Division of Oncology, Section of Medical Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
Mayo Clinic, Phoenix, AZ, 85054, USA.
Breast Cancer Res. 2017 Nov 21;19(1):123. doi: 10.1186/s13058-017-0913-7.
Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).
Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.
Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement.
Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.
ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.
胸苷激酶 1（TK1）是一种细胞周期调控酶，在 DNA 合成的 S 期表达达到峰值，是细胞增殖的有吸引力的生物标志物。血清 TK1 活性在早期乳腺癌患者中具有预后价值。由于细胞周期蛋白依赖性激酶 4/6（CDK4/6）抑制剂可阻止 G1/S 期转变，我们假设血清 TK1 可能是 CDK4/6 抑制剂的生物标志物。我们研究了 NeoPalAna 试验（ClinicalTrials.gov 标识符：NCT01723774）中入组患者的药物诱导的血清 TK1 变化及其与肿瘤 Ki-67 水平变化的相关性。
NeoPalAna 试验中入组的临床分期 II/III 期雌激素受体阳性（ER+）/HER2 阴性乳腺癌患者接受初始 4 周的阿那曲唑治疗，然后在第 1 周期（C1D1）接受哌柏西利治疗，每 28 天为一个周期，持续 4 个周期，除非 C1D15 肿瘤 Ki-67>10%，在这种情况下，由于反应不足，患者停止研究。在最后一次哌柏西利给药后 3-5 周进行手术洗脱，除了 8 名连续接受哌柏西利（第 5 周期）直到手术的患者。在基线、C1D1、C1D15 和手术时测定血清 TK1 活性，发现其与肿瘤 Ki-67 和 TK1 信使 RNA（mRNA）水平相关。
尽管阿那曲唑单药治疗显著降低了肿瘤 Ki-67，但 TK1 活性没有统计学意义的变化。然而，在开始哌柏西利治疗后 2 周（C1D15）观察到 TK1 活性明显下降，然后随着哌柏西利洗脱而显著升高。在 C1D15 时，92%的患者血清 TK1 活性低于检测下限（<20 DiviTum 单位/升[Du/L]），表明哌柏西利有显著的作用。在同一方向上，从 C1D1 到 C1D15 以及从 C1D15 到手术时间点，血清 TK1 和肿瘤 Ki-67 的变化之间具有 89.8%（95%CI：79.2%-96.2%）的高度一致性。基于肿瘤 Ki-67 的反应，由 palbociclib 诱导的血清 TK1 降低的灵敏度和特异性分别为 94.1%（95%CI 86.2%-100%）和 84%（95%CI 69.6%-98.4%）。TK1 和 Ki-67 之间的κ统计量为 0.76（p<0.001），表明存在实质性一致性。
血清 TK1 活性是 ER+乳腺癌中 palbociclib 的有前途的药效动力学标志物，其在预测 CDK4/6 抑制剂反应中的价值值得进一步研究。
ClinicalTrials.gov，NCT01723774。于 2012 年 11 月 6 日注册。
