title: Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel.
abstract: Critics have suggested that neoadjuvant chemotherapy (NACT) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. β-tubulins are chemotherapeutic targets of taxanes and epothilones. Class III β-tubulin overexpression has been linked to chemoresistance and hypoxia. Herein, we describe changes in class III β-tubulin in patients with advanced ovarian carcinoma in response to NACT, in relationship to clinical outcome, and between patients who underwent NACT versus primary debulking; we characterize in vitro chemosensitivity to paclitaxel/patupilone of cell lines established from this patient population, and class III β-tubulin expression following repeated exposure to paclitaxel. Using immunohistochemistry, we observed among 22 paired specimens obtained before/after NACT decreased expression of class III β-tubulin following therapy within stroma (p=0.07), but not tumor (p=0.63). Poor median overall survival was predicted by high levels of class III β-tubulin in both tumor (HR 3.66 [1.11,12.05], p=0.03) and stroma (HR 4.53 [1.28,16.1], p=0.02). Class III β-tubulin expression by quantitative-real-time-polymerase-chain-reaction was higher among patients who received NACT (n=12) compared to primary cytoreduction (n=14) (mean±SD fold-change: 491.2±115.9 vs. 224.1±55.66, p=0.037). In vitro subculture with paclitaxel resulted in class III β-tubulin upregulation, however, cell lines that overexpressed class III β-tubulin remained sensitive to patupilone. Overexpression of class III β-tubulin in patients dispositioned to NACT may thus identify an intrinsically aggressive phenotype, and predict poor overall survival and paclitaxel resistance. Decreases in stromal expression may represent normalization of the tumor microenvironment following therapy. Epothilones warrant study for patients who have received neoadjuvant carboplatin and paclitaxel.
authors.affiliation: Division of Gynecologic Oncology, Yale University School of Medicine, 333 Cedar Street FMB 328, Box 208063, New Haven, CT, 06520, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Roque
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.forename: Michelle
authors.initials: M
authors.lastname: Glasgow
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.forename: Ileana
authors.initials: I
authors.lastname: Bortolomai
authors.forename: Sara
authors.initials: S
authors.lastname: Gasparrini
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D016190:Carboplatin / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D014404:Tubulin / Q000032:analysis / Q000096:biosynthesis*; D059016:Tumor Microenvironment / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D014404:Tubulin; D016190:Carboplatin; D017239:Paclitaxel