Black women with breast cancer had significantly higher rates of lymphedema after axillary lymph node dissection compared with Hispanic, White, and Asian women in a prospective study of breast cancer–related lymphedema presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). In fact, Black race was the strongest predictor of developing lymphedema.¹ The study found that Hispanic women were also more likely to develop lymphedema than Whites or Asians, but the numbers were too small to draw definite conclusions.

Another important finding was that treatment with neoadjuvant chemotherapy followed by axillary lymph node dissection doubled the likelihood of developing lymphedema compared with upfront surgery and sentinel lymph node biopsy.

“[B]ecause our patient population was diverse, we were able to look at race as a risk factor, unlike other studies.”

— Andrea V. Barrio, MD

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“Lymphedema, a well-known side effect of axillary lymph node dissection, causes pain and swelling in the limbs and worsens quality of life for patients with breast cancer,” said lead author Andrea V. Barrio, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center. “Other studies of lymphedema have been retrospective and/or depend on patient reports. Lymphedema has been relatively ignored in the literature. We started this prospective study in 2016 to understand the risk of lymphedema associated with axillary lymph node dissection. We initially expected increasing age and body mass index to be risk factors, but because our patient population was diverse, we were able to look at race as a risk factor, unlike other studies.”

Study Details

Over a period of 4 years, the study enrolled 304 women (aged 18 and older) with breast cancer who received a unilateral axillary lymph node dissection either in the primary setting or after sentinel lymph node biopsy. Lymphedema (defined as an arm volume change from baseline of 10% or more) was assessed by measurements at baseline, postoperatively, and at 6-month intervals.

The analysis Dr. Barrio presented at SABCS included 276 patients with at least one longitudinal arm volume measurement after baseline. Median patient age was 48 years; 60% of participants were White, 20% were Black, 11% were Asian, and 6% were Hispanic; and 3% did not report race or ethnicity. More than two-thirds (68%) had hormone receptor (HR)-positive/HER2-negative breast cancer, 19% had HER2-positive disease, and 13% had HR-negative/HER2-negative disease. Approximately 95% of patients received radiation therapy, and 93% received nodal radiation therapy.

White and Black women were slightly older (median age = 49 years), and Black and Hispanic patients had a higher baseline body mass index compared with the White and Asian patients. Black women were more likely to present with clinically palpable lymph node disease. Factors that did not differ by race and ethnicity included clinical T stage, receptor subtype, histology, differentiation, receipt of neoadjuvant chemotherapy, total number of positive nodes, type of reconstruction, and receipt of any type of radiation therapy.

By 24 months of follow-up, 24.7% of the participants had developed lymphedema. On multivariate analysis, Black race was the strongest predictor of developing lymphedema. At 2 years, Black women had a 3.5-fold greater risk of lymphedema compared with White women (39% and 21%, respectively). Hispanic women had a threefold increase in risk of lymphedema compared with White women (28% at 2 years), but there were just 16 Hispanic patients in the study, Dr. Barrio noted, adding that further study is needed to confirm this finding. The 2-year rate of lymphedema in Asian women was 23.4%.

Receipt of neoadjuvant chemotherapy, older age, increasing number of lymph nodes removed, and increasing time from surgery were independent risk factors associated with an increased chance of developing lymphedema. Women who received neoadjuvant chemotherapy followed by axillary lymph node dissection were twice as likely to develop lymphedema compared with women who had upfront surgery followed by axillary lymph node dissection. The 24-month rate of lymphedema was 30.9% for women treated with neoadjuvant chemotherapy vs 11% those who had upfront surgery (P = .0066).

Commenting on neoadjuvant chemotherapy, Dr. Barrio explained that the population enrolled were clinically node-positive, and most with this finding are treated with chemotherapy. About 70% received neoadjuvant chemotherapy, had residual disease, and underwent axillary lymph node dissection. About 30% had upfront surgery and sentinel lymph node biopsy with at least one positive node and then underwent axillary lymph node dissection. Of the patients who received chemotherapy, either in the neoadjuvant setting or after surgery, 94% were treated with taxane-containing chemotherapy.

