Scientists establish link between deprivation and poor prognosis for BC

Deprivation has long been known to play a role in the development of a wide range of diseases, and to a higher risk of recurrence or death for patients diagnosed with a number of cancers. Previously, the effect of material deprivation on cancer survival in England and Wales was measured by Cancer Research UK, and results showed that cancer survival for adults is generally lower among patients in more deprived groups, even after allowance is made for the higher mortality from all causes of death in these groups.

The reasons for survival rates differing between breast cancer (BC) sufferers from poorer areas and more affluent areas has never been fully understood. Now, researchers from the University of Dundee have established a link between deprivation and the p53 gene, which explains why women from poorer backgrounds are less likely to survive BC. The team identified, for the first time, that p53 mutation in BC is associated with socio-economic deprivation, and that this helps account for the poorer prognosis for women from deprived communities.

As detailed in the 26th January online edition of the British Journal of Cancer (10.1038/sj.bjc.6605540), the scientists found that women from deprived backgrounds were more likely to experience a mutation of p53, and that this linked to higher relapse and mortality rates. According to the team, there are two ways that p53 mutations can come about; one is as a result of genetic predisposition and the other is as a result of lifestyle. Smoking, drinking and poor diet can lead to p53 mutations, and are more common in women from lower socio-economic groups, who are also more likely to experience a recurrence of the disease and to die as a result of BC.

The survey looked at a total of 246 women who underwent treatment for BC between 1997 and 2001. Examining frozen tissue, tests were carried out to determine p53 mutation status. Using the patients' postcodes, a deprivation score was attributed to each and examined against the outcome (full recovery, relapse, death). The team found that patients in the lowest socio-economic group were significantly more likely to have a relapse and die compared to those in more affluent categories. They also demonstrated that the worse survival and shorter disease-free interval in BC for the most deprived patients is associated with tumour p53 mutation.

This research demonstrates a strong link between p53 and deprivation, and then between p53 mutation and recurrence and death. The social application of this work would suggest that if deprivation can be targeted, then the deprived population would be less likely to have problems with their p53 gene and go on to develop BC. In reality, this is unlikely to be achieved, however, there has been numerous work surrounding the p53 protein: Cyclacel Pharmaceuticals' seliciclib (CYC202) is a promising anticancer agent that promotes cancer cell death by downregulation of key proteins, such as p53 and Mcl-1, associated with survival of cancer cells; and new research by Dartmouth Medical School has shown that p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.

Alice Rossiter
Editor, Cancer Drug News

Advexin moves closer to market

Introgen Therapeutics has submitted a BLA to the FDA, while simultaneously Gendux Molecular (Introgen) has submitted an MAA to the EMEA, both seeking marketing approval for Advexin (INGN 201), the company's targeted p53 tumour suppressor gene therapy, to treat recurrent, refractory head and neck cancer. INGN 201 represents the first in a new class of tumour suppressor cancer therapy and is the first of its kind to be submitted for regulatory approval in the US and Europe. Introgen has requested priority review from the FDA for INGN 201, meaning that the treatment could be on the market in early 2009. The news buoyed Introgen's share price as it rose nearly 16 per cent, from a close of US$1.51 on 27th June, to start 30th June at US$1.75.

INGN 201 therapy harnesses the body's natural tumour suppression mechanisms to fight cancer, without the toxicities associated with conventional cancer treatments. Abnormalities in protective tumour suppressor p53 pathways are associated with the majority of all solid cancers. Designed to restore patients' ability to fight cancer, INGN 201 delivers large doses of the normal p53 gene to target abnormal p53 function present in tumour cells, which triggers natural tumour suppression mechanisms in cancer without harming normal cells.

According to Dr Jack Roth, inventor of Advexin and professor at the University of Texas MD Anderson Cancer Center: "This is an important milestone in the clinical application of gene therapy for cancer patients. With the use of p53 biomarkers, Advexin will provide more effective and less toxic treatment for head and neck cancer patients who have limited treatment options."

The submissions are based on pivotal Phase II and III trials evaluating survival, tumour response and safety in patients with recurrent, refractory end-stage, squamous cell carcinoma of the H&N. These studies incorporated common diagnostic tests to identify patients most likely to benefit from INGN 201 based upon pretreatment tissue analyses to determine p53 profile status.

The Phase III trial achieved the study's objectives and demonstrated clinical benefit of INGN 201 in comparison to the control drug, methotrexate. The patients most likely to benefit from INGN 201 treatment with increased tumour responses and survival were identified by prespecified p53 biomarker profiles. Overall, the study results demonstrated that INGN 201 addresses an unmet medical need and the combination of biomarker testing and treatment has the potential to provide recurrent H&N cancer patients with an effective therapy that is less toxic than standard chemotherapies.

INGN 201 is Advexin’s lead product candidate, approval of which may open the door for the company’s other gene therapy drugs. Indeed, INGN 201 is being investigated in Phase II trials for breast, non-small cell lung and oesophageal cancer, as well as earlier-stage studies in prostate, ovarian, bladder, brain and bronchoalveolar cancer. However, it is unclear whether regulatory bodies will even approve INGN 201. The FDA has faced considerable scrutiny in recent years for approving drugs that have turned out to produce dangerous side effects, and it has become more cautious as a result. How the Agency along with the EMEA will view the first in a new class of drugs remains to be seen.

Matthew Dennis - Editor, Cancer Drug News