Treatment based on BRCA1 expression levels fails to improve non-small cell lung cancer outcomes

Issue: November 25, 2017

Receipt of chemotherapy based on mRNA BRCA1 expression level failed to improve survival among node-positive patients with stage II and stage III non-small cell lung cancer, according to results of the phase 3 SCAT trial presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

“Patients with early-stage NSCLC are initially treated with surgery, and if there is lymph node involvement in the surgical specimen, then chemotherapy is the standard of care in clinical practice,” Bartomeu Massuti, MD, head of the medical oncology department at Alicante University Hospital in Spain, said during a press conference. “Our group tested one hypothesis that tried to customize the postsurgery chemotherapy treatment according to one prognostic factor that is well known: BRCA1.”

BRCA1 efficiency enhances resistance to cisplatin, and loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy. Researchers used BRCA1 levels to define a subgroup that could avoid receipt of cisplatin.

Massuti and colleagues randomly assigned 500 patients (median age, 64 years; 79% men; N1, 58%; N2, 48%) with stage II and stage III NSCLC 1:3 to a control arm consisting of three cycles of cisplatin and docetaxel (n = 108), or to an experimental arm with treatment according to BRCA level (n = 382).

Patients with low BRCA1 levels received cisplatin and gemcitabine (n = 110), patients with intermediate levels received cisplatin plus docetaxel (n = 127), and patients with high levels received docetaxel alone (n = 110).

In the total study cohort, 49% of patients had adenocarcinoma, 43% had squamous histology and 8% had another subtype. Fifty-seven percent of patients formerly smoked, 32% currently smoked and 11% never smoked. Twenty-six percent of patients underwent pneumonectomy.

Median mRNA BRCA1 level was 15.78 (range, 0.73-132) overall, and mean levels appeared lower among patients with adenocarcinoma vs. squamous histology (6.95 vs. 20.29; P < .001).

High BRCA levels also correlated with male sex and current smoking status.

OS served as the primary endpoint. Secondary endpoints included DFS, toxicity and compliance, and recurrence pattern.

Median follow-up was 53 months.

Researchers reported a median PFS of 38.7 months in the control arm, 32.2 months in the low-BRCA1-expression arm, 34.3 months in the intermediate-expression arm and 41 months in the high-expression arm.

A similar proportion of patients in the control and experimental groups achieved 5-year EFS (54% vs. 56%). Median OS also appeared similar between these arms (73.3 months vs. 77.5 months), and was 80.2 months in the high BRCA1 expression arm, 80.5 months in the intermediate expression arm, and 74 months in the low expression arm.

“This is not a positive trial in terms of the main endpoint of survival in the control vs. experimental arms,” Massuti said. “But, we have validated the prognostic value of BRCA1 expression levels in these patients with early-stage NSCLC. We have found that in the subgroup with low BRCA1 levels, one combination of cisplatin-gemcitabine was superior to cisplatin-docetaxel. And for the subgroup with high BRCA1 levels, cisplatin — associated with early and long-term toxicity — maybe can be avoided without compromising the survival.” – by Alexandra Todak

Reference:

Massuti B, et al. Abstract 9523. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Oct. 15-18, 2017; Yokohama, Japan.

Disclosures: Massuti reports advisory roles with AstraZeneca, Amgen, Bristol-Myers Squibb, Merck and Roche; travel grants from Merck and Roche; clinical trial support from Sanofi Spain. Please see the abstract for a list of all other authors’ relevant financial disclosures.