bluuebunny/crossref_metadata_2025 huggingface dataset:
ProCAID: A randomized double-blind phase II clinical trial of capivasertib (C) in combination with docetaxel and prednisolone chemotherapy (DP) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Crabb Simon J. , Griffiths Gareth Owen , Marwood Ellice , Dunkley Denise , Downs Nichola , Martin Karen , Light Michelle , Northey Josh , Whitehead Amy , Shaw Emily C , Birtle Alison Jane , Bahl Amit , Elliott Tony , Westbury Charlotte , Sundar Santhanam , Robinson Angus , Jagdev Satinder , Kumar Satish , Khoo Vincent , Jones Robert J.
Published: May 2020

5520

Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or > 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m2 IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368 . [Table: see text]
A urine exosomal circRNA classifier for detection of high-grade prostate cancer at initial biopsy: A multicenter, retrospective study.
Authors: Li Liaoyuan , Tao Wen , He Yadi , He Tao , Li Qing , Wu Zhenquan , Deng Weiming , Zhang Lingxiao
Published: May 2020

5522

Background: The low specificity of prostate-specific antigen (PSA) has resulted in the overdiagnosis and overtreatment of clinically indolent prostate cancer (PCa). We aimed to identify a urine exosomal circular RNA (circRNA) classifier that could detect high-grade (Gleason score [GS]7 or greater) PCa. Methods: We did a three-stage study that enrolled eligible participants, including PCa-free men, 45 years or older, scheduled for an initial prostate biopsy due to suspicious digital rectal examination findings and/or PSA levels (limit range, 2.0-20.0 ng/mL), from four hospitals in China. We used RNA sequencing and digital droplet polymerase chain reaction to identify 18 candidate urine exosomal circRNAs that were increased in 11 patients with high-grade PCa compared with 11 case-matched patients with benign prostatic hyperplasia. Using a training cohort of eligible participants, we built a urine exosomal circRNA classifier (Ccirc) to detect high-grade PCa. We then evaluated the classifier in discrimination of GS7 or greater from GS6 and benign disease on initial biopsy in two independent cohorts. We used the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to evaluate diagnostic performance, and compared Ccirc with standard of care (SOC) (ie, PSA level, age, race, and family history). Results: Between June 1, 2016, and July 31, 2019, we recruited 356 participants to the training cohort, and 442 and 325 participants to the two independent validation cohorts. We identified a Ccirc containing five differentially expressed circRNAs (circ_0049335, circ_0056536, circ_0004028, circ_0008475, and circ_0126027) that could detect high-grade PCa. Ccirc showed higher accuracy than SOC to distinguish individuals with high-grade PCa from controls in both the training cohort and the validation cohorts. (AUC 0.831 [95% CI 0.765-0.883] vs 0.724 [0.705-0.852], P = 0.032 in the training cohort; 0.823 [0.762-0.871] vs 0.706 [0.649-0.762], P = 0.007 in validation cohort 1; and 0.878 [0.802-0.943] vs 0.785 [0.701-0.890], P = 0.021 for validation cohort 2). In all three cohorts, Ccirc had higher sensitivity (range 71.6-87.2%) and specificity (82.3-90.7%) than did SOC (sensitivity, 42.3-68.2%; specificity, 40.1-62.3%) to detect high-grade PCa. Using a predefined cut point, 202 of 767 (26.3%) biopsies would have been avoided, missing only 6% of patients with dominant pattern 4 high-risk GS 7 disease. Conclusions: Ccirc is a potential biomarker for high-grade PCa among suspicious men.
AR enhancer and locus genomic alterations as cell-free DNA biomarkers of primary resistance to AR-directed treatment of metastatic prostate cancer.
Authors: Maher Chris , Dang Ha X. , Chauhan Pradeep S. , Ellis Haley , Feng Wenjia , Harris Peter , Smith Grace , Qiao Mark , Dienstbach Katherine , Beck Rachel , Atkocius Andrew , Qaium Faridi , Luo Jingqin , Michalski Jeff , Picus Joel , Pachynski Russell Kent , Chaudhuri Aadel
Published: May 2020

