title: Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors.
abstract: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors.
  
  
  
  Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test.
  
  
  
  Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001).
  
  
  
  Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: jhaverik@mskcc.org.
authors.forename: Komal
authors.initials: K
authors.lastname: Jhaveri
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Neil
authors.initials: N
authors.lastname: Iyengar
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY; Beaumont Hospital, Dublin, Ireland.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Morris
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Adriana D
authors.initials: AD
authors.lastname: Corben
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Akram
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Russell
authors.initials: R
authors.lastname: Towers
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human
keywords: Biomarker; Client proteins; HER2; HSP90; Solid tumors