Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers
. Biomarkers may facilitate identification of these ...responding tumors
. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer
. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
Abstract Background Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). ...However, a large fraction of nonresponding patients are AR-V7–negative. Objective To investigate if a comprehensive liquid biopsy–based AR profile may improve patient stratification in the context of second-line endocrine therapy. Design, setting, and participants Peripheral blood was collected from patients with CRPC ( n = 30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Outcome measurements and statistical analysis Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Results and limitations Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424–14.41; p = 0.0105). Six out of 17 poor responders were AR-V7–negative, but four carried other AR perturbations. Conclusions Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Patient summary Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy.
Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14–20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor ...response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis–liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any‐rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co‐option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival (p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow‐up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously‐treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases.
Background
Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) ...have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients.
Materials and methods
Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (
n
= 21) and standard follow-up (
n
= 20). “Cross-over” was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining.
Results
Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3–67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm
n
= 9 and control arm
n
= 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1–6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE’s occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers.
Conclusion
TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.
To infer the prognostic value of simultaneous androgen receptor (
) and
profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of
...signaling inhibitors (ARSi).
Between March 2014 and April 2017, we recruited patients with mCRPC (
= 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight
splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of
and
was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models.
Overall, no single
perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS.
inactivation harbored independent prognostic value HR 1.88; 95% confidence interval (CI), 1.18-3.00;
= 0.008, and outperformed ARV expression and detection of genomic
alterations. Using Cox coefficient analysis of clinical parameters and
status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months;
< 0.0001), which was validated in an independent mCRPC cohort (
= 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months;
< 0.0001).
In an all-comer cohort, tumor burden estimates and
outperform any
perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.
The encroachment of a growing tumor upon the cells and structures of surrounding normal tissue results in a series of histopathological growth patterns (HGPs). These morphological changes can be ...assessed in hematoxylin-and-eosin (H&E) stained tissue sections from primary and metastatic tumors and have been characterized in a range of tissue types including liver, lung, lymph node and skin. HGPs in different tissues share certain general characteristics like the extent of angiogenesis, but also appropriate tissue-specific mechanisms which ultimately determine differences in the biology of HGP subtypes. For instance, in the well-characterized HGPs of liver metastases, the two main subtypes, replacement and desmoplastic, recapitulate two responses of the normal liver to injury: regeneration and fibrosis. HGP subtypes have distinct cytokine profiles and differing levels of lymphocytic infiltration which suggests that they are indicative of immune status in the tumor microenvironment. HGPs predict response to bevacizumab and are associated with overall survival (OS) after surgery for liver metastases in colorectal cancer (CRC). In addition, HGPs can change over time in response to therapy. With standard scoring methods being developed, HGPs represent an easily accessible, dynamic biomarker to consider when determining strategies for treatment using anti-VEGF and immunomodulatory drugs.
Background
The outcome to treatment administered to patients with metastatic castration‐resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers ...guiding treatment decision making.
Objective
To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second‐line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies.
Design, Settings, and Participants
In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10‐12 weeks a follow‐up sample was collected.
Outcome Measurements and Statistical Analysis
For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10‐12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression‐free survival (PFS), overall survival (OS), and PSA changes at 10‐12 weeks were compared between groups.
Results
Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9‐6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7‐24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9‐8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2‐1.9; P = 0.002) and increasing CTCs at follow‐up (HR 3.3, 95%CI 1.4‐7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9‐25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4‐3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4‐15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10‐12 weeks on therapy (χ2 test: P < 0.01).
Conclusions
CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs.
Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the ...distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.
Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.
Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).
The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC).
To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and ...circulating tumor DNA (ctDNA) in the ABACUS trial.
ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy.
Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected.
The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements.
The median follow-up time was 25 mo (95% confidence interval CI 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio HR 0.60 95% CI 0.24-1.5, p = 0.26, and 0.72 95% CI 0.31-1.7, p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 95% CI 0.09-0.68, p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 95% CI 1.3-13, p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work.
Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future.
We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas
. Novel medicines and vaccines are urgently needed
. ...An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4
T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.
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