5529

Background: Predicting primary resistance to androgen receptor (AR)-directed therapies is critical for personalizing treatment of metastatic prostate cancer (mPCa). Analyses of liquid biopsies are potential tools but remained underutilized due to limited sensitivity. We developed a cell-free DNA (cfDNA) assay (EnhanceAR-Seq) to monitor genomic alterations in mPCa including AR enhancer duplication, a resistance marker recently discovered in ~81% of mPCa patients. Here we show that applying EnhanceAR-Seq to plasma cfDNA to monitor alterations of AR gene and enhancer ( AR/enhancer) predicted primary resistance with high sensitivity and outperformed the clinically validated CTC AR-V7 assay. Methods: Forty mPCa patients were prospectively enrolled at the Washington University School of Medicine Siteman Cancer Center with plasma cfDNA analyzed by EnhanceAR-Seq. Twenty-five of them also had the Oncotype DX AR-V7 Nucleus Detect CTC assay performed at a similar timepoint at the discretion of the treating oncologist. All patients received AR-directed therapy (eg. abiraterone, enzalutamide) and underwent standard-of-care clinical and laboratory follow-up. Primary resistance was defined as PSA progression, change of treatment or death within 4 months of treatment initiation, or radiographic progression within 6 months. Results: Median clinical follow up after diagnosis was 50 months. EnhanceAR-Seq detected alterations targeting AR/enhancer in 18 patients (45%), TP53 in 8 patients (20%), and PTEN in 6 patients (15%). We found that AR/enhancer alterations (copy gain, tandem duplication, and point mutation) in cfDNA were strongly predictive of primary resistance to AR-directed therapy (PPV = 100%, Sens. = 89%). Our assay outperformed the CTC AR-V7 assay, which was positive in only two patients (PPV = 50%, Sens. = 6%). Furthermore, patients with AR/enhancer alterations had significantly worse progression-free survival (P = 0.0015; HR = 11.5) and overall survival (P = 0.0002; HR = 6.8). Finally, serial cell-free DNA analysis of 10 patients showed that AR/enhancer copy number gain was maintained or acquired in 5 of 6 AR-resistant cases, and neutrality maintained in 4 of 4 AR-sensitive cases. Conclusions: cfDNA-based AR/enhancer locus genomic alterations could potentially be used to predict primary resistance to AR-directed therapy with higher sensitivity than the clinically validated CTC AR-V7 assay, be used for serial timepoint monitoring and guiding personalized clinical decision-making.
Comparative effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer: A parametric survival network meta-analysis of randomized controlled trials.
Authors: Wang Lin , Paller Channing Judith , Hong Hwanhee , De Felice Anthony , Alexander Caleb , Brawley Otis W.
Published: May 2020

5532

Background: Treatment decision-making for metastatic castration-sensitive prostate cancer (mCSPC) is complicated by the unclear comparative effectiveness and widely varying costs of competing strategies. Objective: To compare the effectiveness and safety of systemic treatments for mCSPC. Methods: We searched bibliographic databases, regulatory documents, and trial registries for randomized controlled trials testing active drugs added to androgen deprivation therapy (ADT) for mCSPC. We used Cochrane risk-of-bias tool (version 2) to assess trial quality and Bayesian network meta-analysis (NMA) to estimate the relative effects of competing treatments. In addition to combing published time-invariant hazard ratios (HRs), we reconstructed survival data from Kaplan Meier curves to enable parametric survival NMA that allows time-varying HR. Results: Seven trials with 7,236 patients were included comparing six treatments (Table). Risk of bias is a concern for trials with open label (N=4), missing data (N=3), or unprespecified analysis (N=3). Ordered from the most to the least effective, treatments significantly improving overall survival (OS) include abiraterone acetate, apalutamide, and docetaxel; treatments significantly improving radiographic progression-free survival (rPFS) include enzalutamide, abiraterone, apalutamide, and docetaxel. (see HRs in Table) Allowing time-varying HR produced similar treatment rankings. Serious adverse events (SAE) were substantially increased for docetaxel (odds ratio [OR] 104.17, 95% credible interval [CI] 24.85-1012.32) and slightly increased for abiraterone (OR 1.42, 95% CI 1.11-1.83). Conclusions: Abiraterone provided the largest OS benefit with slightly increased risk of SAE. Apalutamide offered comparable OS benefit with abiraterone without increasing SAE risk. Although enzalutamide delayed rPFS to the greatest extent, longer follow-up is needed to examine its OS benefit. [Table: see text]
Overall survival (OS) with docetaxel (D) vs novel hormonal therapy (NHT) with abiraterone (A) or enzalutamide (E) after a prior NHT in patients (Pts) with metastatic prostate cancer (mPC): Results from a real-world dataset.
Authors: Swami Umang , Sinnott Jennifer Anne , Haaland Ben , Maughan Benjamin Louis , Rathi Nityam , McFarland Taylor Ryan , Kohli Manish , Nussenzveig Roberto , Pal Sumanta K. , Agarwal Neeraj
Published: May 2020

