bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular determinants of prostate specific antigen (PSA) kinetics and clinical response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in SPARTAN.
Authors: Saad Fred , Graff Julie N , Hadaschik Boris A. , Oudard Stephane , Mainwaring Paul N. , Bhaumik Amitabha , Gormley Michael , Londhe Anil , Thomas Shibu , Lopez-Gitlitz Angela , Mundle Suneel , Davicioni Elai , Small Eric Jay , Smith Matthew Raymond , Feng Felix Y
Published: May 2020

5521

Background: In SPARTAN, APA + androgen deprivation therapy (ADT) prolonged metastasis-free survival (MFS) and improved PSA kinetics over placebo (PBO) + ADT in high-risk nmCRPC. All molecular subtypes derived benefit in MFS from APA (Feng FY, et al. ASCO GU 2019; abstract 42). We evaluated the association of PSA decline and efficacy outcomes in SPARTAN pts with different molecular subtypes. Methods: Gene expression from archival primary tumors (biomarker population) was assessed with the DECIPHER platform (Decipher Biosciences, Inc.) and stratified into genomic classifier (GC) high- and low-to-average risk using GC score > 0.6 and ≤ 0.6, respectively, and ADT-resistant or -sensitive basal or luminal A/B (PAM50 classifier) subtypes. PSA nadir and confirmed PSA decline (Table) were assessed in APA pts overall and at 3, 6, and 12 mo. Associations between molecular subtypes and outcomes were assessed. Results: Of 233 available samples, 154 were from APA pts; 49% of APA pts had high GC score and 66% had basal subtype. PSA levels at baseline were similar across all subtypes. Regardless of GC score or basal/luminal subtype, > 50% of patients achieved ≥ 90% reduction in PSA with APA. PSA declined faster and PSA reduction was deeper at 6 mo (Table) in GC low to average vs GC high risk and luminal vs basal subtypes. Overall, only luminal vs basal subtypes had a significantly higher % of pts with ≥ 90% PSA decline (Chi square p = 0.037). In luminal pts, deeper PSA decline with APA was consistent with improved MFS vs basal pts. In GC high pts, MFS benefit with APA was similar to that in GC low to average pts despite lower PSA decline. Although GC low to average and luminal pts had more rapid and deeper PSA responses than GC high or basal pts, respectively, all pts derived MFS benefit. Association of long-term outcomes with PSA decline in these molecular subtypes will be presented. Conclusions: In SPARTAN, all molecular subtypes of pts with nmCRPC treated with APA + ADT had MFS benefit and rapid and sustained PSA decline. PSA responses were deepest and most rapid in GC low to average and luminal subtypes. Clinical trial information: NCT01946204 . [Table: see text]
Clinical analysis of the extracellular vesicle-fingerprint score blood test to refine the prediction of clinically significant prostate cancer and avoid prostate biopsy.
Authors: Fairey Adrian S. , Paproski Robert J , Pink Desmond , Sosnowski Deborah L , Vasquez Catalina , Donnelly Bryan , Hyndman M. Eric , Aprikian Armen G. , Beatty Perrin , Lewis John D
Published: May 2020

5530

Background: The accuracy of the extracellular vesicle-fingerprint score (EV-FPS) test to predict clinically significant prostate cancer (PCa; Gleason grade (GG) ≥ 3) from indolent disease (GG ≤ 2) and avoid unnecessary prostate biopsies was determined at the point of prostate biopsy decision. Methods: Clinical data, health information, and blood samples were collected from a prospective validation cohort of 415 men, without prior PCa diagnosis, referred to urology clinics for prostate biopsy or transurethral prostate surgery (June 2014-Dec 2016). The patient’s EV-FPS risk score was calculated by combining machine learning model-analyzed microflow cytometry data from EV biomarkers with logistic regression-analyzed patient-centric clinical features. The plasma-derived EV biomarkers were prostate-specific membrane antigen, polysialic acid and ghrelin-growth hormone receptor. The patient clinical features were; age, ethnicity, PCa family history, PSA levels, abnormal digital rectal examination (DRE) and prior negative prostate biopsy. Together, the biomarkers and clinical features provided specificity for clinically significant PCa. Results: The EV-FPS test identified clinically significant PCa patients with high accuracy (0.81 area under curve) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cut-off after test validation; 95% of the patients with GG ≥ 3 would have been found before biopsy, 35% biopsies would have been avoided and diagnosis of GG ≥ 3 PCa would have been missed in only 5% of the cohort. Conclusions: This minimally invasive EV-FPS test accurately predicted clinically significant PCa in men with high EV-FPS risk scores, high PSA level and/or abnormal DRE. Therefore, men with low EV-FPS risk scores could potentially avoid unnecessary prostate biopsies. Clinical care cut-offs to calculate the number of biopsies that could have been avoided, and the percentage of GG ≥ 1 to GG ≥ 3 PCa that could have had a delayed diagnosis. [Table: see text]
KEYNOTE-199 cohorts (C) 4 and 5: Phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hoimes Christopher J. , Graff Julie N , Tagawa Scott T. , Hwang Clara , Kilari Deepak , Ten Tije A. J. , Omlin Aurelius , McDermott Raymond S. , Vaishampayan Ulka N. , Elliott Tony , Gerritsen Winald R. , Wu Haiyan , Kim Jeri , Schloss Charles , De Bono Johann S. , Antonarakis Emmanuel S.
Published: May 2020

