Gender survival differences linked to EGFr variants

A study by researchers at the University of Southern California (USC) and Keck School of Medicine has found evidence that supports gender-related differences in the development and survival of metastatic colorectal cancer (CRC). The study, which was published in the 15th April edition of Cancer Research (2008;68:3037-3042), found that specific gene variants in EGFr linked to the development of CRC resulted in opposite survival outcomes for men and women.

Germline variations in EGFr DNA have been linked with poor prognosis in CRC, however, when researchers looked at EGFr as a prognostic factor, they found that it had opposite implications for men and women. The scientists expected to find that high expression would correlate with a poor prognosis and faster growth of the cancer. What they found, however, was that men followed the expected trend, while women's response was the opposite.

In the study, researchers analysed 318 patients (177 men and 141 women) with metastatic CRC that were treated at the USC/Norris Comprehensive Cancer Center and the LAC+USC Medical Center between 1992 and 2003. The team studied two independent functional polymorphisms of EGFr, one at codon 497 in the extracellular domain of the EGFr gene and the other related to dinucleotide repeats within intron 1. All the patients were exposed to similar chemotherapy treatments. When genomic DNA samples were analysed, the investigators found that women who had specific gene variants linked with high expression of EGFr had higher overall survival (OS) rates, while men with the same variants had lower survival.

Specifically, median OS in men with the Arg/Arg variant of the 497 polymorphism was 10.3 months, while for those with a Lys allele it was 13.7 months. Among women, the corresponding figures were 16.0 and 14.0 months. For the intron polymorphism, a repeat length <20>20. The corresponding survival rates for women were 17.6 and 14.1 months.

According to Dr Heinz-Josef Lenz, Professor of Medicine at the Keck School of Medicine: "This is the first report to show that the prognostic value of EGFr depends on gender. This may suggest that, in the future, molecular markers should be evaluated differently in women and men and that treatment decisions may depend on gender and not only on molecular or clinical findings."

As to mechanisms that might explain these differences, the researchers point out that the colon expresses both oestrogen receptor beta and androgen receptor, and that EGFr interacts with both. Therefore, EGFr may have molecular intermediates that interact in a gender-specific way to effect EGFr pathway activation. Previous research has shown a protective effect of female hormones in CRC survival. The new findings indicate that hormone receptors are important in signal pathways related to the survival of patients. Research will now need to be performed to determine whether men and women respond differently to certain cancer therapies. This may lead to targeted chemotherapy that is tailored to get the best response from male and female patients.

Matthew Dennis - Editor, Cancer Drug News