5537

Background: NHT (A and E) are approved first-line (1L) treatment (Rx) for mPC. After progression on NHT, Rx include either alternate NHT or D. However, OS from a randomized trial comparing NHT vs D after progression on 1L NHT has not been reported. Methods: Pts data were extracted from the Flatiron Health EHR-derived de-identified database. Inclusion: diagnosis of mPC; 1L Rx with single agent A or E only, single-agent Rx with alternate NHT (E or A) or D in second line (2L). Exclusion: > 180 days between date of diagnosis of mPC and date of next visit to ensure Pts were actively engaged in care at data-providing site; Rx with NHT in non-metastatic setting, any prior exposure to D. OS was compared using Cox proportional hazards model stratified by Rx propensity score. Each Pts’ probability of receiving D (rather than NHT) was modeled via a random forest based on Pts and disease characteristics which may drive treatment selection. These included pre-2L Rx ECOG scores, PSA, LDH, ALPH, Hb, age, ICD codes for liver metastasis, diabetes, neuropathy, and heart failure; insurance payer, year of start of 2L Rx, time on 1 L NHT, Gleason score, PSA at the original diagnosis of mPC. Subgroup analyses included 1L Rx duration < 12 mos. Results: 1165 Pts between 2/5/2013 to 9/27/2019 were eligible. Median follow up 8 mos (range 0.1-64.5). Median OS after 1L A was higher with E as compared to D (15.7 vs. 9.4 mos). Median OS after 1L E was higher with A as compared to D (13.3 vs. 9.7 mos) (table). Propensity distributions were overlapping among Rx arms and showed only modest imbalance. In 2L, D had a worse adjusted hazard ratio of 1.29 and 1.35 as compared to E and A respectively (p < 0.05). Similar results were seen with 1L Rx duration of < 12 mos (p < 0.05). Conclusions: These hypothesis-generating data provide real-world OS estimates with 2L D & NHT in mPC. In propensity-stratified analyses, mPC Pts who progressed on NHT had a worse OS with 2L D as compared to alternate NHT. Results were consistent in unadjusted analysis & subgroup analyses of 1L Rx < 12 mos. Results are subject to residual confounding and missingness. After prospective validation these data may aid in Rx sequencing, Pts counselling, and design of future clinical trials in this setting. [Table: see text]
Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.
Authors: Conteduca Vincenza , Castro Elena , Wetterskog Daniel , Scarpi Emanuela , Romero-Laorden Nuria , Gurioli Giorgia , Jayaram Anuradha , Lolli Cristian , Schepisi Giuseppe , Wingate Anna , Casadei Chiara , Lozano Rebeca , Brighi Nicole , Aragon Isabel , Marín-Aguilera Mercedes , González-Billalabeitia Enrique , Mellado Begona , Olmos David , Attard Gerhardt , De Giorgi Ugo
Published: May 2020

5546

Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p<0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.
Cabazitaxel versus enzalutamide/abiraterone in CARD eligible mCRPC patients with or without germline HRR defects.
Authors: Romero-Laorden Nuria , Lozano Rebeca , Llacer Perez Casilda , Piulats Rodriguez Jose Maria M. , Puente Javier , Lorente David , Medina Ana , Cattrini Carlo , Vitrone Francesca , Almagro Elena , Borrega Pablo , Lainez Nuria , Rivera Leticia , Villatoro Rosa , Hernandez Amaia , Rodriguez-Vida Alejo , López-Casas Pedro P. , Gallardo Diaz Enrique , Castro Elena , Olmos David
Published: May 2020

5554

Background: The CARD trial proved that in mCPRC patients (pts), previously treated with docetaxel and an androgen-receptor signaling inhibitor (ARSi), cabazitaxel (CBZ) significantly improves progression-free (PFS) and Overall Survival (OS) compared with the alternative ARSi. Concurrently, the PROFOUND study showed the superiority of olaparib vs. ARSi in pts with similar prior treatment history and genetic alterations in Homologus Recombination DNA repair related genes (HRR). Methods: PROREPAIR-B (NCT03075735) is a prospective study which aimed to demonstrate the prognostic role of germline deleterious mutations in (g)HRR genes and the benefit of first (1L), second (2L) and subsequent therapy lines for mCRPC. Outcomes with 1-2L have been previously reported. Here we evaluated radiographic (r)-PFS, clinical (c)-PFS, and OS in PROREPAIR-B pts who meet CARD study eligibility criteria and who received CBZ and/or ARSi. Survival analysis were performed using Kaplan Meier method and Cox regression models. Results: 95 out of 419 mCRPC pts included in PROREPAIR-B meet CARD eligibility criteria and received CBZ (n=60) or ARSi (n=35) including 14 gHRR carriers, 8/6 treated with CBZ/ARSi, respectively. Visceral metastases were more frequent among pts treated with CBZ (p=0.01). ECOG 2, M1 at diagnosis, Abiraterone as 1st ARSi and prior radiographic PD (all p<0.05) were more frequent in our pts than in the CARD study. Overall, CBZ was superior to ARSi in terms of rPFS (median 6.0 vs. 3.7 months (m), p=0.03), cPFS (median 4.4 vs. 3.4 m, p=0.01) and PSA50 responses (39% vs. 17%, p=0.027). Differences in OS were not observed, although approximately 60% of patients in ARSi had crossed to CBZ at the time of the analyses. Results of subgroups analyses were similar to those reported by CARD. In this series, gHRR carriers had a significant worse prognosis (OS HR 1.9; rPFS HR 2.4; cPFS HR 2.6) than non-carriers. In gHRR carriers CBZ was not superior to ARSi in terms of rPFS (2.5 vs. 3.0 m, p=0.8), cPFS (2.5 vs. 2.4 m, p=0.8) and OS (4.5 vs. 3.7, p=0.8). Cox MVA models adjusted for unbalances and CARD grouping factors confirmed a significant interaction between treatment and gHRR status for rPFS and cPFS, suggesting that the benefit of CBZ was not observed in gHRR. Conclusions: Our results confirm the benefit of CBZ treatment over a second ARSi (either abiraterone or enzalutamide) in unselected mCRPC population. However, the outcomes in gHRR carriers are poor with either CBZ or ARSi supporting the need of novel therapies in this setting. Clinical trial information: NCT03075735 .
Prospective evaluation of 18F-DCFPyL PET/CT in biochemically recurrent prostate cancer: Analysis of lesion localization and distribution.
Authors: Song Hong , Duan Heying , Harrison Caitlyn , Guja Kip , Hatami Negin , Franc Benjamin Lewis , Moradi Farshad , Mari Aparici Carina , Davidzon Guido , Srinivas Sandy , Iagaru Andrei
Published: May 2020

