基于BRCA1表达的治疗并未改善NSCLC的生存

BRCA1/2是两种具有抑制恶性肿瘤发生的基因，分别位于第17号和第13号染色体上，在调节人体细胞的复制、遗传物质DNA损伤修复、细胞的正常生长方面有重要作用。该基因突变的家族倾向于高乳腺癌/卵巢癌发生率。

本文探索了BRCA1在非小细胞肺癌中的地位。

Treatment Based on BRCA1 Expression Did Not Improve Survival in NSCLC

基于BRCA1表达的治疗并未改善NSCLC的生存

IN PATIENTS with early-stage non–small cell lung cancer (NSCLC), the use of expression of BRCA1 failed as an approach to customize chemotherapy, investigators from the Spanish Lung Cancer Cooperative Group reported at the 2017 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Yokohama, Japan.

在日本横滨举行的2017年国际肺癌研究协会（IASLC）世界肺癌大会上，来自西班牙肺癌协作组的研究者报告，在早期非小细胞肺癌（NSCLC）患者中，应用BRCA1表达作为一个定制化疗的方法失败。

Customization of adjuvant chemotherapy according to BRCA1 levels did not result in a significant overall survival benefit—the study’s primary endpoint—in the general population of patients with node-positive resected NSCLC in the phase III SCAT trial, according to Bartomeu Massuti, MD, of Alicante University Hospital ISABIAL in Spain. “Our conclusion is that the trial is not positive, but itdidvalidate the prognostic value of BRCA1 expression levels in early-stage NSCLC,” said Dr. Massuti.

据西班牙阿利坎特大学医院ISABIAL Bartomeu Massuti博士介绍，在SCAT Ⅲ期试验中的淋巴结阳性切除的NSCLC总患者群中，根据BRCA1基因水平定制辅助化疗，并未带来显著的总生存——研究的主要终点——获益。“我们的结论是，该试验不是阳性结果，但它确实证实了BRCA1表达水平对早期NSCLC的预后价值，”Massuti博士说。

Study Rationale

研究的理论基础

POSTOPERATIVE PLATINUM-BASED chemotherapy is the standard of care for resected NSCLC with lymph node involvement. BRCA1 is an enzyme within the DNA-repair pathway that may regulate response to cisplatin and antimicrotubule agents. Specifically, the loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy, such as cisplatin, and may also be associated with resistanceto spindle poisons such as taxanes.

术后铂基化疗是淋巴结受累的NSCLC切除后的标准治疗。BRCA1是DNA修复路径中的一个酶，可调节对顺铂和抗微管药物的应答。具体来说，BRCA1功能的丧失与对DNA损伤性化疗（如顺铂）的敏感性相关，也可能与对纺锤体毒物如紫杉类耐药有关。

“BRCA1 is a key component of one of the pathways in homologous recombination. We know BRCA1 can impact prognosis. When tumors have high levels, the course is poor. With low levels, prognosis is better. We also know that based on this fact, we can customize treatment,” Dr. Massuti said at a press briefing.

“BRCA1是同源重组途径之一的一个关键部分。我们知道BRCA1可以影响预后。当肿瘤具有高水平时，预后不好。低水平者，预后较好。我们也知道，基于这个事实，我们可以定制治疗，”Massuti博士在一个新闻发布会上说。

The study’s hypothesis was that patients with low BRCA1 levels would be more sensitive to cisplatin, whereas those with high levels would be more resistant to cisplatin and more sensitive to docetaxel.

该研究的假设是，BRCA1水平低的患者或许对顺铂更敏感，而高水平的患者或许对顺铂更耐药而对多西他赛更敏感。

SCAT Details

SCAT细节

THE MULTICENTER randomized phase III SCAT trial evaluated chemotherapy regimens that were individualized according to patients’ BRCA1 expression. Median mRNA BRCA1 levels were 12.09 in the control group; in the experimental arms, they were 4.84 in the low-expression group, 13.16 in the intermediate-expression group, and 30.75 in the high-expression group.

多中心随机Ⅲ期SCAT试验评估了基于患者BRCA1表达的个体化化疗方案。在对照组中，中位mRNA BRCA1水平是12.09；在实验组中，低表达组为4.84，中间表达组为13.16，高表达组为30.75。

After surgery, 500 patients (median age, 63 years) with stage II and III NSCLC were randomized 1:3 to the control arm (3 cycles of cisplatin/docetaxel) or 1 of 3 experimental arms in which patients with low BRCA1 levels received cisplatin/gemcitabine; those with intermediate levels received cisplatin/docetaxel; and those with high levels received docetaxel alone.

手术后，将500例（平均年龄63岁）Ⅱ、Ⅲ期NSCLC患者按1∶3随机分入对照组（3周期顺铂/多西他赛）或3个实验组中的1个，其中BRCA1水平低的患者接受顺铂/吉西他滨；中间水平者接受顺铂/多西他赛；而高水平者接受多西他赛单药。

The primary endpoint was overall survival. The statistical hypothesis was that the expected 5-year survival rate of 45% in the control arm could be increased by 20% with the experimental regimens.

