Treatment Based on BRCA1 Expression Did Not Improve Survival in NSCLC
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.
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。
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.
“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.
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.
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.
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.
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.
Primary Endpoint Not Met, but Some Differences Observed
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.
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.
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.
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.
“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.”
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.
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.
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。