5556

Background: 18F-DCFPyL, a promising PET agent targeting prostate specific membrane antigen (PSMA), is prospectively evaluated in a single academic center for detecting recurrent lesions in prostate cancer patients with biochemical recurrence (BCR). Methods: We prospectively enrolled 150 men (51-91 years old, mean ± SD: 70.3±7.5) with biochemical recurrence (PSA median 2.38 ng/mL, range 0.12 to 698.4) after primary definitive treatment with prostatectomy (65%), radiotherapy (35%) or both (19%). The 18F-DCFPyL positive lesions compatible with prostate cancer were evaluated by two independent readers. Impact of 18F-DCFPyL PET/CT on patient management was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 83% (125 scans), which increased with higher prostate specific antigen (PSA) levels (ng/mL): 63% (PSA < 0.5), 75% (0.5≤PSA < 1), 91% (1≤PSA < 2), 95% (2≤PSA < 5) and 98% (PSA≥5), respectively. In the cohort who underwent prostatectomy, 18F-DCFPyL PET/CT had higher positivity rate in patients with shorter PSA doubling time (PSAdt) (94% in PSAdt 0-3 months vs. 53% in PSAdt > 12 months, P< 0.01). No difference of 18F-DCFPyL positivity rate was observed in post-radiation patients with different PSAdt, nor were there differences between patients with low grade (Gleason 6) or higher-grade prostate cancer (Gleason 7-10). 20 patients (13%) had lesions in the prostate bed only and 41 patients (27%) had oligometastatic disease (1-3 lesions), making them candidates for locally targeted therapy. We identified a total of 1455 18F-DCFPyL positive lesions, including 51 lesions in the prostate bed, 271 pelvic and 463 extra-pelvic lymph nodes, approximately 585 osseous lesions, including 5 patients with diffuse osseous metastases, and 85 lesions in other organs (most commonly in the lungs). 91 out of 150 patients (61%) had change in treatment after 18F-DCFPyL PET and, most noticeably, 48 of these patients (32% total) had lesions only localized on 18F-DCFPyL PET/CT despite negative conventional imaging. Conclusions: 18F-DCFPyL PET/CT holds great potential to be a “one-stop shop” diagnostic tool in the work-up of BCR prostate cancer, with high (61%) impact on the management of these patients. Clinical trial information: NCT03501940 .
Association of detectable levels of circulating tumor DNA (ctDNA) with disease burden in prostate cancer (PC).
Authors: Attard Gerhardt , Gormley Michael , Urtishak Karen , Simon Jason S. , Ricci Deborah S. , Parekh Trilok V. , Cheng Shinta , Chi Kim N. , Smith Matthew Raymond
Published: May 2020

5562

Background: PC is characterized by a relatively low prevalence of recurrent somatic point mutations. ctDNA is shed from PC and can be analyzed to profile somatic point mutations and copy number changes. We evaluated a computational approach to detect ctDNA (ie. ctDNA+) in PC based on allele frequencies of polymorphisms and mutations. We then sought to confirm the association of this biomarker with disease burden and clinical outcome. Methods: Customized, hybrid capture, high-depth next-generation sequencing was performed on pre-treatment (PT) plasma samples from a phase 2 line 3+ metastatic castration-resistant PC (mCRPC) study (NCT02854436, GALAHAD) and PT and end of treatment (EOT) samples from randomized Phase 3 study in non-metastatic (nm) CRPC (NCT01946204, SPARTAN) and from metastatic castration-sensitive PC (mCSPC) (NCT02489318, TITAN). Associations of ctDNA+ with bone lesions (number), visceral metastases (+/-), circulating tumor cells count (CTCc), and serum prostate specific antigen (PSA), alkaline phosphatase (AP) and lactate dehydrogenase (LD) were tested. Also, associations of ctDNA+ with overall survival (OS) and second progression free survival (PFS2) were evaluated in randomized studies using Cox regression. Results: ctDNA+ at PT was 7.5% in nmCRPC, 23.7% in mCSPC and 66% in heavily pre-treated mCRPC. ctDNA+ increased from PT to EOT in nmCRPC (7.5% to 27%) and mCSPC (23.7% to 63.6%). Disease burden metrics were evaluated in ctDNA+ vs ctDNA- patients. ctDNA+ was associated with higher disease burden in mCRPC (Table), nmCRPC and mCSPC. At EOT, ctDNA+ patients had shorter OS and PFS2 in nmCRPC (HR [95% CI] OS: 2.73 [1.83, 4.08], p < 0.0001; PFS2: 2.00 [1.38, 2.90], p = 0.0002) and mCSPC (HR [95% CI] OS: 7.59 [3.22, 17.91], p < 0.0001; PFS2: 4.84 [2.47, 9.47], p < 0.0001). Conclusions: ctDNA+ assessed using our novel, composite biomarker increases with advanced disease state and disease progression, is significantly associated with disease burden and poor clinical outcome in PC and could be a clinically relevant metric for monitoring response to therapy. Clinical trial information: NCT02854436 . [Table: see text]
Association between BRCA2 status and histologic variants (intraductal [IDC] and cribriform [CRIB] histology) in prostate cancer (PC).
Authors: Castro Elena , Salles Daniela Correia , Lozano Rebeca , Thorne Heather , Aragon Isabel , Lopez Campos Fernando , Rubio Jose , Gutierrez Pecharroman Ana , Prieto Daniel , García Isabel , Pacheco Maria I , Llacer Perez Casilda , Maldonado Laneisha , Romero-Laorden Nuria , Zambrana Francisco , López-Casas Pedro P. , Sandhu Shahneen Kaur , Antonarakis Emmanuel S. , Olmos David , Lotan Tamara L.
Published: May 2020

