Jennifer Kwan
Princess Margaret Cancer Centre radiation oncology resident Dr. Jennifer Yin Yee Kwan published the first study to evaluate mammographic breast density to predict lymphedema occurrence and severity. (Photo: Nathan Chan)

Scientists at the Princess Margaret Cancer Centre have discovered a new risk factor for determining which breast cancer patients will develop lymphedema, a chronic abnormal swelling in the arm, breast or torso after treatment.

About one in seven patients with breast cancer who undergo surgery to remove cancerous lymph nodes will experience lymphedema as a surgical complication. The risk almost doubles when surgery is combined with radiotherapy.

Currently, it is challenging to predict who will get it. As a result, about one-third of patients are diagnosed in the late stages of lymphedema when there are fewer treatment options.

Understanding who is at greater risk could help women try and prevent or treat it early, when treatments are most effective. These include: compression garments, physiotherapy, massage therapy, weight management and preventing infection by protecting the skin from cracking and breakdown.

Examining 373 women with breast cancer at the Princess Margaret, the study found that patients with low breast mammogram density – or fatty breasts – are at higher risk of developing severe lymphedema.

Study results are published in an open access article in JAMA Network Open by first author, radiation oncology resident and PhD candidate, Dr. Jennifer Yin Yee Kwan, and senior author, Dr. Fei-Fei Liu, Chief of the Radiation Medicine Program and Senior Scientist, Princess Margaret Cancer Centre.

"To our knowledge, this is the first study to evaluate mammographic breast density to predict lymphedema occurrence and severity," says Dr. Kwan, adding that current risk models based on cancer and treatment risk factors – such as number of lymph nodes removed – do not fully explain or predict who will develop lymphedema.

Fei-Fei Liu
Dr. Fei-Fei Liu, Chief of the Radiation Medicine Program, Princess Margaret Cancer Centre, says there is a need to identify high-risk patients early so they can benefit from treatments. (Photo: Jeffrey Truitt)

"We need to look at patient-specific factors that will help us more accurately pinpoint individual risk," says Dr. Liu, who is also Professor and Chair, Department of Radiation Oncology, University of Toronto.

"We need to identify the high-risk group of patients early on so that we can focus future therapy on those who would benefit from it the most."

Lymphedema occurs after cancer treatments that damage or remove lymph nodes. This results in a build-up of lymphatic fluid in affected areas of the body, with symptoms such as swelling, achiness, heaviness, decreased flexibility or tightness, and scarring of the soft tissue in advanced stages. There is also an increased risk of infection, disability and a rare risk of developing a lethal cancer called a lymphangiosarcoma.

Mammograms are X-ray images of breast tissue. Studies have shown that women with extremely dense breasts – those containing connective and glandular tissue – have a greater risk of developing cancer.

But this risk does not hold true for women with low density breasts, which are composed of mostly fatty tissue, with few glandular and connective tissues.

However, fatty breasts have been linked to metabolic syndrome, a disorder related to fat storage. Excess fat accumulation is also seen in severe lymphedema.

So the researchers wondered if low density breasts might be a more accurate way to predict and estimate lymphedema than, for example, body mass index (BMI), which is a rough metric of body fat, and a well-known individual patient risk factor.

"We flipped the density metric on its head into something novel and new," says Dr. Kwan. "We wanted to see if that measure could be helpful in estimating lymphedema severity."

Mammography more precise than BMI in relation to lymphedema

Data was collected from July 2018 to March 2020 from female patients at the Princess Margaret who completed treatment for a first diagnosis of breast cancer, with no recurrent or metastatic diagnoses. Patients with and without lymphedema were included.

In total, five factors were found to be related to lymphedema: age, body mass index (BMI), mammographic breast density, number of cancerous lymph nodes and type of surgical treatment.

Specifically, breast density as measured by diagnostic mammography, was found to predict risk of lymphedema independently of BMI, a previously established patient risk factor for lymphedema. Moreover, low breast density was also linked to severity of the condition.

"Mammography is more precise than BMI in relation to lymphedema," explains Dr. Liu, adding that since it is the standard of care for breast cancer screening and diagnosis, mammograms are an easy and cost-effective way to stratify those patients most at risk.

For patients with severe lymphedema, it is akin to carrying an extra two cups of fluid inside their arm, explains Dr. Kwan, and for those with a milder form, it is like having one cup of fluid in their arm.

"It is incredibly uncomfortable, and is a frustrating condition for both patients and clinicians," she says. "We want to offer treatments to patients as early as possible to give them the best chance of controlling this condition."

The work was funded by the Canadian Institutes of Health Research, University of Toronto Faculty of Medicine, Ontario Ministry of Health, Peter and Shelagh Godsoe Chair in Rehabilitation Medicine and The Princess Margaret Cancer Foundation.

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