The researchers then looked at factors associated with the severity of lymphedema. However, no differences were found among racial and ethnic groups in arm volume changes over time.

“At this time, we are still acquiring additional measurements from about 100 women to complete the study,” Dr. Barrio commented.

In a separate interview with The ASCO Post, Dr. Barrio explained that the response to chemotherapy for patients with node-positive disease differs. “We routinely use chemotherapy to downstage the axilla in an attempt to avoid axillary lymph node dissection and use sentinel lymph node biopsy. This works very well in [patients with] triple-negative breast cancer and HER2-positive breast cancer, but estrogen receptor (ER)-positive/HER2-negative breast cancers do not respond as well to neoadjuvant chemotherapy and have a lower chance of avoiding axillary lymph node dissection. In patients who are unlikely to be downstaged on neoadjuvant chemotherapy, the question is: do we give them neoadjuvant chemotherapy to try to downstage the axilla, recognizing that if they don’t have a complete response they may have a higher risk of lymphedema? Or should these patients have upfront surgery? Our study highlights an unmet need for alternative strategies, such as clinical trials of sentinel node biopsy alone in clinically node-positive, estrogen-receptor positiveand HER2-negative breast cancer to avoid axillary lymph node dissection,”she continued.

Future Areas of Study

The fact that Black women who underwent axillary lymph node dissection are at increased risk for breast cancer–related lymphedema suggests ongoing research is needed to prevent lymphedema from occurring in these women.

In her opinion, more research is needed to understand the mechanisms behind lymphedema development. “We believe inflammation may be related. Black women may have more inflammation at baseline or a stronger inflammatory response to radiation. We plan to study biomarkers of inflammation in breast tissue to determine why lymphedema develops,” she said.

“We plan to study biomarkers of inflammation in breast tissue to determine why lymphedema develops.”

— Andrea V. Barrio, MD

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Other strategies under study at Memorial Sloan Kettering Cancer Center include using immediate lymphatic reconstruction at the time of axillary lymph node dissection. Such a study is underway, and additional follow-up is needed to determine whether this is effective, she noted.

Discussion About the Study

At a press conference held during the symposium, SABCS Co-Director and moderator Virginia Kaklamani, MD, Professor of Medicine and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, commented on the lymphedema study.

“This is a very important study looking at how ethnicity plays a role in potential adverse reactions in our patients. We know that Black women have higher rates

Virginia Kaklamani, MD

of aggressive cancer. This study tells us that Black women with breast cancer have higher rates of lymphedema. I think it is important to be able to recognize this early and treat our patients preemptively so we can prevent this from occurring,” Dr. Kaklamani stated.

Dr. Kaklamani suggested a possible approach. “We need to prevent lymphedema and offer these women physical therapy before they develop lymphedema,” she said. “We have to stratify patients for the risk of lymphedema and identify which patients can benefit from a preventive strategy.”

During the question-and-answer session, Dr. Kaklamani asked: “Should oncologists favor upfront surgery followed by axillary lymph node dissection?”

Dr. Barrio said it would be a mistake to “ditch” neoadjuvant chemotherapy, particularly in patients with triple-negative and HER2-positive disease. “The majority of cohort consisted of patients with ER-positive/HER2-negative cancer with residual nodal disease after neoadjuvant chemotherapy. We should be thinking differently about this group of patients and using Oncotype DX [to inform treatment]. We also need to look at trials of surgical de-escalation to avoid lymphedema,” she stated. 

DISCLOSURE: The study was funded by the Chanel Entertainment for Survivorship Research and the Manhasset Women’s Coalition Against Breast Cancer. Dr. Barrio reported no conflicts of interest. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics and as a speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, Seattle Genetics; and has received research funding from Eisai.

REFERENCE

1. Barrio A, Montagna G, Sevilimedu V, et al: Impact of race and ethnicity on incidence and severity of breast cancer–related lymphedema after axillary lymph node dissection: Results of a prospective screening study. 2021 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 10, 2021.