5579

Background: IDC histology in PC has been suggested to associate with germline BRCA2 mutations (gBRCA2) in small series, leading to the potential recommendation of genetic testing for all PC patients with IDC in the primary tumor. Methods: We conducted a case-control study in which primary PC from 58 germline BRCA2 mutation carriers ( gBRCA2) and 116 from non-carriers (NC) were matched 1:2 by Gleason score and specimen type (core biopsy/prostatectomy). Samples were independently reviewed by two expert pathologists blinded to genetic status who established the presence of IDC and/or CRIB morphology with supportive immunohistochemical stains in a subset of cases. Next-generation sequencing, aCGH and/or FISH were used to assess for somatic mono-/bi-allelic BRCA2 alterations. PTEN protein loss was determined by IHC, and TMPRSS2-ERG was detected by FISH/qRT-PCR. Chi-square tests were used to compare the frequency of IDC and cribriform histology in gBRCA2 vs NC, as well as to assess the associations with other variables. Logistic regression models were built to identify independent factors associated with IDC and CRIB histology. Results: gBRCA2 cases were younger at diagnosis (median 61.3 vs 64, p < 0.01) and had T3-4 disease more often than NC cases (31% vs 10.5%, p < 0.01), but the two groups did not differ in any other clinical-pathologic characteristics. After independent histopathological review, 79 cases demonstrated IDC histology and 81 had CRIB histology. No differences in the prevalence of IDC (50% NC vs 36% gBRCA2, p = 0.09) or CRIB (43% NC vs 53% gBRCA2, p = 0.20) patterns were observed. The probability of IDC was higher in PC with bi-allelic BRCA2 alterations (OR 5.1, 95%CI 2.1-12.6), PTEN loss (OR 5.1, 95%CI 1.9-13.5) or both (OR 23.0, 95%CI 4.9-107.2) compared to those without these alterations. Bi-allelic BRCA2 alteration was also associated with higher probability of CRIB histology (OR 7.2, 95%CI 3.1-16.4). TMPRSS2-ERG fusions were not associated with IDC or CRIB histology. MVA confirmed the independent association of bi-allelic BRCA2 alteration (p < 0.01) and PTEN loss (p < 0.01) with IDC histology. Bi-allelic BRCA2 alteration (p < 0.01) and Gleason >8 (p < 0.01) were independent risk factors for CRIB histology. Conclusions: Primary PC with bi-allelic BRCA2 alterations was significantly associated with IDC and CRIB histology, independent of other clinical-pathologic factors (while gBRCA2 status alone was not). PTEN loss in primary PC was also independently associated with IDC, but not CRIB, histology.
Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.
Authors: Huang Xin , Wu Huanwen M. , Zhu Changbin , Shao Di , Guo Dan , Zhou Yidong , Lin Yan , Chen Chang , Xu Ying , Zhao Bin , Song Yu , Lu Tao , Sun Qiang ,   Xiehe
Published: May 2020

558

Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]
The impact of age on early breast cancer after breast conserving therapy: Results of a subanalysis from the accelerated partial breast irradiation IMRT Florence trial.
Authors: Meattini Icro , Saieva Calogero , Desideri Isacco , Marrazzo Livia , Simontacchi Gabriele , Bonomo Pierluigi , Pallotta Stefania , Livi Lorenzo
Published: May 2020