5543

Background: Initial evidence suggests activity of pembro + enza in patients (pts) resistant to enza. We present results from the multicohort phase II study KEYNOTE-199 (NCT02787005) in chemotherapy-naive pts with mCRPC treated with pembro + enza after progression with enza and who had RECIST-measurable (C4) or bone-predominant (C5) disease. Methods: Pts who did or did previously receive abiraterone and for whom enza treatment failed after clinically meaningful response received pembro 200 mg Q3W, with continuation of enza for up to 2 y or until progression, toxicity, or withdrawal. End point was ORR per RECIST v1.1 (C4) by blinded independent central review (primary); DOR (C4), time to PSA progression, rPFS, OS, and safety. Results: A total of126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4-1667) in C4 and 19 ng/mL (1-1750) in C5.Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6 mo (3+ to 13); 60% of pts had DOR ≥6 mo. DCR (CR + PR + SD) was 51% in C4 and C5. Median (95% CI) time to PSA progression was 4 mo (4-4) in C4 and 4 mo (4-4) in C5. Median (95% CI) rPFS was 4 mo (3-6) for C4 and 4 mo (3-6) for C5; 12-mo rPFS rate was 17% in C4 and 23% in C5. Median (95% CI) OS was NR (16-NR) in C4 and 19 (14-NR) mo in C5; 12-mo OS rate was 70% in C4 and 75% in C5. Shorter median OS was more associated with prior enza treatment <6 mo than with prior enza treatment ≥6 mo. Liver metastasis was associated with shorter median OS however, median OS in visceral disease subgroups appeared longer than expected. Any-grade/grade ≥3 treatment-related AEs occurred in 75%/26% of pts in C4 and 69%/24% in C5. Two pts in C5 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Any-grade/grade 3/4 rash (regardless of relatedness) was higher than that in prior reports for individual agents (33%/6%). Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in an ongoing phase III combination trial. Clinical trial information: NCT02787005 . [Table: see text]
Detection of prostate cancer and determination of its significance using explainable artificial intelligence.
Authors: Eminaga Okyaz , Loening Andreas , Lu Andrew , Brooks James D , Rubin Daniel
Published: May 2020

5555

Background: The variation of the human perception has limited the potential of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in determining prostate cancer and identifying significant prostate cancer. The current study aims to overcome this limitation and utilizes an explainable artificial intelligence to leverage the diagnostic potential of mpMRI in detecting prostate cancer (PCa) and determining its significance. Methods: A total of 6,020 MR images from 1,498 cases were considered (1,785 T2 images, 2,719 DWI images, and 1,516 ADC maps). The treatment determined the significance of PCa. Cases who received radical prostatectomy were considered significant, whereas cases with active surveillance and followed for at least two years were considered insignificant. The negative biopsy cases have either a single biopsy setting or multiple biopsy settings with the PCa exclusion. The images were randomly divided into development (80%) and test sets (20%) after stratifying according to the case in each image type. The development set was then divided into a training set (90%) and a validation set (10%). We developed deep learning models for PCa detection and the determination of significant PCa based on the PlexusNet architecture that supports explainable deep learning and volumetric input data. The input data for PCa detection was T2-weighted images, whereas the input data for determining significant PCa include all images types. The performance of PCa detection and determination of significant PCa was measured using the area under receiving characteristic operating curve (AUROC) and compared to the maximum PiRAD score (version 2) at the case level. The 10,000 times bootstrapping resampling was applied to measure the 95% confidence interval (CI) of AUROC. Results: The AUROC for the PCa detection was 0.833 (95% CI: 0.788-0.879) compared to the PiRAD score with 0.75 (0.718-0.764). The DL models to detect significant PCa using the ADC map or DWI images achieved the highest AUROC [ADC: 0.945 (95% CI: 0.913-0.982; DWI: 0.912 (95% CI: 0.871-0.954)] compared to a DL model using T2 weighted (0.850; 95% CI: 0.791-0.908) or PiRAD scores (0.604; 95% CI: 0.544-0.663). Finally, the attention map of PlexusNet from mpMRI with PCa correctly showed areas that contain PCa after matching with corresponding prostatectomy slice. Conclusions: We found that explainable deep learning is feasible on mpMRI and achieves high accuracy in determining cases with PCa and identifying cases with significant PCa.
Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC): Matching-adjusted indirect comparisons.
Authors: Jiang Shan , Terasawa Emi , Horton Viviana Garcia , Ayyagari Rajeev , Waldeck A. Reginald , Halabi Susan , Shore Neal D.
Published: May 2020

