Breast Cancer Susceptibility Gene Predicts Outcome And Response To Treatment In Lung Cancer

Dr Rafael Rosell told the European Cancer Conference in Barcelona September 25, 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 than those patients with low levels of BRCA1 expression.

In addition, Dr Rosell, who is chief of the Medical Oncology Service and scientific director of oncology research at the Catalan Institute of Oncology in Barcelona, Spain, 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 cancers growing by stopping cell division.

"Our research shows that patients whose tumours had high BRCA1 expression had significantly worse survival and should be candidates for adjuvant chemotherapy," said Dr Rosell. "Earlier studies have shown the way that different levels of BRCA1 expression affect response to different types of chemotherapy, and, 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. We believe that patients with the highest expression levels should receive antimicrotubule, non-platinum-based chemotherapy."

Dr Rosell and his colleagues from Poland and Italy investigated gene expression in tumour samples from 126 patients in Poland who had received 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), and TRX1 (thioredoxin-1), associated with poor prognosis and TWIST1, which is involved in metastasis.

In a statistical analysis of the results, only BRCA1 and the stage of the disease emerged as independent predictors of survival: patients with high levels of BRCA1 expression had a 1.98 higher risk (i.e. nearly double) of dying within three years than did patients with low levels, while patients with advanced disease (stage IIIA) had a 7.91 higher risk (i.e. nearly eight times higher) 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 an average survival figure could not be calculated), but for 36 patients with high levels of BRCA1, the average event-free survival was 22 months (with a range of 14.9 to 29 months). When the average overall survival was analysed, the majority of 83 patients with low BRCA1 levels were still alive (and therefore a median average survival could not be calculated), while of 40 patients with high BRCA1 levels, average survival was 29 months.

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

Dr Rosell said: "Our study showed that over-expression 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.

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, our results indicate that cisplatin will be ineffective in patients with high BRCA1 levels, though they will benefit from treatment with docetaxel or vinorelbine. The implementation of this concept in clinical practice could lead to major improvements in lung cancer treatment."