566

Background: The impact of age on local recurrence rate of patients affected by early breast cancer is still unclear. The standard of care for older adult largely varies depending on patient- and tumor-related features, but also on national guidelines. We recently presented the 10 years median follow update of the APBI-IMRT Florence phase III trial. The primary aim of the present analysis is to identify the potential relationship between age and ipsilateral breast tumor recurrence (IBTR) in this setting of patients. Methods: This retrospective analysis was performed on the whole series of 520 patients who were enrolled in the trial after breast conserving surgery and randomized to receive APBI or whole breast irradiation. We analyzed patients stratified by age (70+ vs 40-69 years). Results: At a median follow up time of 10.7 years, we recorded 15 IBTR events. Four hundred and three patients (77.5%) were aged less than 70 years old (11 IBTR) and 117 patients (22.5%) were aged 70 years or older (4 IBTR). At the univariate analysis the age (70+ vs 40-69 years) was not significantly correlated with IBTR occurrence (HR 1.33, 95% CI 0.42-4.17; p=0.63). The only significant prognostic factor was adjuvant endocrine therapy, also at the multivariable analysis (HR 0.26, 95% CI 0.07-0.94; p=0.041). Main results are summarized in the table. Within the luminal-like patients (n=437; 12 IBTR events), the age did not impact on the IBTR rate (HR 0.91, 95% CI 0.19-4.31; p=0.91) and adjuvant endocrine therapy lost its significance (HR 0.32, 95% CI 0.09-1.11; p=0.072). Conclusions: Our trial subanalysis did not demonstrate a significant effect of age on IBTR rate for early breast cancer patients receiving a breast conserving therapy. Due to the low number of events, the benefit of adjuvant endocrine therapy is unclear and calls for further investigations. Clinical trial information: NCT02104895 . [Table: see text]
Factors associated with axillary conversion after neoadjuvant chemotherapy in initially node positive breast cancer patients: A transSENTINA analysis.
Authors: Kolberg Hans-Christian , Kühn Thorsten , Krajewska Maja , Bauerfeind Ingo , Fehm Tanja N. , Fleige Barbara , Helms Gisela , Lebeau Annette , Staebler Annette , Loibl Sibylle , Untch Michael , Kolberg-Liedtke Cornelia
Published: May 2020

567

Background: Current study concepts in early breast cancer after neoadjuvant chemotherapy (NAT) are aiming at reducing morbidity by omission of axillary surgery in selected patients. Selection criteria for this strategy have to include the probability of conversion from cN1 to ycN0. We analyzed the association of clinical/pathological parameters and axillary conversion with data from arms C and D of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were recruited to Arms C/D of the SENTINA trial in case they presented with clinically positive nodes before NAT. Based on their response to NAT they were then assigned to either arm C (clinically conversion to ycN0) or arm D (no clinical conversion (ycN+). In both the pre- and post-NAT scenarios, clinically involved lymph nodes were defined as palpable and/or suspect by ultrasound. Univariate logistic regression analyses were carried out to evaluate the association between clinical/pathological parameters and axillary conversion after NAT. Results: Of the 892 patients in arms C and D of the SENTINA trial 716 were evaluable for this analysis. After NAT, 593 patients converted to ycN0 and were therefore assigned to arm C; in contrast, 123 patients still had involved lymph nodes after NAT (ycN+) and were assigned to Arm D. Arms C and D were compared regarding the clinical/pathological parameters tumor diameter by ultrasound before and after NAT, grading, multifocality, ER status, PR status, HER2 status, pathological complete remission in the breast (breast pCR), morphology, lymphovascular invasion (LVI) and hemangiosis. Only small tumor diameter after NAT (p = 0.0038), achievement of breast pCR (p = 0.0001) and lack of LVI (p = 0.0009) were positively associated with axillary conversion from cN1 to ycN0 after NAT. Conclusions: Because of the small patient number in arm D, we were not able to identify an association between parameters of tumor biology (ER, PR, HER2 and TN status) and axillary conversion. However, favorable response of the primary tumor (represented both clinically by tumor diameter after NAT and pathologically by pCR in the breast) were positively associated with conversion from cN1 to ycN0. These results justify including patients with clinical and pathological response of the primary tumor in trials investigating de-escalation of axillary surgery after NAT.
4R Program results in breast cancer: the impact of 4R Care Delivery Model on timing and sequence of guideline recommended care.
Authors: Weldon Christine B. , Trosman Julia Rachel , Makower Della F. , Rapkin Bruce D. , Perez Claudia Beth , Kulkarni Swati , Schaeffer Cathleen M. , Hoskins Kent , Gallagher Christopher , Lo Shelly S. , Grace-Louthen Cathy , Throckmorton Alyssa , Krueger Editha , Van Horn Jennifer , Reaves Brieyona Chardee , Ravelo Arliene , Yu Elaine , Benson Al Bowen , Schapira Lidia , Gradishar William John
Published: May 2020

