Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma

2012 ◽  
Vol 34 (7) ◽  
pp. 678-682 ◽  
Author(s):  
Sarah Glaze ◽  
Jill Nation ◽  
Martin Köbel
2015 ◽  
Vol 33 (22) ◽  
pp. 2457-2463 ◽  
Author(s):  
Steffen Böhm ◽  
Asma Faruqi ◽  
Ian Said ◽  
Michelle Lockley ◽  
Elly Brockbank ◽  
...  

Purpose To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. Patients and Methods A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. Results The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. Conclusion The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research.


2016 ◽  
Vol 141 ◽  
pp. 151-152
Author(s):  
R.C. Arend ◽  
Z.C. Dobbin ◽  
D.K. Crossman ◽  
B.K. Erickson ◽  
J.D. Boone ◽  
...  

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
H. Al-Hussaini ◽  
D. Hogg ◽  
M. E. Blackstein ◽  
B. O'Sullivan ◽  
C. N. Catton ◽  
...  

Background. There remains controversy on the routine use of chemotherapy in localized SS.Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed.Results. Median age for AP and PP was 37.6 (range 15–76) and 14 (range 0.4–18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of10%and40%, respectively. 5-year EFS and OS was69.3±4.8%and80.3±4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without.Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Michael Driscoll Toboni ◽  
Hollie M Noia ◽  
Danny Wilke ◽  
...  

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.


2016 ◽  
Vol 22 (12) ◽  
pp. 3025-3036 ◽  
Author(s):  
Steffen Böhm ◽  
Anne Montfort ◽  
Oliver M.T. Pearce ◽  
Joanne Topping ◽  
Probir Chakravarty ◽  
...  

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