主要终点是总生存。统计学假设是，对照组预期5年生存率为45%，用试验方案可提高20%。

Primary Endpoint Not Met, but Some Differences Observed

主要终点未达到，但观察到一些差异

AFTER A MEDIAN follow-up of 53 months, median overall survival was 69.3 months in the control arm and 82.4 months for the three experimental arms together. Although a numerical difference was observed, it was not statistically significant (hazard ratio [HR] = 0.946), Dr. Massuti reported.

中位随访53个月后，对照组的中位总生存期是69.3个月，三个试验组合计为82.4个月。Massuti博士报告，虽然观察到数值差异，但统计学上没有显著意义（风险比[HR]=0.946）。

Among the experimental arms, median survival was 74.0 months for the low-BRCA1 group (42.2% of patients) treated with cisplatin/gemcitabine, 80.5 months for the intermediate-BRCA1 group (30% of patients) receiving cisplatin/docetaxel, and 80.2 months for high-BRCA1 expressors (27.6% of patients) receiving docetaxel alone. “In the experimental arm, where treatment was customized according to BRCA1 levels, survival was not very different among the three groups,” he said.

实验组中，接受顺铂/吉西他滨的低BRCA1组（42.2%的患者）中位生存期是74.0个月，接受顺铂/多西他赛的中间BRCA1组（30％的患者）为80.5个月，而接受多西他赛单药的高BRCA1表达者（27.6%的患者）为80.2个月。“在根据BRCA1水平定制治疗的实验组中，三组的生存差别不大。”他说。

However, BRCA1 level did make a difference in outcome. Overall survival in the control group was 82.4 months for the low expressors, not reached for the intermediate expressors, and 40.1 months for patients with high BRCA1 expression. The prognostic power of BRCA1 was validated by the poor prognosis observed in patients in the control arm with high BRCA1 expression, he commented.

然而，BRCA1水平确实对结果产生影响。对照组的总生存期是：低表达者82.4个月，中间表达者未达到，而高BRCA1表达的患者为40.1个月。他评论说，在高BRCA1表达的对照组患者中，BRCA1的预后能力被观察到的不良预后所证实。

Higher BRCA1 expression was associated with male sex, squamous histology, and current or former smoking. The treatment effect in BRCA1 subgroups is shown in Table 1.

更高的BRCA1表达与男性、鳞状组织学以及当前或既往吸烟有关。BRCA1亚组的治疗效果如表1所示。

“In the subgroup with low BRCA1 expression, we’ve seen that cisplatin plus gemcitabine is better than cisplatin plus docetaxel,” he continued. “For patients with high BRCA1, median survival was the same in patients who received docetaxel plus cisplatin or docetaxel alone.”

他继续说,“在低BRCA1表达的亚组中，我们已经看到顺铂加吉西他滨优于顺铂加多西他赛。”对于高BRCA1的患者，接受多西他赛加顺铂或多西他赛单药的患者中位生存期相同。

Although in the control arm BRCA1 level, age, and N stage were significant predictors of survival in the univariate analysis, in the multivariate analysis, BRCA1 remained the only predictor. Dose delays and reductions were significantly less frequent with docetaxel alone vs the other arms (P< .001). With single-agent docetaxel, more patients remained alive without disease (43.6%). There was a trend for lower noncancer-related deaths among patients treated without cisplatin.

在单变量分析中，虽然对照组BRCA1水平、年龄和N分期均是显著的生存预测因素，但在多变量分析中，BRCA1仍然是唯一的预测因子。与其他组相比，多西他赛单药的给药延迟和减量明显更少（P＜0.001）。单药多西他赛，更多患者仍然无病生存（43.6%）。未接受顺铂治疗的患者中非癌症相关死亡有下降的趋势。

An important finding was that for patients with high levels of BRCA1, chemotherapy without cisplatin was not detrimental. These patients may be able to avoid the toxicity of cisplatin without compromising survival, the investigators concluded.

一个重要的发现是，对于BRCA1高水平的患者，不含顺铂的化疗不是有害的。研究人员总结说，这些患者可能能够避免顺铂的毒性而不影响生存。

Massuti B, Cobo-Dols MC, Rodriguez-Paniagua M, et al: SCAT phase III trial: Adjuvant CT based on BRCA1 levels in NSCLC node-positive resected patients: Final survival results of a Spanish Lung Cancer Group Trial. 2017 World Conference on Lung Cancer.Abstract PL 02.04. Presented October 17, 2017.

Massuti B, Cobo-Dols MC, Rodriguez-Paniagua M, 等：SCAT Ⅲ期试验：基于BRCA1水平的辅助化疗治疗NSCLC淋巴结阳性切除术后患者：西班牙肺癌组一项试验的最终生存结果。2017年世界肺癌大会。摘要PL 02.04。发表于2017年10月17日。