5561

Background: Randomized nmCRPC trials comparing darolutamide (D), apalutamide (A) and enzalutamide (E) have not been reported. Safety of these therapeutics has important implications in assessing patient risk-benefit concerns. Matching-adjusted indirect comparison (MAIC) is a method to perform indirect treatment comparisons adjusting for cross-trial heterogeneity. Objective: To compare the safety outcomes of D vs. A or E using MAIC. Methods: Data from the ARAMIS (D vs. placebo [PBO]), SPARTAN (A vs. PBO) and PROSPER (E vs. PBO) trials were used. Key safety outcomes including adverse events (AEs) that have central nervous system relevance were compared using anchored MAIC. Individual patient level data (IPD) from ARAMIS were selected and re-weighted to match the inclusion criteria and baseline characteristics published in SPARTAN and PROSPER (no access to their IPD). The Benjamini-Hochberg approach was applied to adjust for multiplicity. The D vs A MAIC matched on 7 covariates: age, prostate-specific antigen (PSA) level and doubling time, Eastern Cooperative Oncology Group (ECOG), Gleason score, bone-sparing agent use and prior surgery. Sensitivity analyses were conducted matching on different sets of covariates. D vs. E were matched on age, region, PSA level and doubling time, ECOG, Gleason score and bone-sparing agent use. Risk difference (RD) ([DARO – PBOARAMIS] – [ENZA – PBOPROSPER]) and odds ratio (OR) (ORARAMIS/ORPROSPER) were calculated. RD<0 or OR<1 indicate lower AE risk for D. Results: For D vs. A, the effective sample sizes (ESS) of D and its placebo (PBO) arm were 604 and 391 after matching. Fall, fracture, and rash were statistically significantly lower for D vs. A (Table). For D vs. E, the ESS of D and PBO arm were 580 and 395, respectively. Fall, dizziness, mental impairment, hypertension, fatigue and severe fatigue were statistically significantly lower for D vs. E. Conclusions: After adjusting for trial differences, D showed favorable safety profile in fall, dizziness, mental-impairment, hypertension, rash, fatigue, and fracture. [Table: see text]
The quantitation of thioredoxin 1 from serum as a novel means to detect breast cancer (BC).
Authors: Suh Kyoung Hoon
Published: May 2020

557

Background: Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in women. Enormous effort has been conducted without success to develop a means to detect BC using the blood. We have reported that the level of thioredoxin 1 (Trx1) in serum could be a novel standard to evaluate the risk of BC. Therefore, we have investigated the clinical utility of Trx1 as a biomarker to detect BC by testing sera from normal women, women with BC, women with five other types of cancer. Methods: We have developed an ELISA kit that quantitates Trx1 in sera. The level of Trx1 was determined in each serum from normal healthy women (n = 114), as well as patients with BC (n = 106), cervical cancer (n = 17), lung cancer (n = 14), stomach cancer (n = 9), and thyroid cancer (n = 4). BC patients were recruited according to their age and cancer stage. Each test was duplicated more than three times, and test results were analyzed by ROC analysis, one-way ANOVA tests, and unpaired t-tests. Results: The mean value of Trx1 from normal women was 5.60±4.39(±SD) and that from BC was 22.25±7.07. The Trx1 level was effective to distinguish BC serum from healthy serum with a sensitivity of 94.3% and specificity of 93.9% (AUC 0.985, p< 0.001). The levels of Trx1 from BC patients were higher than the cut-off value of 14.13 U/ml regardless of age, stage, histological grade, type, ER/PR/HER2 expression profile, and proliferation activity of BC cells. The levels of Trx1 from the other five types of cancers (2.34±1.82 - 3.64±2.99) were low enough to be distinguishable from BC. Especially, Trx1 levels could rescue patients whose mammography resulted in a false judgement. Conclusions: These results indicated that the blood level of Trx1 is an effective and accurate method to detect breast cancer, and particularly as a complement to mammography.
Incidence of PI3K pathway alteration and response to neoadjuvant therapy (NAT) in triple negative breast cancer (TNBC) subtypes.
Authors: Basho Reva K , Yam Clinton , White Jason B , Zhao Li , Huo Lei , Mittendorf Elizabeth A. , Thompson Alastair Mark , Litton Jennifer Keating , Arun Banu , Lim Bora , Valero Vicente , Tripathy Debu , Zhang Jianhua , Adrada Beatriz E , Santiago Lumarie , Ravenberg Elizabeth , Moulder Stacy L. , Damodaran Senthil
Published: May 2020

561

Background: Limited cell line and human data suggest that TNBCs characterized as mesenchymal and luminal androgen receptor (LAR) commonly have alterations in the PI3K pathway. More data is needed to better characterize the role of the PI3K pathway across TNBC subtypes. Methods: Pre-treatment tumor biopsies were collected from operable TNBC patients (pts) enrolled on a clinical trial of genomically tailored NAT (ARTEMIS; NCT02276443). Tumors were categorized into 5 groups using the Pietenpol criteria: basal-like (BL) comprised of BL-1 and BL-2, mesenchymal and mesenchymal stem-like (M), immunomodulatory (IM), LAR, or unspecified (UNS). Using whole exome sequencing data, variants (single nucleotide polymorphisms and insertions/deletions) and copy number variations (CNVs) were identified in 32 genes known to activate the PI3K pathway. Results: Tumor subtyping and pathologic response to NAT was available in 127 pts (clinical stage I: 9; II: 84; III: 34). PI3K pathway alteration defined as a variant in one of the evaluated genes and/or deletion of PTEN was seen in 76 (60%) tumors. The most frequent alterations were: PTEN deletion (21%), PIK3CA variant (11%), and PIK3R1 variant (8%). PI3K alteration and residual cancer burden (RCB) rates across TNBC subtypes are shown in the table. There was a significant difference in pathologic complete response (pCR)/RCB 0 rate after NAT across TNBC subtypes (chi2 test; P = 0.02). There was a significant difference in the incidence of PI3K pathway alteration across TNBC subtypes (chi2 test; P < 0.01). Overall, the presence of PI3K alteration was not associated with pCR (Fisher exact test; P = 0.85). Pts with M tumors had a higher rate of substantial residual disease (RCB II-III) after NAT. Presence of PI3K pathway alteration was common in the M subtype and associated with RCB II-III (82% in PI3K-altered vs 33% in wild-type tumors; Fisher exact test; P = 0.02). Presence of PI3K pathway alteration was common but not associated with response in the LAR subtype. Conclusions: The incidence of PI3K pathway alteration varied by TNBC subtype but was not associated with pathologic response to NAT with the exception of increased substantial residual disease (RCB II-III) in the M subtype. [Table: see text]
Validation of nomograms to predict non-sentinel lymph node metastasis after positive sentinel lymph node in breast cancer: Indian cohort background.
Authors: Reddy Asha , Nair Nita S. , Mokal Smruti , Shet Tanuja , Parmar Vani , Joshi Shalaka P , Chitkara Garvit , Thakkar Purvi , Badwe Rajendra
Published: May 2020

