BRCA1 overexpression is strongly linked to poor outcome in NSCLC patients treated with cisplatin

BARCELONA, Spain—Researchers have found that the breast cancer susceptibility gene BRCA1 plays a significant role in non-small-cell lung cancer. Not only can it be used to predict outcome for patients with NSCLC but it also may prove to be a valuable tool in choosing the best therapy.

Speaking at the 14th European Cancer Conference (ECCO abstract 6506), Rafael Rosell, MD, said that analysis of the expression of five different genes had shown that those NSCLC patients who had high levels of expression of BRCA1 had nearly double the risk of dying early from the disease, compared with patients with low levels of BRCA1 expression.

Dr. Rosell is chief of the Medical Oncology Service and scientific director of oncology research at the Catalan Institute of Oncology in Barcelona.

He said that earlier studies in breast cancer and a study by him and his colleagues in NSCLC had linked low levels of BRCA1 expression with high sensitivity to cisplatin-based chemotherapies, while high levels of BRCA1 expression were linked with lack of response to cisplatin but an increased sensitivity to antimicrotubule agents (taxanes) that prevent tumor growth by stopping cell division.

"Our research shows that patients whose tumors had high BRCA1 expression had significantly worse survival and should be candidates for adjuvant chemotherapy," Dr. Rosell said.

Earlier studies, he said, have shown how different levels of BRCA1 expression affect response to different types of chemotherapy. "Therefore, we believe that BRCA1 could be a landmark predictor of chemosensitivity in NSCLC, and assessment of its expression could be useful for customizing adjuvant chemotherapy," Dr. Rosell said. "We believe that patients with the highest expression levels should receive antimicrotubule, nonplatinum-based chemotherapy."

Five genes analyzed

Dr. Rosell and his colleagues from Poland and Italy investigated gene expression in frozen tumor samples from 126 patients in Poland who had undergone surgery for NSCLC between 2000 and 2004. In addition to BRCA1, they also looked at the expression of four other genes: nucleotide excision repair genes ERCC1 and MZF1 (myeloid zinc finger); TRX1 (thioredoxin-1), which is associated with poor prognosis; and TWIST1, which is involved in metastasis.

In a statistical analysis of the results, only BRCA1 and the stage of disease emerged as independent predictors of survival: Patients with high levels of BRCA1 expression had a 1.98 higher risk of dying within 3 years than did patients with low levels, while patients with advanced disease (stage IIIa) had a 7.91 higher risk of dying than patients with early-stage disease.

Out of 77 patients with low levels of BRCA1, the majority were still alive without relapse (and therefore median survival could not be calculated), but for 36 patients with high levels of BRCA1, the median event-free survival was 22 months (range, 14.9 to 29 months) (P = .01).

When the median overall survival was analyzed, the majority of 83 patients with low BRCA1 levels were still alive (and therefore median survival could not be calculated), while of 40 patients with high BRCA1 levels, median survival was 29 months.

Study validated

The researchers checked these findings by examining NSCLC tumor samples from a separate group of 58 Italian patients followed for 40 months. They found that high BRCA1 expression in these patients increased the risk of dying by 2.4 (ie, more than double the risk of patients with low BRCA1 expression).

Dr. Rosell said, "Our study showed that overexpression of BRCA1 was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set from the Italian patients further strengthened this association. We suggest that patients with high BRCA1 levels will benefit from taxane-based—and not cisplatin-based—chemotherapy."

The researchers are using the information gained from this work to run a prospective clinical trial to test adjuvant chemotherapy in 450 patients and another trial in January 2008 for 700 patients with metastatic disease.

Different chemotherapy regimens will be given, based on the patients' BRCA1 levels: Those with low expression will receive gemcitabine (Gemzar) and cisplatin; those with intermediate expression will receive doxetaxel (Taxotere) and cisplatin; and those with high expression will receive docetaxel alone.

Changing the landscape

Dr. Rosell concluded: "Our findings represent a drastic change from the currently accepted view that cisplatin-based adjuvant chemotherapy can reduce the risk of relapse in resected NSCLC patients."

To the contrary, he said, the results indicate that cisplatin will be ineffective in patients with high BRCA1 levels, although they will benefit from treatment with docetaxel or vinorelbine (Navelbine).

"The implementation of this concept in clinical practice could lead to major improvements in lung cancer treatment," Dr. Rosell said.

Alexander Eggermont, MD, PhD, of Erasmus University, Rotterdam, The Netherlands, commented at a press conference on Dr. Rosell's findings: "This research is at an early stage, but if it is confirmed in the ongoing clinical trials, it could potentially change the landscape of lung cancer treatment."