573

Background: We previously proposed a 4R care delivery model which enables patients and care teams to manage timing and sequence of interdependent, time sensitive care with a novel multimodality 4R Care Sequence plan (NCI ASCO Teams Project; Trosman, JOP 2016). We report final results of a program which tested 4R at 10 US centers (4 academic and 6 non-academic) from 2016 to 2019. Methods: 4R Sequences were provided to stage 0-III breast cancer patients (4R cohort, N = 422) at participating centers. Analyses of clinical and patient-reported data compared the 4R cohort to a historical control cohort of patients who received care pre-4R at the same centers (N = 466). Results: We significantly improved 5 guideline recommended referral metrics and 4 referral completion metrics indicating receipt of care by patients who were referred (Table). Although significantly increased, referrals to dental visit and smoking cessation before treatment remained low (< 20% and < 10% respectively). Patient survey comments indicated that insufficient lead time to quit smoking or obtain fertility consult before cancer treatment was a key barrier for completing these referrals. Conclusions: 4R markedly improved referral and receipt of interdependent guideline recommended breast cancer care for most metrics. Future 4R program should optimize the timing of referrals within the 4R Care Sequence to allow sufficient time for smoking cessation and fertility care before treatment initiation. [Table: see text]
Sentinel-Lymphnode Biopsy in primary breast cancer: 99mTc versus ICG—A prospective, randomized trial.
Authors: Kern Peter , Bittner Ann-Kathrin , Hoffmann Oliver , Kimmig Rainer , Schoffer Ariane , Moukas Stephanos , Friedrichs Kay
Published: May 2020

575

Background: Sentinel-Lymphnode Biopsy (SLNB) is the standard procedure in primary breast cancer, routinely performed with 99mTechnetium radioactive tracers. Awareness of nuclear waste, costs and time consumption lead to the desire of breast surgeons to find safe and effective alternative options for detection of sentinel lymph nodes (SLN) in breast cancer and melanoma. Indocyaningreen is a tracer which emits fluorescence with near-infrared light of 780-810 nm when injected in the peritumoral or periareolar region, enabling surgeons to detect SLN and lymphatic pathways at the breast. Methods: We performed a prospective, randomized trial with patients with primary breast cancer. Both detection methods have been applied to patients of the study cohort comparing the preparation time, time to identify, concordance of the two methods and costs. Reference method was preoperative lymphszintigraphy. Results: 55 patients have been analyzed in this first report. Preparation time was 75,8 min (range 60-120 min) for 99mTc-tracer and a standard of 20 min for ICG. Time to identify SLN at a mean of 3,8 min(range 1-15 min) for 99mTc and 3 min (range 1-8 min) for ICG. Concordance rates were 98,2 % for the 1st SLN, 93,8 % both for 2nd and 3rd SLN. After neoadjuvant chemotherapy, all SLN have been been detected by both techniques, in 3 patients additional SLN have been found by ICG. Costs have been cut down to 1/10 with the use of ICG, coming up to saving of 27 000 US-$ per each 100 SLNB procedures performed. Conclusions: We report a high concordance rate between the 2 techniques - 99mTechnetium and ICG with near-infrared - for detection of SLN in breast cancer. Preparation time is cut down to less than 30 %, and costs to less the 10 % of radioactive labelling. Clinical trial information: 18-8054-BO .
Re-excision rates among older breast cancer patients undergoing breast-conserving surgery (BCS): Impact of the SSO-ASTRO consensus guideline on margins.
Authors: Chavez-MacGregor Mariana , Lei Xiudong , Tamirisa Nina , Caudle Abigail Suzanne , Giordano Sharon H.
Published: May 2020

576

Background: BCS has been historically associated with a high re-excision rate, driven in part by the need of obtaining negative margins. The SSO-ASTRO consensus guideline on invasive margins, defined a negative margin as no ink on tumor. In this large population-based study of older breast cancer patients undergoing BCS for invasive breast cancer we evaluate the guideline impact on re-excision rates. Methods: Female patients diagnosed with stage I-II breast cancer between 2012-2015 were identified in the SEER-Medicare database. Patients were >66 years and underwent BCS. Patients treated with neoadjuvant chemotherapy were excluded. We defined the following time periods: pre-guideline (January 2012-September 2013); peri-guideline (October 2013-March 2014) and post-guideline (April 2014-December 2016). Re-excision was defined as a resection, BCS or mastectomy identified using ICD-9 or CPT codes between 4 and 90 days after initial BCS. Overall re-excision rates and 95%CI were calculated and groups compared using X2test. Within subgroups we calculated re-excision rates for the pre and post-guideline periods and report the relative percent change. Regression model evaluated the association between time periods and re-excision while adjusting for important covariates, risk ratios (RRs) and 95%CI are presented. Results: 17001 patients were included. 6762 of them had BCS in the pre, 1786 in the peri, and 8453 in the post-guideline periods. Overall 22.6% of the patients had a re-excision. The rate decreased from 24.8% pre-guideline to 20.3% post-guideline (P < 0.001). The relative change in re-excision varied according to region (Midwest 3-7.3%, Northeast -20%, West -16.5% and South -13.5%) Differences in the relative change according to race/ethnicity were also seen (Whites -19.2, Blacks -15.3% and Hispanics -9.9%). In the multivariable model, BCS in the post-guideline period was associated with a decreased risk of re-excision (RR = 0.83; 95%CI 0.79-0.88). Lobular histology was associated with a higher risk of re-excision (RR = 1.31; 95%CI 1.21-1.42); greater surgeon volume was associated with lower risk of re-excision (RR = 0.89; 95%CI 0.82-0.95). Conclusions: There has been a statistically significant decrease in the re-excision rate after BCS associated with the dissemination of the SSO-ASTRO consensus guideline on invasive margins. Our study confirms the impact that guidelines have modifying patterns or practice, reducing the frequency of unnecessary interventions.
Four-year follow-up of a phase III study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer in neoadjuvant setting.
Authors: Pivot Xavier , Pegram Mark D. , Cortes Javier , Lüftner Diana , Rugo Hope S. , Lyman Gary H. , Curigliano Giuseppe , Bondarenko Igor , Dvorkin Mikhail , Yoon Ye Chan , Kim Younsoo , Kim Chul
Published: May 2020