568

Background: Axillary lymph node metastasis is still the important prognostic factor in the management of breast cancer (BC). Where we have moved towards axillary conservation in clinically node negative (cN0), the debate on what after 1-2 sentinel lymph nodes positive (SLN+ve) still continues. The ideal situation would be wherein we can accurately predict which patient has a risk of additional non SLN+ve. Several nomograms have been developed to predict the risk of NonSLN+ve. But in view of the differences in tumor size and nodal burden between our patients and the western data, we conducted a study to validate some of these nomograms in our cohort of early BC with positive LN on Low axillary sampling (LAS). Methods: Clinico-pathological data was collected for operable BC (OBC) with cN0 who underwent upfront SLNB or AS. This was entered into the various nomograms and the probability of the Non SLN+ve was calculated. Nomograms with AUC of greater than 0.7 were pre-defined as considerable discrimination. Results: From 2013 to 2018, 2350 women with cN0 OBC underwent LAS. Of which, 670 (28.5%) had a positive node on LAS. Median pT size was 3 cm with 327 (48%), LVI +ve 152 (77%) ENI +ve, 525 (78.4%) Hormone receptor +ve and 485 (72.4%) grade 3 tumors. Of 670, 239 (35.7%) had a NonSLN+ve on completion axillary dissection. The AUC values for nomograms included,ie. MSKCC, MDAnderson, Tenon, Cambridge, Shanghai, Mayo clinic and Turkish were 0.769, 0.77, 0.55, 0.74, 0.65, 0.529, 0.563 respectively. Only three nomograms, MDA, MSKCC and Cambridge had an AUC of more than 0.7. However, they were associated with poor sensitivity and specificity and high FNR (Table) making them clinically unreliable for this cohort. Conclusions: All 7 nomograms were not validated in our study. The larger T size and higher nodal burden of our cohort may be responsible for the same. We thus need to develop an Indian nomogram to predict the risk of non SLN+ve for our patients. [Table: see text]
Psychosocial outcomes following surgery in women with unilateral, nonhereditary breast cancer.
Authors: Lim David Wai , Retrouvey Helene , Kerrebijn Isabel , Butler Kate , O'Neill Anne C , Cil Tulin , Zhong Toni , Hofer Stefan , McCready David R. , Metcalfe Kelly A.
Published: May 2020

570

Background: Rates of bilateral mastectomy continue to rise in average-risk women with unilateral breast cancer. We aim to characterize psychosocial predictors of surgical procedure and how psychosocial outcomes change over time after surgery for breast cancer. Methods: A prospective cohort of women with unilateral, nonhereditary breast cancer were recruited at University Health Network in Toronto, Canada between 2014-2017. Women completed validated psychosocial questionnaires (BREAST-Q) pre-operatively, and 6 and 12 months after surgery. Outcomes were assessed between three surgical groups (unilateral lumpectomy, unilateral mastectomy, bilateral mastectomy). Predictors of surgical procedure were identified using a multinomial logistic regression model. Change in psychosocial scores over time according to procedure was assessed using linear mixed models. All models control for age, stage, reconstruction and treatment. P values < .05 were considered statistically significant. Results: 506 women underwent surgery as follows: 216 unilateral lumpectomy (43%), 181 unilateral mastectomy (36%) and 109 bilateral mastectomy (22%). In the multinomial regression model, younger age (p < .01), and lower chest physical (p = .03) and sexual well-being (p = .02) predicted having bilateral mastectomy over unilateral lumpectomy while younger age (p < .01) and lower disease stage (p = .02) predicted bilateral mastectomy over unilateral mastectomy. The mixed model demonstrates that breast satisfaction follows a non-linear pattern of change over time, with 6- but not 12-month scores being significantly different from baseline (p = .015). Procedure predicts baseline satisfaction (p = .016), with bilateral mastectomy having worse satisfaction than unilateral lumpectomy. Procedure also predicts change in satisfaction, with unilateral and bilateral mastectomy having lower scores across time than lumpectomy. While a significant improvement in psychological well-being is detected by 12 months (p = .02), those with unilateral and bilateral mastectomy have worse psychological well-being over time compared to lumpectomy. Women having mastectomy start with worse physical well-being than those in the lumpectomy group, but their physical well-being does not decline as much as the lumpectomy group over time (p < .01). Conclusions: Definitive surgical procedure affects the trajectory of psychosocial functioning over time. This emerging data may be used to further facilitate surgical decision-making in women considering contralateral prophylactic mastectomy.
Prognostic impact of high stromal tumor-infiltrating lymphocytes (sTIL) in the absence of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in early stage triple negative breast cancer (TNBC).
Authors: Abuhadra Nour , Sun Ryan , Litton Jennifer Keating , Rauch Gaiane M , Thompson Alastair Mark , Lim Bora , Adrada Beatriz E , Mittendorf Elizabeth A. , White Jason B , Ravenberg Elizabeth , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Ueno Naoto T. , Santiago Lumarie , Murthy Rashmi Krishna , Ibrahim Nuhad K. , Symmans William Fraser , Moulder Stacy L. , Huo Lei
Published: May 2020

