Research shows genes predict your chance of secondary lymphedema

New research adds genetic differences to the list of demographic and clinical factors that predict your risk of lymphedema following breast cancer treatment.

The chance of developing chronic lymphatic swelling following treatment for breast cancer is commonly reported as 30-40%.  While predisposing factors have been identified, it is still not possible to predict which patients will go on to develop the condition.  Identifying susceptible patients would allow for health resources to be directed towards delaying and preventing the onset of this condition.

The most comprehensive clinical study to date on this topic was published in April (Miaskowski C., Dodd M., et al. Lymphatic and Angiogenic Candidate Genes Predict the Development of Secondary Lymphedema following Breast Cancer Surgery. PLoS One. 2013 Apr 16;8(4)). The authors examined a total of 542 patients for a wide range of demographic and clinical characteristics (including age, ethnicity, BMI, stage of disease, type of surgery, adjuvant therapies, etc., etc.).  Many of the characteristics they examined, such as the type of cancer therapy received, have previously been shown to be risk factors for developing lymphedema (see our blog post here).  Past studies have suggested that demographic and clinical characteristics can go a long way to explaining why some patients develop lymphedema while others do not, but a full explanation for the differences between patients has remained elusive.  For this reason the authors of this new study decided to also investigate the possibility that genetic differences between patients (called ‘polymorphisms’) may play a role in developing lymphedema.

To address this question the authors looked for genetic differences between patients who developed lymphedema and those who did not for 17 genes that are either known to be involved in primary lymphedema in humans (where lymphatic abnormalities are present at birth) or that can be mutated to induce lymphedema experimentally in animals.

The researchers found no differences between patients with and without lymphedema for the majority of demographic and clinical factors studied. However, in support of previous research, they did find that breast cancer patients with lymphedema were significantly more likely to have:

• a significantly higher body mass index (BMI),
• a lower overall patient reported health score,
• lung disease,
• a higher number of lymph nodes removed,
• a higher number of positive nodes,
• more advanced disease at the time of diagnosis,
• had an axillary lymph node dissection (ANLD,) but not a sentinel lymph node biopsy (SLNB),
• received chemotherapy prior to or following surgery,
• received radiation therapy following surgery

As expected, these patient characteristics are unable to fully explain why some patients develop lymphedema and others do not.  Could there also be a genetic predisposition to developing lymphedema in some patients?

To answer this question the researchers examined the 17 candidate genes that they identified as potentially capable of altering normal lymphatic function.  For nine of these genes (called ANGPT2, FOXC2, LCP2, NRP2, SOX 17, SYK, VCAM1, VEGFC, and VEGFR2) the researchers discovered that differences in gene sequence existed, and that these differences strongly correlated with the likelihood of developing lymphedema.  For example, patients with a particular form of the gene SYK had a 3.43-fold increase in the odds of developing lymphedema post cancer treatment, while patients with a rare form of the LCP2 gene had a 63% decreased odds of developing lymphedema. This is a very interesting result.

While genetic variation between humans is common (and mostly benign), it’s fascinating that in a relatively small sample population the researchers were able to identify gene polymorphisms that appeared to alter the probability of developing secondary lymphedema.  In other words, while primary lymphedema may arise due to mutations that eliminate the function of one or more of the genes responsible for normal lymphatic development, secondary lymphedema such as breast cancer related lymphedema might arise in part due to more subtle functional variations within these same genes, that under normal circumstances would have no tangible consequence.

It’s exciting to consider the possibility that in the near future genetic tests in combination with demographic and clinical predictors may be used to identify patients who are predisposed to lymphedema.  Uncovering this population would allow for targeted treatment modifications and preventative measures that could potentially delay or minimize (or eliminate?) the onset of lymphedema in breast cancer patients.