Epigenetic Signatures to Predict Pathological Nodal Stage for De-escalation of Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer
Abstract
Clinical trials have shown that removing lymph nodes with surgery as part of breast cancer treatment does not improve cancer outcomes for many patients with breast cancer. The results of these practice-changing clinical trials have changed the way we treat breast cancer patients currently. However, these trials notably excluded patients who presented with cancer already spread to the lymph nodes, known as clinically positive nodes. Because of this, the standard of care for breast cancer patients who have lymph node disease at diagnosis and who do not receive chemotherapy drugs before surgery (neoadjuvant chemotherapy NAC) remains axillary lymph node dissection (ALND), whereby up to 20 lymph nodes in the underarm area are routinely removed with surgery. The majority of these patients have estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancers, which accounts for more than two-thirds of all breast cancers. ALND carries a number of undesirable side effects for breast cancer patients, including fluid buildup in the arm and swelling (lymphedema) and impairment of limb function (functional morbidity), which can be disabling. Yet, recent work from our group and others has shown that more than half of breast cancer patients with ER+/HER2- breast cancer who undergo ALND for clinically positive nodes have only limited disease in their lymph nodes at surgery (< 3 positive lymph nodes). As a result, most of these patients have a significant number of normal, healthy lymph nodes removed from their bodies and only a small number of diseased lymph nodes. ALND, a highly invasive surgical procedure, is likely unnecessary for many patients with clinically node positive breast cancer and represents a glaring overtreatment for patients with only limited lymph node disease. However, a reliable method to identify which patients have limited lymph node disease from those who carry a higher disease burden (4 or more positive lymph nodes) without surgical removal of the nodes has remained elusive. There is a critical need to fill this gap, to avoid invasive ALND for patients where it is otherwise unnecessary and reduce overtreatment of breast cancer. This proposal addresses the Fiscal Year 2022 Breast Cancer Research Program Overarching Challenge: surgical overtreatment. Our research group has identified three distinct epigenetic signatures (EpiSig) in patients with ER+/HER2- breast cancer that show high accuracy for distinguishing which patients have low lymph node burden from those who have higher lymph node burden. Indeed, our preliminary work shows that these epigenetic profiles, which we have termed EpiSig 10, EpiSig 13, and EpiSig 14, have high accuracy (AUC=0.98) in identifying patients with low nodal disease. We hypothesize that these EpiSig of primary invasive, ER+/HER2- breast cancers can effectively stratify patients into categories of low or high nodal disease burden. These EpiSig have great promise for providing a highly reliable, non-invasive method for determining a breast cancer patient’s lymph node stage that can reduce or prevent unnecessary surgical intervention, thereby providing individualized management of care and reducing the surgical overtreatment of breast cancer patients who are found to have limited nodal disease. We will address the gap in knowledge by testing and validating our three EpiSig in cohorts of breast cancer patients who present with clinically positive lymph node disease. We will test the efficacy of the EpiSig in accurately identifying patients with low nodal disease from tumor DNA of an independent cohort of these patients. We will also develop and optimize a reliable assay that targets our EpiSig that will be clinically useful and easy to adopt for clinical translation. The assay will be developed based on the distinct genomic regions of the signature with the highest accuracy and optimized for use in patient biopsies taken before the patient has
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310030
Entities
People
- Maggie Dinome
Organizations
- Duke University
- United States Army