Recent studies have identified higher recurrence and lower survival with a minimally-invasive approach (MIS) versus abdominal approach to radical hysterectomy for early-stage cervical cancer. We aim ...to compare recurrence rate, progression-free survival, and overall survival for cervical cancer after MIS versus abdominal radical hysterectomy.
We searched Medline, Embase, Central, and the Cochrane Library to identify studies from 1990 to 2020 that included women with stage 1 or higher cervical cancer treated with primary radical hysterectomy and compared recurrence and/or progession-free survival (PFS) and overall survival with MIS versus abdominal hysterectomy (PROSPERO 2020 CRD42020173600).
50 studies, including 22,593 women with cervical cancer, met inclusion criteria. 29% of studies had less than 30 months of follow-up and 14% had 60+ months of follow-up. Of the 37 studies reporting PFS, 29 reported no difference and 8 reported decreased PFS with MIS approach. Of the 37 studies reporting OS, 2 studies reported improved OS with MIS approach, 31 reported no difference, and 4 reported decreased overall survival with MIS approach. For progression-free survival, the odds were non-significantly worse for women undergoing MIS radical hysterectomy (OR 1.25, 95% CI 0.98-1.52, 14 studies) when all studies were included. When limited to studies with 30+ months follow-up, the odds of progression-free survival were worse with MIS radical hysterectomy (OR 1.39 for 30+ months, 95% CI 1.09-1.70, 12 studies; OR 1.49 for 48+ months, 95% CI 0.94-2.03, 4 studies). For overall survival, the odds were not significantly different for MIS vs. abdominal hysterectomy (OR 0.82, 95% CI 0.58-1.06, 14 studies). When limited to studies with longer follow-up, the odds of overall survival remained non-significantly different for MIS vs. abdominal (OR 0.90 for 30+ months, 95% CI 0.53-1.26, 11 studies; OR 0.94 for 48+ months, 95% CI 0.42-1.46, 4 studies; OR 1.70 for 60+ months, 95% CI 0.62-2.78, 2 studies).
In our meta-analysis of 50 studies, MIS radical hysterectomy was associated with worse progression-free survival compared to open radical hysterectomy for cervical cancer in studies with 30+ months of follow-up. The emergence of this finding with longer follow-up highlights the importance of high-quality studies to guide cancer and surgical treatment.
A recent randomized controlled trial of minimally invasive (MIS) radical hysterectomy versus open surgery for early-stage cervical cancer has demonstrated higher recurrence and lower survival with ...MIS. However, given the lower operative morbidity of MIS, multiple groups have attempted to define subgroups of patients who may be able to undergo laparoscopic or robotic radical hysterectomy safely in retrospective cohort studies.
We conducted a systematic review and meta-analysis of cohort studies and randomized controlled trials from 1990 to 2020 comparing MIS radical hysterectomy to open radical hysterectomy in early-stage cervical cancer (PROSPERO 2020 CRD42020173600). Cancer histology, laparoscopic or robotic approach, and overall survival (OS), progression-free survival (PFS), and recurrence rate were recorded for each study. We conducted a random-effects meta-analysis with inverse-probability weighting.
41 studies including 22,593 unique women (10,686 MIS, 47%) were eligible for analysis; 6 reported outcomes by histology. Squamous cell carcinoma was the most common histology (79%). For adenocarcinoma, meta-analysis of 3 studies no differences in recurrence (RR 0.87, 95% CI 0.41-1.85), PFS (RR 0.98, 95% CI 0.07-1.89), or OS (RR 1.41, 95% CI 0.56-2.27) between open and MIS surgery. For SCC, two studies showed no change in PFS, and one large study reported decreased OS (HR 1.65, 95% CI 1.17-2.33). One small study found no difference in PFS or OS for neuroendocrine tumors of the cervix. One large study showed decreased OS with robotic versus open radical hysterectomy (HR 1.61, 95% CI 1.2-2.2), but no difference with laparoscopic versus open surgery (HR 1.50, 95% CI 0.97-2.3).
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This meta-analysis contributes to examination of current evidence on surgical approach to early-stage cervical cancer. Our results suggest that there is no histological group for which MIS radical hysterectomy is superior to open radical hysterectomy, and equivalent to inferior outcomes with robotic or conventional laparoscopic surgery versus open surgery. Subgroup analysis generally showed equivocal or inferior outcomes with MIS compared to open surgery, though results remain limited by sample size.
systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the ...development of effective combination therapies. Here, we demonstrate the ability to interrogate
response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response
Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.
Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of
profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts.
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Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic ...screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a ...treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.
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•Anti-PD-1 monotherapy can induce complete tumor remission in uterine leiomyosarcoma•Longitudinal profiling of patient tumors reveals response and resistance mechanisms•Tumor neoantigens are patient specific and can induce long-term immunoreactivity•Biallelic PTEN loss is associated with resistance to PD-1 blockade in sarcoma
George et al. report an exceptional responder to anti-PD-1 monotherapy in uterine leiomyosarcoma and propose mediators of treatment sensitivity and resistance. Neoantigen-directed immunoreactivity was associated with sensitivity to anti-PD-1 monotherapy, whereas resistance was associated with reduction in neoantigen expression consistent with immune evasion, and biallelic PTEN loss was associated with induction of an immunosuppressive microenvironment.
Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a ...clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor ...heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8⁺ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.
Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. ...Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance
. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to ...targeted therapies
, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
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