerability of bintrafusp alfa in combination with current standard-of-care therapies in pts with P/R/M or LA cervical cancer. Results: As of November 25, 2021, 8 pts in cohort 1A, 9 in cohort 1B, and 8 in cohort 2 had received bintrafusp alfa for a median of 11.6, 10.0, and 5.6 cycles, respectively. At the time of this analysis, 11 of 25 pts remained on bintrafusp alfa therapy. Any-grade bintrafusp alfa–related adverse events (AEs) occurred in 75.0%, 100.0%, and 75.0% of pts in cohorts 1A, 1B, and 2, respectively (Table). The most-common grade ≥3 AEs were anemia and hematuria (25.0% each) in cohort 1A and vaginal hemorrhage (22.2%) in cohort 1B. One pt had grade 4 anemia and vaginal hemorrhage in cohort 1B. No treatment-related deaths occurred. AEs led to permanent discontinuation of bintrafusp alfa in 37.5%, 33.3%, and 12.5% of pts in cohorts 1A, 1B, and 2, respectively; the most common any-grade AE was vaginal hemorrhage (22.2%). Conclusions: No new safety signals were observed with first-line bintrafusp alfa plus chemotherapy ± bevacizumab or chemoradiotherapy in pts with P/R/M or LA cervical cancer. Clinical trial information: NCT04551950. [Table: see text]
Toripalimab combined with chemoradiotherapy for patients with locally advanced cervical squamous cell carcinoma.
Authors: Ou Dan , Xu Haoping 
Published: June 2022

5538 Background: To assess the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma (Chinese Clinical Trial Registry number, ChiCTR2000032879). Methods: Twenty-two locally advanced cervical cancer patients, regardless of programmed death ligand-1 status, received toripalimab treatment combined with concurrent chemoradiotherapy. Concurrent chemoradiotherapy(CCRT) includes cisplatin (40 mg/m2, once a week for 5 weeks), radiotherapy (external irradiation 45-50.4Gy/25-28Fx, 5 fractions a week, followed by brachytherapy 24-30Gy/3-5Fx) and toripalimab (240mg on days 1, 22 and 43). The primary end-point was safety and feasibility. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS). Results: The median age was 55 years old (range, 42 to 72 years old), with 2 patients in FIGO stage II, 15 patients in stage IIIC, and 5 patients in stage IVA. All patients have received CCRT successfully. Grade III and higher adverse events (AEs) were observed in 10 patients (10/22, 45.5%), and no patient had a grade V AE. The most frequent grade III AE was leukopenia (8/22, 36.4%). The most common immunotherapy-related adverse reaction was hypothyroidism (2/22, 9.1%). The 3-month ORR rate was 95.5%. At data cutoff (Jan 31, 2022), the median follow-up was 10 months (range, 3.30 to 16.73 months). One patient developed multiple metastases 3 months after treatment, and 1 patient developed lung metastasis 6 months after treatment. The ORR was 100%, while the PFS rate was 90.1%, and the OS rate was 95.5%. Conclusions: Toripalimab combined with concurrent chemoradiotherapy demonstrated a manageable safety profile and promising anti-tumor activity in patients with locally advanced cervical cancer, thus might represent a novel treatment option for this patient population. Longer follow-up results and further phase II/III studies are expected. Clinical trial information: ChiCTR2000032879.
Racial differences in the mutational landscape of serous endometrial cancer.
Authors: Schink Julian C. , Garg Ruchi , Buttin Barbara , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Farley John H. , Markman Maurie 
Published: June 2022

5600 Background: Tumor comprehensive genomic profiling (CGP) identifying genomic alterations (GA) that have diagnostic, prognostic and are potentially therapeutically targetable is essential to precision oncology. 2022 NCCN Uterine Neoplasm guidelines recommend tumor genetic evaluation as part of initial evaluation. As racial disparities in endometrial cancer outcomes have been widely reported, we analyzed our CGP results from a large series of serous endometrial cancer patients treated in a nationwide cancer network to identify GA differences that may contribute to worse prognosis and help inform better therapy selection. Methods: 86 Pts with serous endometrial underwent hybrid-capture based CGP for up to 324 cancer-related genes of archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 07-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Statistical analysis performed with Fisher Exact test comparing Black and White women. Results: Median age was 63 years (range, 38-85), 37% were White, 58% were Black and 5% were Asian. GA were identified in 94% (81/86) of these patients. TP 53 mutations which is characteristic of serous cancer were present in 80 of 86 patients (93%). GA predicted to activate PI3-Kinase pathway signaling ( PIK3CA, PIK3R1, PTEN) were significantly more common in White women occurring in 13 of 32 (41%), compared with 8 of 50 (16%) of Black women (p. < 0.02). An important, but not statistically significant trend of greater percentage of CCNE1 amplification in Black women is also noted, see table below: Mutation frequencies were similar between Black and White women for the following genes: PPP2R1A 23%; MYC 19%; FBXW7 14%; ARID1A 9%. Conclusions: In this 86 patient series of women with Serous Endometrial Cancer we note that PIK3CA mutations, an important resistance factor in anti-HER2 therapy, were significantly more common in White women (41%) compared with Black women (16%) (p. < 0.02) and ERBB2 mutations occurred in 19% of White women and only 10% of Black women. This study cohort also identified a larger percentage of black women with CCNE1 amplification. Increased CCNE1 amplification has been linked to the racial disparities in cancer outcomes and may explain the disparities seen with endometrial cancers. [Table: see text]