bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.