Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors,Clinical Colorectal Cancer

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Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
Clinical Colorectal Cancer ( IF 3.3 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.clcc.2020.11.005
Koji Ando ₁ , Al Ozonoff ₂ , Shin-Yin Lee ₃ , Michael Voisine ₃ , Julian-Taylor Parker ₃ , Ryota Nakanishi ₄ , Sho Nishimura ₄ , Jing Yang ₅ , Zhao Grace ₅ , Ben Tran ₆ , Thomas J Diefenbach ₇ , Yoshihiko Maehara ₄ , Hiroshi Yasui ₈ , Tomoyuki Irino ₉ , Ravi Salgia ₁₀ , Masanori Terashima ₈ , Peter Gibbs ₆ , Ramesh K Ramanathan ₁₁ , Eiji Oki ₄ , Masaki Mori ₄ , Matthew Kulke ₃ , Kevan Hartshorn ₃ , Ajit Bharti ₃

Affiliation

Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Infectious Diseases, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA.
Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Pathology, Boston University School of Medicine, Boston, MA.
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA.
Division of Gastric Surgery and Division of Gastrointestinal Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA.
Mayo Clinic Cancer Center, Phoenix, AZ.

Purpose

The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response.

Patients and Methods

The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti–phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically.

Results

We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93).

Conclusion

The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.

中文翻译：

拓扑异构酶 I 抑制剂预测性生物标志物的多队列回顾性验证

目的

喜树碱 (CPT) 类似物拓扑替康和伊立替康专门靶向拓扑异构酶 I (topoI)，用于治疗结直肠癌、胃癌和胰腺癌。这类药物的反应率从 10% 到 30% 不等，并且没有根据反应对患者进行分层的预测性生物标志物。基于我们对 CPT 耐药机制的理解，我们开发了一种基于免疫组织化学的预测测试，P-topoI-Dx，将患者人群分为有反应和没有反应的人群。

患者和方法

回顾性验证研究包括胃癌 (GC) 患者的训练集 (n = 79) 和验证队列 (n = 27)，以及 8 个结直肠癌 (CRC) 患者组织队列 (n = 176)。6 个月的无进展生存期被认为是对基于 CPT 的治疗的积极反应。福尔马林固定、石蜡包埋的载玻片用抗磷酸化特异性 topoI-Serine10 (topoI-pS10) 进行免疫组织化学染色、定量并进行统计分析。

结果

我们确定了 35% 阳性染色的阈值，以提供 GC 中的最佳测试特性。GC (n = 79) 训练集表现出 76.6%（95% 置信区间，64-86）的敏感性；68.8% (41-88) 特异性；阳性预测值 (PPV) 92.5% (81-98)；和阴性预测值 (NPV) 42.3% (24-62)。GC 验证集 (n = 27) 表现出 82.4% (56-95) 的灵敏度和 70.0% (35-92) 的特异性。估计的 PPV 和 NPV 分别为 82.4% (56-95) 和 70.0% (35-92)。在 CRC 验证集 (n = 176) 中，40% 的阈值表现出 87.5% (78-94) 的敏感性；70.0% (59-79) 特异性；PPV 70.7% (61-79)；和 NPV 87.0% (77-93)。