583

Background: Pathologic complete response is an excellent surrogate for disease-free survival (DFS) and overall survival (OS) in TNBC. High sTIL is associated with improved pCR rates in TNBC. Recent data suggest that high sTIL is also associated with improved outcomes in patients who received no chemotherapy for early stage TNBC (Park, Annals of Oncology, 2019). Thus, we hypothesized that high sTIL may have prognostic impact in patients who do not achieve pCR to NAT. Methods: Pretreatment core biopsies from 182 patients with early-stage TNBC enrolled on the ARTEMIS trial (NCT02276443) were evaluated for sTIL by H&E. Patients were stratified according to sTIL (low < 30%, and high > 30%) and pCR (patients with pCR vs. no pCR). The primary outcome measure was DFS, defined from the date of diagnosis to the first local recurrence, distant metastases or death. Cox proportional hazards regression model was used. During follow-up 33 events for DFS were observed. Results: Among subjects who achieve pCR, DFS was excellent regardless of sTIL status and significantly better than those without pCR (p < 0.05). However, patients with high sTIL and no pCR demonstrated significantly worse DFS compared to all subjects having pCR (HR 0.18, 95% CI 0.04-0.76, p = 0.02). Additionally, we did not find a significant difference between high and low sTIL patients who did not achieve pCR. Conclusions: In early TNBC receiving NAT, for patients failing to achieve pCR, high sTIL was not associated with improved DFS; outcomes were comparable to those with low sTIL without pCR. Thus, high sTIL at baseline does not appear to confer an intrinsic prognostic benefit in the absence of pCR.
Differential effects of epirubicin and docetaxel on the immune system in patients with breast cancer (BC).
Authors: Wimmer Kerstin , Sachet Monika , Birnleitner Hanna , Exner Ruth , Filipits Martin , Gnant Michael , Fitzal Florian , Oehler Rudolf
Published: May 2020

588

Background: Neoadjuvant chemotherapy (NAC) with epirubicin/cyclophosphamid (EC) followed by docetaxel (D) is currently a standard of care therapy in women with early, high-risk breast cancer (BC). New approaches aim to improve the outcome by combining chemo- with immunotherapy. It is therefore of great interest if chemotherapeutics differ in their effect on the immune system and if some substances are superior combination partners than others. Methods: 79 BC patients, who participated in the ABCSG-34 trial, were included. 39 patients were treated with 6 cycles of EC followed by 6 cycles of D and 40 received the reverse sequence (D→EC). Blood was collected before and after 6 cycles. The plasma levels of a variety of immune mediators were determined by multiplex bead array assay. The response to therapy was measured by Residual Cancer Burden (RCB)-score. A score of ≤1.36 was determined as good response. Lymphocyte activation was assessed after stimulation with phytohaemagglutinin (PHA) by flow cytometric analysis of IFNgamma. Additionally, lymphocytes of 6 healthy probands were stimulated with PHA and treated with E or D. The stimulation was quantified by measuring cluster formation after 5 days. Further, a human BC cell line (SK-BR3) was treated with E or D. The induced cell death was determined morphologically as well as by flow cytometry after staining of phosphatidylserine, Sub-G1 DNA and active caspase-3. Results: The treatment of BC patients with 6 cycles of EC resulted in a decrease of lymphocyte stimulation whereas 6 cycles of D had no effect. The plasma levels of most immune mediators decreased significantly after six cycles EC when compared to baseline. Under the influence of D, the effect was much weaker. The changes of Eotaxin and OPG during the first 6 cycles of D correlated with the RCB-score in the reverse group. A decrease in Eotaxin (p = 0.0136) or in OPG (p = 0.0487) correlated with good response. The in vitro lymphocyte stimulation assay showed that E and D have similar inhibitory effects on lymphocytes.The annexin V/PI analysis confirmed that E more often leads to apoptotic cell death in SK-BR3 cells than D (E:53% vs. D:14%). SK-BR3 cells formed more often polyploid cells when treated with D. This suggests that D induces a regulated form of necrosis whereas E apoptosis. Conclusions: This study is the first to compare the immunomodulatory effect of E and D in BC patients. E inhibits lymphocyte activation in vitro and in vivo and suppresses many soluble immune mediators. This suggests that it is not suited for combination with immunotherapies. D showed a much weaker effect.
Long-term outcomes of patients with HER2+ breast cancer with small-size residual disease (≤ypT1) in the absence of pathological response after trastuzumab-based neoadjuvant chemotherapy and without adjuvant T-DM1: A monocentric retrospective study.
Authors: Doucet Ludovic , Moreau-Bachelard Camille , Gourmelon Carole , Robert Marie , Berton Dominique , Bourbouloux Emmanuelle , Guerin Catherine , Blonz Cyriac , Andrieux Nicole , Campone Mario , Frenel Jean-Sebastien
Published: May 2020

