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Illustration of a gene panel for the breast cancer index.
The breast cancer index can help with one of the most challenging decisions in ongoing breast cancer treatment.

A Biomarker for Selecting Extended Adjuvant Endocrine Therapy in Breast Cancer

The HOXB13/IL17BR ratio is standardizing which early-stage, HR+ breast cancer patients are selected for extended adjuvant endocrine therapy

Mark Pegram, MD

Mark Pegram, MD, is the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology at the Stanford University School of Medicine, as well as associate dean for clinical research quality. He...

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Published:Oct 31, 2022
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Photo portrait of Dr. Mark Pegram
Mark Pegram, MD, is the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology at the Stanford University School of Medicine, as well as associate dean for clinical research quality. He is also the medical director of the Stanford Clinical Translational Research Unit, which specializes in first-in-human Phase 1 clinical trials. Pegram’s breast cancer research focuses on the cancer-associated gene that encodes HER2 and on developing novel therapies for HER2-positive metastatic breast cancer.

Many breast cancer patients who are between their third and fifth year after diagnosis struggle with persistent adverse effects associated with adjuvant endocrine therapies like tamoxifen and aromatase inhibitors. Although the risk of distant recurrence continues well beyond five years for these patients, the number of those who will benefit from extended adjuvant endocrine therapy is difficult to predict based on clinicopathologic parameters alone. Therefore, it would be ideal to gain insight into which patients are more likely to benefit from extended adjuvant endocrine therapy and which patients might safely discontinue endocrine medications at year five, avoiding ongoing toxicities from extended adjuvant endocrine therapies. For example, tamoxifen and arthralgias may cause endometrial cancer and thrombosis, while aromatase inhibition may cause loss of bone mineral density.

Among the biomarkers used to guide decision-making in endocrine therapy, the HOXB13/IL17BR (H/I) ratio (aka Breast Cancer IndexTM or BCI) is unique because in addition to being prognostic, it is the only genomic test that can predict favorable response to extended adjuvant endocrine therapy up to 10 years. The gene expression assay consists of two functional biomarker panels—the HOXB13/IL17BR, orH/I, ratio and the molecular grade index (MGI), which analyzes estrogen signaling and proliferation pathways in breast cancer by measuring the expression (by RT-PCR) of five genes. These five genes (BUB1B, CENPA, NEK2, RACGAP1, and RRM2) are selected based on 1) functional annotation of the genes (genes involved in different cell cycle phases and processes), 2) association with clinical outcome, and 3) correlation with tumor grade.

The prognostic score derived from the algorithmic combination of H/I and MGI indicates a patient’s overall risk of recurrence (0–10 years) and late distant recurrence (5–10 years). But even more compelling is the predictive component of HOXB13/IL17BR, which indicates whether a patient is likely to benefit from extended endocrine therapy. “Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early-stage HR+ breast cancer,” concluded one study in 2020.2

While standard clinicopathologic factors may help in the prognostic evaluation of the risk of recurrence, these factors and other commercially available tests have not been validated for predicting benefit from extended adjuvant endocrine therapy beyond five years. Across multiple trials, prognostic models like Clinical Treatment Score post 5-years (CTS5) and other assays have not demonstrated reliable, predictive results to help direct targeted endocrine treatment. In fact, in April 2022, the American Society of Clinical Oncology (ASCO) updated its recommendations and recognized BCI as the only genomic test to help guide extended endocrine treatment decisions for early-stage, HR+ breast cancer patients with node-negative or node-positive (1–3 positive nodes) disease. Notably, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) also recognize HOXB13/IL17BR for its unique ability to predict the benefit of extended adjuvant endocrine therapy.

HOXB13/IL17BR is typically performed using the original tumor specimen when a patient is approaching the fifth year after diagnosis and has remained disease free. This unique biomarker, which has been recognized across several guidelines, is validated to help oncologists and patients weigh one of the most challenging decisions in ongoing breast cancer treatment. Further, in one report, 82 percent of women who were recommended extended endocrine therapy from their HOXB13/IL17BR results reported that they were more likely to take their medications as prescribed. For selected patients, BCI may serve as a useful adjunct in clinical decision-making for either continuing or discontinuing adjuvant endocrine therapy, and it is increasingly important for clinicians and their patients to familiarize themselves with the test as it continues to be incorporated into routine care for patients with early-stage, HR+ breast cancer.