Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors

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• 作者：Komal Jhaveri¹ ; ^{jhaverik@mskcc.org" class="auth_mail" title="E-mail the corresponding author} ; Sarat Chandarlapaty¹ ; Neil Iyengar¹ ; Patrick G. Morris¹ ; ² ; Adriana D. Corben¹ ; Sujata Patil¹ ; Muzaffar Akram¹ ; Russell Towers¹ ; Rita A. Sakr¹ ; Tari A. King¹ ; Larry Norton¹ ; Neal Rosen¹ ; Clifford Hudis¹ ; Shanu Modi¹
• 关键词：Biomarker ; Client proteins ; HER2 ; HSP90 ; Solid tumors
• 刊名：Clinical Breast Cancer
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：16
• 期：4
• 页码：276-283
• 全文大小：1005 K

文摘

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.

Patients and Methods

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.

Results

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).

Conclusion

Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.