589

Background: The Katherine trial has shown that adjuvant T-DM1 improved invasive disease free survival (iDFS) of patients with HER2+ breast cancer who did not achieve a pathological complete response (pCR) with trastuzumab-based neoadjuvant chemotherapy (NAC). However, some subgroups may benefit less from this treatment escalation. Methods: All HER2+ breast cancer patients treated with trastuzumab-based NAC between 2006 and 2016 were retrieved from our institution’s database. Neo- or adjuvant T-DM1 was an exclusion criterion. We then selected the patients who did not achieve a pCR and analyzed the outcome (iDFS and overall survival (OS)) according to ypT, ypN and several factors analyzed in the Katherine trial. Results: Out of the 182 patients, 117 patients reached the inclusion criteria. Patient’s characteristics were similar to the trastuzumab arm of the Katherine trial. With a median follow-up of 75.4 months (29.3–149.7), 28 events (24%) occurred, among which 22 distant relapses. In univariate analysis, ≤ypT1 vs > ypT1, ypN0 vs ypN+, no capsular rupture, signs of histological response (Sataloff not D in T or N) were associated with a better iDFS. In multivariate analysis, only ypT status remained significant. Of note, patients with ≤ypT1 (ypTis, ypT0, ypTmic, ypT1) (n = 81; 69%) had an excellent outcome: 3 years (y) and 5y iDFS rates of 90% (83.6-96.8) and 88.6% (81.9-95.9) respectively. The remaining patients (n = 36; 31%) had a significantly lower 3y and 5y iDFS: 69.2% (55.6-86.2) and 59.5% (45-78.6) respectively (p = 0.0017). OS in a multivariate analysis was also improved in pts with the smaller residual and/or node negative disease (3y OS rates of 100% (100-100) vs 92.1% (85.7-99); 5y OS rates of 96% (90.7-100) vs 81.1% (71.6-91.9); p = 0.02). Conclusions: In the absence of pCR after trastuzumab-based NAC, patients with pathological response scored as ≤ypT1 (ypTis,ypT0, ypTmic, ypT1) have an excellent outcome. These patients may derive less benefit from adjuvant T-DM1.
Liquid biopsy of the immune environment: Evaluation of peripheral blood mononuclear cells (PBMCs) with CyTOF and response to trastuzumab (T)-based neoadjuvant chemotherapy (NAC) in HER2+ breast cancer (BC).
Authors: Leon-Ferre Roberto Antonio , McGrath Kaitlyn , Suman Vera J. , Carter Jodi M , Kalari Krishna R. , Weinshilboum Richard M. , Wang Liewei , Ingle James N. , Knutson Keith L. , Ansell Stephen M. , Boughey Judy Caroline , Villasboas Jose Caetano , Goetz Matthew P.
Published: May 2020

592

Background: Immune responses in the tumor microenvironment have prognostic and predictive value in BC. However, the potential of immune responses observed in peripheral blood as biomarkers in BC remains unclear. We have shown that a higher frequency of circulating monocytes and a lower frequency of antigen-experienced memory CD8+ T cells are associated with response to NAC in triple negative BC (Leon-Ferre et al SABCS 2019). Here, we used cytometry by time-of-flight (CyTOF) to evaluate associations between circulating immune cells, clinical features and response to T-based NAC in HER2+ BC. Methods: PBMC suspensions from 36 pts with stage I-III HER2+ BC were prospectively collected prior to initiation of T-based NAC, stained with 29 metal-tagged antibodies optimized to identify major human immune cell subsets, and acquired in the Helios CyTOF instrument. Differential abundance analysis of immune cells by clinical characteristics and by NAC response was evaluated using Wilcoxon rank sum test. % of immune cell subsets is presented as % of all PBMCs. Results: Most pts presented with ER- tumors (56%), measuring > 5cm (64%) and with nodal metastases (78%). After NAC, 16 pts (44%) achieved pathologic complete response (pCR). Analysis of preNAC PBMCs demonstrated a significantly higher number of B cells (8% vs 5%, p = 0.05) and effector memory CD8+ T cells (CD45RA-/CCR7-, 3 vs 1%, p = 0.02) in pts with pCR compared to those with residual disease. Of the B cell subsets, naïve B cells (CD24-/CD27-) were higher in pts who achieved pCR vs not (7% vs 4%, 0 = 0.04). Regarding clinical characteristics, cN+ pts at presentation exhibited a lower number of peripheral blood T cells compared to cN- pts (47% vs 63%, p = 0.03). Of the T cell subsets, overall CD4+ and naïve CD4+ T cells (CD45RA+/CCR7+) were lower in cN+ vs cN- pts (31% vs 45%, p = 0.05; and 11% vs 24%, p = 0.04). We also observed differences in CD56+/CD16- NK cells by ER status (ER- 1% vs ER+ 3%, p = 0.01), and a moderate negative correlation between age and % circulating CD8+ T cells (rho -0.4669, p = 0.004). Conclusions: Distinct peripheral blood immune cell profiles are observed in HER2+ BC at diagnosis, and are associated with response to T-based NAC and initial clinical characteristics. Notably, pts who later achieved pCR had a relative abundance of B cells and effector memory CD8+ T cells at diagnosis. These data suggest that immune cell phenotyping in peripheral blood may have potential as a biomarker to predict response to NAC in BC.
A randomized phase II/III trial of conventional paclitaxel and carboplatin with/without bevacizumab versus dose-dense paclitaxel and carboplatin with/without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Results of the phase II part.
Authors: Ishikawa Mitsuya , Kitagawa Ryo , Shibata Taro , Tokunaga Hideki , Iwata Takashi , Nishio Shin , Takada Toshio , Mori Masahiko , Horie Koji , Kudaka Wataru , Kagabu Masahiro , Tanikawa Michihiro , Kobayashi Hiroaki , Yaegashi Nobuo
Published: May 2020

