Presentation at the 4th IMPAKT Breast Cancer Conference
Breast cancer in young women is a biologically unique disease that requires customized management strategies, researchers report at the 4th IMPAKT Breast Cancer Conference, in Brussels, Belgium.
The reported findings have potentially important implications for treatment, because breast cancer in young women is often aggressive and diagnosed at an advanced stage, meaning the prognosis for these patients is often poor.
Dr. Hatem A. Azim Jr., a medical oncologist from Institut Jules Bordet in Brussels, and colleagues showed that breast cancer in women forty-years or younger is enriched with the aggressive basal-like tumors. Moreover, these patients have a significantly higher risk of relapse independent of stage, histological grade, breast cancer molecular subtypes and treatment received.
A subgroup analysis showed a particularly poor trend in patients with luminal tumors, i.e. estrogen receptor positive. "While some investigators could refer this to poor compliance of young women to hormonal therapies, we performed another analysis in 1,188 women who did not receive any systemic therapy and indeed found significant poor outcome in young women both in luminal-A and luminal-B tumors," Dr Azim said. Luminal-A cancers are ER+ and low-grade, while Luminal-B cancers are ER+ but often high grade.
To elucidate the possible reasons behind the poor outcome in young women, Dr Azim and co-workers went on to study the expression of a variety of genes in women with breast cancer to see if they correlated with age. They adjusted their findings to take into account the size of the tumor at diagnosis, whether the disease had spread to lymph nodes and breast cancer molecular subtype, in addition to other variables.
The researchers performed their analysis on two independent datasets, including 1,188 and 2,334 patients, and found the same results in both cases.
"What we found was that even after adjustment for these parameters, there are several genes and gene signatures that are significantly associated with age in breast cancer patients," Dr Azim explained. "Some were highly expressed in young women --including stem cells, luminal progenitors, RANK-ligand (RANKL) and c-kit-- while others were down-regulated, such as genes related to programmed cell death, or apoptosis."
The findings show that breast cancer arising at a young age seems to be associated with age-related biological processes, which appear to be independent of other prognostic factors that are commonly used by oncologists.
The genomic analysis also identified a number of signaling pathways in the breast cancers of young women that could be potential targets for treatment, Dr Azim's group reports.
For example, a gene signature of the phosphoinositide 3-kinase molecular pathway was highly associated with young age. "PI3k is an important targetable signaling pathway in breast cancer and perhaps these results could encourage investigating its role in breast cancer arising in young women," Dr Azim said.
The researchers also found that a gene called RANKL is highly expressed in young women with breast cancer. RANKL is known to play a vital role in the spread of cancer to the bones, and emerging preclinical data have shown that RANKL appears to have an anti-tumor effect apart from its role in bone metastasis.
"Putting all the information in context, we hypothesize that perhaps targeting RANKL could be particularly interesting in young breast cancer patients," Dr Azim said. The researchers from Institut Jules Bordet are in fact planning a clinical trial in which premenopausal breast cancer patients will receive two injections of a drug called denosumab, which is a RANK-ligand inhibitor, one week before surgery. The aim of the study is to evaluate the effect of RANK-ligand targeting on the biology of the tumor. The study, called D-BEYOND, is expected to start in 2012 in three Belgian centers.
In other results presented at IMPAKT, the researchers investigated the prognostic performance of known gene expression signatures according to age.
"As breast cancer arising below the age of 40 is relatively uncommon, we lack information on whether different gene signatures provide prognostic information in a uniform way across different age groups," Dr Azim said. "We tested three proliferation-related signatures and found that they add prognostic information in all patients with ER+ breast cancer, irrespective of age."
"This is clinically relevant as it underscores that these gene signatures could identify women below the age of 40 with ER+ disease who are at a low risk of relapse independent of clinical prognostic tools," Dr Azim explained.
Commenting on the recently published study, which he was not involved in, Prof Bryan Hennessy, from Beaumont Hospital in Dublin, said: "Young women with breast cancer tend to have a poorer prognosis. This study provides evidence that breast cancer in young women is associated with unique underlying biologic processes, highlighting important information that may allow us to design tailored therapy approaches to improve outcomes in this population."