578

Background: SB3 was approved in the US and EU as a biosimilar of reference trastuzumab (TRZ). Here, we report 4-year cardiac safety and survival outcomes. Methods: After completing neoadjuvant-adjuvant therapy in patients with HER2 positive early breast cancer, patients from selected countries participated in a 5-year follow-up study of a phase III trial (Pivot et al. Eur J Cancer 2019). The aim was to observe long-term cardiac safety and survival. EFS and OS were analyzed in subgroups by ADCC status within TRZ in ad-hoc analyses. Results: Of 875 patients randomized in the phase III trial, 367 patients (SB3, N=186; TRZ, N=181) were enrolled in the follow-up study. The median follow-up was 53 months. During the follow-up, the incidence of asymptomatic significant left ventricular ejection fraction (LVEF) decrease was low (SB3, n=1; TRZ, n=2), with all patients recovering with LVEF ≥ 50%. No cases of symptomatic congestive heart failure, cardiac death, or other significant cardiac condition were reported. 4-year EFS rates were 83.4% for SB3 and 80.7% for TRZ with a HR of 0.77 [95% CI 0.47, 1.27]. 4-year OS rates were 94.3% for SB3 and 89.6% for TRZ with a HR of 0.53 [95% CI 0.24, 1.16]. From ad-hoc analysis, a difference in EFS and OS was seen between Non-drifted TRZ and Drifted TRZ; Difference between SB3 and Non-drifted TRZ was not statistically significant. Conclusions: In a subset of patients from the phase III trial, comparable long-term cardiac safety and survival at 4-year supports biosimilarity between SB3 and TRZ. Ad-hoc analysis results by ADCC status suggest a possible correlation between ADCC and clinical efficacy. Further follow-up is needed. Clinical trial information: NCT02771795 . [Table: see text]
Survival analysis of the prospective randomized Cher-Lob study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer (BC).
Authors: Guarneri Valentina , Dieci Maria Vittoria , Bisagni Giancarlo , Generali Daniele Giulio , Cagossi Katia , Sarti Samanta , Frassoldati Antonio , Gianni Lorenzo , Cavanna Luigi , Pinotti Graziella , Musolino Antonino , Piacentini Federico , Michelotti Andrea , Cinieri Saverio , Griguolo Gaia , Miglietta Federica , De Salvo Gian Luca , Conte Pier Franco
Published: May 2020

582

Background: The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here we report the results of survival analysis according to treatment arm and pCR. Methods: The CherLOB study randomized 121 HER2-positive, stage II-IIIA breast cancer patients to anthracyclines/taxane-based chemotherapy plus trastuzumab, lapatinib, or both. After surgery, patients received adjuvant trastuzumab for up to 1 year. The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib (Guarneri, J Clin Oncol 2012). Relapse-free survival (RFS) was calculated from randomization to breast cancer recurrence (locoregional or distant) or death from any cause, whichever first. Overall survival (OS) was calculated from randomization to death from any cause. Results: At a median follow up of 8.8 years, RFS rates at 5 years were: 85.8% in the trastuzumab + lapatinib arm, 77.8% in the trastuzumab arm, 78.1% in the lapatinib arm (log-rank p = 0.160). Patients treated with dual HER2 blockade (trastuzumab + lapatinib arm) experienced numerically better RFS as compared to patients treated with single HER2 blockade (trastuzumab arm and lapatinib arm combined): 5-yr RFS 85.8% vs 78.0%, log-rank p = 0.087; HR = 0.51, 95% CI 0.23-1.12, p = 0.093. The achievement of pCR was a strong prognostic factor. 5-yr RFS rate was 97.3% for pCR patients vs 72.9% for non-pCR patients (log-rank p < 0.001, HR = 0.12, 95% CI 0.03-0.49, p = 0.003); similar significant results were observed in both the estrogen receptor-negative and estrogen-receptor positive subgroups. OS was also improved in pCR patients: 8-yr OS rates were 97.2% vs 80.0% for non pCR patients (log-rank p = 0.028, HR = 0.14, 95% CI 0.02-1.08, p = 0.060). Conclusions: In the Cher-LOB study, there was a not statistically significant signal for a better RFS for patients who received dual HER2 blockade with trastuzumab and lapatinib plus chemotherapy as compared to patients treated with single anti-HER2 agent (trastuzumab or lapatinib) plus chemotherapy. Patients achieving a pCR had longer RFS and OS as compared to non-pCR patients. Clinical trial information: NCT00429299 .