6027

Background: A randomized controlled trial was conducted to assess the efficacy and safety of dose-dense, weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab (Bmab) compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without Bmab, in metastatic or recurrent cervical carcinoma not amenable to curative treatments with local therapy. Methods: Patients were randomly assigned to either a cTC or a ddTC regimen. After Bmab was approved in Japan (in May 2016) the protocol was amended, and patients on both arms received Bmab if not contraindicated. The cTC was paclitaxel 175 mg/m2 intravenously (IV) for 3 h on day 1 followed by carboplatin at an area under the curve of five IV for 1 h on day 1. The ddTC was paclitaxel 80 mg/m2 IV for 1 h on day 1 followed by carboplatin at an area under the curve of five IV for 1 h on day 1 and paclitaxel 80 mg/m2 IV for 1 h on day 8 and day 15. Both cTC and ddTC treatments were repeated every three weeks, for up to nine cycles. Bmab 15 mg/kg IV was repeated until progression or unacceptable toxicity. The primary endpoint of phase II was the response rate (RR) in patients with measurable lesion, who had received Bmab. If the RR of the ddTC + Bmab arm was greater than that of the cTC + Bmab arm for more than 5%, the study would proceed to phase III, which had overall survival (OS) as its primary endpoint. The planned sample size in the phase II part was 56 to select the ddTC arm with a probability of at least 75% if the difference of RR was 15% or more (45% vs. 60%). Results: Patient accrual started in October 2015. It was suspended in May 2019 because the number of Bmab-treated patients with measurable lesions reached 56. In total, 122 patients were enrolled and randomly assigned to either the cTC arm (cTC: 29 patients; cTC + Bmab: 32 patients) or the ddTC arm (ddTC: 30 patients; ddTC + Bmab: 31 patients). The primary analysis of the phase II part was conducted in November 2019. The RRs of each regimen were 67.9% [95% CI, 47.7-84.1] (19/28, cTC + Bmab), 60.7% [40.6-78.5] (17/28, ddTC + Bmab), 55.2% [35.7-73.6] (16/29, cTC), and 50.0% [29.9-70.1] (13/26, ddTC). Conclusions: The study did not meet the primary endpoint of phase II. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma. Clinical trial information: jRCTs031180007.
Survival differences by race after minimally invasive versus open radical hysterectomy.
Authors: Summey Rebekah , Pike Jordyn , Williams-Brown Marian Yvette
Published: May 2020

6029

Background: Black patients with cervical cancer have historically experienced worse survival compared with white women, as well as decreased rates of minimally invasive surgery (MIS) including radical hysterectomy. The goal of our study is to evaluate if this disparity in survival outcomes reverses in light of new findings favoring an open approach for patients with stage IA2 and IB1 cervical cancer compared to MIS. Methods: The National Cancer Database was queried, and all black and white women with stages IA2 and IB1 cervical cancer who underwent radical hysterectomy from 2010 to 2015 were included. Patients without survival data or documented surgical approach were excluded. Demographic factors were compared using student t-tests and Z-test of proportions as appropriate. Hazard ratios (HR) for the event of mortality were calculated by race and by route of surgery. Kaplan-Meier plots were created to compare survival between groups, and the Cox proportional hazards model was used to adjust for covariates. Results: 4915 patients were identified for inclusion, 12.1% black and 87.9% white. 43.0% of patients underwent open surgery (84.9% white and 15.1% black) and 57.0% underwent MIS (90.1% white and 9.9% black). Average follow up time between groups was 39.5 months for black patients and 40.6 months for white patients. Black patients who underwent open surgery had a hazard ratio (HR) for mortality of 1.44 (95% CI: 1.03-2.00), and those who underwent MIS had a HR of 1.48 (95% CI: 1.03-2.12), when compared to white patients. Mortality rates for black patients undergoing open radical hysterectomy remained higher than those for white patients who underwent MIS. When adjusted for age, insurance status, neighborhood income and educational level, tumor type, Hispanic ethnicity, node positivity and tumor size, these hazard ratios were no longer significant. Conclusions: Following discoveries of improved outcomes following abdominal radical hysterectomy as compared with MIS, we have identified that the discrepancy in ability to undergo MIS did not resolve previously identified disparities in the outcome of death for black women.
Gut microbiome diversity as an independent predictor of survival in cervical cancer patients receiving chemoradiation.
Authors: Sims Travis T. , Alam Molly B. , Karpinets Tatiana , Yoshida-Court Kyoko , Biegert Greyson W.G. , Ahmed-Kaddar Mustapha , Wu Xiaogang , Medrano Andrea Delgado , Chapman Bhavana Sree Vangara , Solley Travis , Aparna Mitra , Mezzari Melissa P. , Ramondetta Lois M. , Lin Lilie L. , Jhingran Anuja , Schmeler Kathleen M. , Ajami Nadim J , Wargo Jennifer Ann , Colbert Lauren Elizabeth , Klopp Ann
Published: May 2020

