Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma

Böhm, Steffen; Faruqi, Asma; Said, Ian; Lockley, Michelle; Brockbank, Elly; Jeyarajah, Arjun; Fitzpatrick, Amanda; Ennis, Darren; Dowe, Thomas; Santos, Jennifer L.; Cook, Linda S.; Tinker, Anna V.; Le, Nhu D.; Gilks, C. Blake; Singh, Naveena

doi:10.1200/jco.2014.60.5212

Cited by 245 publications

(333 citation statements)

References 27 publications

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“…As described above, the response to chemotherapy was assessed in the IDS biopsies using the CRS (18). CRS1 samples show minimal response to chemotherapy, CRS2, "poor" responders, have easily identifiable malignant cells in the omentum after NACT and CRS3, "good" responders, usually show extensive regression-associated fibroinflammatory changes with absent or minimal numbers of malignant cells (18). None of the IDS samples in our experiments, by chance and due to prevalence, scored as CRS1.…”

Section: Resultsmentioning

confidence: 99%

“…We demonstrate that NACT induces activation of CD4 þ T cells and that CD8 þ T cells and CD45RO þ memory cells are present in omental metastases after NACT. By incorporating a recently developed prognostically significant histologic score (18), we show that omental metastases biopsies from patients with good response (CRS3) to NACT have more pronounced T-cell activation and reduced Treg cell infiltration compared with poor responders (CRS2). Importantly, even those patients who had a poor response to three cycles of platinum-based chemotherapy had high densities of CD8 þ T cells and CD45RO chemotherapy-resistant.…”

Section: Discussionmentioning

confidence: 99%

“…CRS1 samples show minimal response to chemotherapy, CRS2, "poor" responders, have easily identifiable malignant cells in the omentum after NACT and CRS3, "good" responders, usually show extensive regression-associated fibroinflammatory changes with absent or minimal numbers of malignant cells (18).…”

Section: Patients and Samplesmentioning

confidence: 99%

“…We therefore studied a cohort of 54 women with stage IIIC and stage IV HGSC receiving NACT, as well as 6 women who underwent surgery before chemotherapy. Using transcriptional and protein analyses of prospectively collected metastatic peritoneal (omental) specimens, as well as plasma samples, we investigated the effects of platinum-based NACT on the immune microenvironment in patients and compared this to their response to chemotherapy as assessed by a recently published prognostic histologic score (18).…”

Section: Introductionmentioning

confidence: 99%

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Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Böhm

Montfort

Pearce

et al. 2016

Clinical Cancer Research

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130

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Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.Experimental Design: We obtained pre-and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4 þ T cells showed enhanced IFNg production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8 þ T-cell and CD45RO þ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3 þ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in postversus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. Ó2016 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Patients and Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Böhm

Montfort

Pearce

et al. 2016

Clinical Cancer Research

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130

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“…Furthermore, many other factors affect PFS and OS, including the histological type, stage, residual tumor size, and age. Chemosensitivity is also influenced by many factors 24, 25, 26, 27, 28. In the patients with epithelial OC, a sensitivity to both paclitaxel and platinum affected their response to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Functional role of the Tau protein in epithelial ovarian cancer cells

Yamauchi

Kobayashi

Oikiri

et al. 2017

Reprod Medicine & Biology

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AimThe microtubule‐associated Tau protein is a marker of paclitaxel sensitivity in ovarian cancer. The aim of the present study was to elucidate the function of the Tau protein in epithelial ovarian cancer.MethodsThe correlation between Tau protein expression and the response to paclitaxel by using several ovarian cancer cell lines was investigated.ResultsA Western blot showed that the expression level of the Tau protein was the highest in the TOV112D cells. A cell‐counting kit showed that the proliferation rates were more inhibited in the cells with down‐regulated Tau protein than in the control cells, both with and without paclitaxel treatment. The proliferation rates of the control cells and the TOV112D cells also were compared with Tau protein overexpression. The level of cell proliferation was more inhibited in the cells that overexpressed the Tau protein, compared to the control cells, both with and without paclitaxel treatment. It was shown that both the down‐regulation and the overexpression of the Tau protein were related to the inhibition of TOV112D cell proliferation. Early and late apoptosis of the TOV112D cells that were transfected with Tau cDNA plasmid construct or Tau small interfering RNA significantly increased.ConclusionThese findings suggest that the molecular targeting of the Tau protein could be a potential treatment for ovarian cancer.

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Small extracellular vesicles from malignant ascites of patients with advanced ovarian cancer provide insights into the dynamics of the extracellular matrix

et al. 2021

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The exact role of malignant ascites in the development of intraperitoneal metastases remains unclear, and the mechanisms by which extracellular vesicles (EVs) promote tumor progression in the pre‐metastatic niche have not been fully discovered. In this study, we characterized ascites from high‐grade epithelial ovarian cancer patients. Small‐EVs (30–150 nm) were isolated from two sources—the bulk ascites and the ascitic fluid‐derived tumor cell cultures—and assessed with a combination of imaging, proteomic profiling, and protein expression analyses. In addition, Gene Ontology and pathway analysis were performed using different databases and bioinformatic tools. The results proved that the small‐EVs derived from the two sources exhibited significantly different stiffness and size distributions. The bulk ascitic fluid‐derived small‐EVs were predominantly involved in the complement and coagulation cascade. Small‐EVs derived from ascites cell cultures contained a robust proteomic profile of extracellular matrix remodeling regulators, and we observed an increase in transforming growth factor‐β‐I (TGFβI), plasminogen activator inhibitor 1 (PAI‐1), and fibronectin expression after neoadjuvant chemotherapy. When measured in the two sources, we demonstrated that fibronectin exhibited opposite expression patterns in small‐EVs in response to chemotherapy. These findings highlight the importance of an ascites cell isolation workflow in investigating the treatment‐induced cancer adaption processes.

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Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma

Cited by 245 publications

References 27 publications

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Functional role of the Tau protein in epithelial ovarian cancer cells

Small extracellular vesicles from malignant ascites of patients with advanced ovarian cancer provide insights into the dynamics of the extracellular matrix

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