6036

Background: Diversity of the gut microbiome is associated with response rates for patients receiving immunotherapy. Studies investigating the gut microbiome and outcomes in cancer patients often do not adjust for confounding patient and tumor characteristics. We sought to identify independent gut microbial risk factors in cervical cancer (CC) patients receiving chemoradiation (CRT) and to evaluate their impact on survival. Methods: We analyzed baseline 16S rDNA fecal microbiomes of CC patients receiving standard CRT. Patient and tumor characteristics were analyzed by univariate and multivariate Cox regression models for Recurrence-free survival (RFS) and Overall survival (OS) based on univariate p-value>0.2. Characteristics included age, body mass index (BMI), race, stage, grade, histology, nodal status, and max tumor size. Alpha (within sample) diversity was evaluated using Shannon diversity index (SDI). Kaplan-Meier curves were generated for patients with normal BMI and overweight/obese BMI based on Cox analysis. Results: 55 CC patients were included. Univariate analysis identified older age (Hazard Ratio (HR) of 0.93 (95% CI = 0.87-0.98, p = 0.0096)), SDI (HR of 0.51 (95% CI = 0.23-1.1, p = 0.087)) and BMI (HR of 0.92 (95% CI = 0.84-1, p = 0.096)) as risk factors for RFS. Multivariate survival analyses identified BMI and SDI as independent prognostic factors for RFS with a HR of 0.87 (95% CI = 0.77-0.98, p = 0.02) and 0.36 (95% CI = 0.15-0.84, p = 0.018) respectively. For OS, multivariate survival analyses again identified BMI and SDI as independent prognostic factors with a HR of 0.78 (95% CI = 0.623-0.97, p = 0.025) and 0.19 (95% CI = 0.043-0.83, p = 0.028) respectively. Conclusions: Gut diversity is a significant factor for predicting OS in CC patients undergoing CRT when BMI is accounted for, and may help explain the “obesity paradox” in cancer response. Studies exploring the relationship between gut diversity, CRT, and treatment efficacy are needed to further understand the role of the gut microbiome in treatment outcomes. [Table: see text]
Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC): Efficacy by BRCA1 or BRCA2 mutation in the phase III PAOLA-1 trial.
Authors: Lorusso Domenica , Lotz Jean-Pierre , Harter Philipp , Cropet Claire , Rubio Pérez Maria Jesus , Schauer Christian , Matsumoto Takashi , Vergote Ignace , Colombo Nicoletta , Noettrup Trine Jakobi , Bourgeois Hugues Pierre , Schnelzer Andreas , Pignata Sandro , Garcia Yolanda , Provansal Magali , Hanker Lars Christian , Berton Dominique , Bauerschlag Dirk , Joly Florence , Ray-Coquard Isabelle Laure
Published: May 2020

6039

Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (<1%) had both. Median PFS follow-up was 24.1 and 27.4 months in BRCA1m and BRCA2m pts, respectively. At primary data cutoff, PFS was prolonged with olaparib plus bev versus placebo plus bev in BRCA1m pts and BRCA2m pts (Table). The percentage of BRCA1m pts who received olaparib plus bev and were progression-free at 1 and 2 years was 95% and 73% (vs. 70% and 29% for placebo plus bev) and for BRCA2m pts was 89% and 84% (vs. 84% and 53%) (Kaplan-Meier estimates). Conclusions: In PAOLA-1, maintenance olaparib plus bev provided a significant PFS benefit versus placebo plus bev in all pts analysed, regardless of whether they had BRCA1m or BRCA2m. The median PFS in the control arm suggests a role for bev in this subgroup and the hazard ratio versus an active control arm shows the value of adding maintenance olaparib to bev. Clinical trial information: NCT02477644. [Table: see text]
A randomized multicenter phase II trial to evaluate the safety and efficacy of vaccination with folate receptor alpha (FRα) peptides admixed with GM-CSF as an adjuvant versus GM-CSF alone in patients with platinum-sensitive ovarian cancer (EOC).
Authors: O'Cearbhaill Roisin Eilish , Konner Jason A. , Block Matthew Stephen , Potts James , Garrett Gerald , Kenney Richard , Wenham Robert Michael ,   TPIV200 Ovarian Cancer Study Group
Published: May 2020

6040

Background: FRα is overexpressed on > 90% of high-grade EOC. We conducted a randomized double-blind multicenter phase II clinical trial to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF adjuvant) versus GM-CSF alone as a control in patients with stage III-IV high-grade platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma in first complete or partial remission, irrespective of baseline level of FRα expression. Methods: Patients with stage III-IV high-grade serous, high-grade endometrioid, carcinosarcoma or poorly differentiated EOC who had previously completed standard upfront therapy without evidence of disease progression and who were within a year of last platinum were randomized 1:1 to intradermal vaccination of TPIV200 versus intradermal GM-CSF alone. The vaccination period included 6 administrations of the study drug at 4-week intervals. Up to 6 booster vaccinations at 12-week intervals were permitted for patients who did not have disease progression. AEs were assessed using CTCAE. Tumor response was assessed via RECIST every 12 weeks. The primary endpoint, progression free survival (PFS), was calculated from date of first vaccination to the date of progression, death or study termination. Results: Of 120 patients randomized, 63 (53%) were treated on the TPIV200 arm. The median age at study entry was 63 years (range 37-88). AEs were generally mild. Injection site reaction was more frequent in the TPIV200 (63%) versus GM-CSF arm (39%). The other most common AEs, abdominal pain (25%) and fatigue (23%), were comparable in both arms. At study termination with a median follow-up of 15.2 months (range: 1.2-28.3 months), 68 of 119 intention-to-treat patients had progressed (55% in the TPIV200 arm and 59% in the GM-CSF arm). The median PFS was 11.1 months (95% CI: 8.3-16.6 months) and there was no statistically significant difference in median PFS between the arms (10.9 months with TPIV200 versus 11.1 months with GM-CSF, HR = 0.85 [upper 90% CI = 1.17]). Conclusions: Although TPIV200 had a manageable safety profile, the study was terminated for futility after the planned interim analysis. Future development of FRα-targeted therapy will likely focus on the careful selection of patients whose cancers show high FRα expression. Clinical trial information: NCT02978222.